MINISTRY OF EDUCATION AND TRAINING THE MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY NGUYEN HOANG YEN STUDY ON CLINICAL AND SUBCLINICAL FEATURES AND EVALUATION OF TREATMENT RESULTS FOR SLEEP APNEA SYNDR[.]
MINISTRY OF EDUCATION AND TRAINING - THE MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY NGUYEN HOANG YEN STUDY ON CLINICAL AND SUBCLINICAL FEATURES AND EVALUATION OF TREATMENT RESULTS FOR SLEEP APNEA SYNDROME IN CHILDREN WITH ASTHMA Major: Pediatrics Code: 9720135 DOCTORAL THESIS SUMMARY OF MEDICINE HANOI - 2022 THESIS COMPLETED IN: HA NOI MEDICAL UNIVERSITY Supervisor: Prof Duong Quy Sy, MD, PhD, FCCP Assoc Prof Dr Nguyen Thi Dieu Thuy Reviewer 1: Prof Pham Van Thuc, MD, PhD Reviewer 2: Assoc Prof Dr Le Thi Hong Hanh Reviewer 3: Assoc Prof Dr Nguyen Trung Kien Thesis was defended at Univeristy level Doctoral thesis assessment committee in Ha Noi Medical University At Date ., 2022 Thesis can be found out in: National library of Viet Nam Ha Noi Medical University library THE PUBLISHED PAPER RELATED TO THE THESIS Nguyen Hoang Yen, Nguyen Thị Dieu Thuy, Duong Quy Sy (2017) Study of the clinical and functional charateristics of asthmatic children with obstructive sleep apnea Journal of Asthma and allergy, 10: 285–292 Nguyen Hoang Yen, Nguyen Thi Binh (2018) Laboratory techniques for diagnosis of obstructive sleep apnea (OSA) in children Journal of Functional vetilation and pulmonology, 27(9); 3-10 Nguyen Hoang Yen, Nguyen Thị Dieu Thuy, Duong Quy Sy (2020) Medical treatment of obstructive sleep apnea in asthmatic children Journal of Functional vetilation and pulmonology 33(11): 12-18 STATEMENTS OF THE PROBLEM Obstructive sleep apnea syndrome (OSAS): Is a continuous repetition of partial or complete obstruction of the upper respiratory tract during sleep resulting in decreased breathing or complete apnea despite respiratory exertion Obstructive sleep apnea syndrome is the most common form of respiratory disorders during sleep, which is relatively common In North America, there are over 12 million sufferers, of which females make up 3% and males are 9% of adult age In children, over the past few decades sleep obstructive apnea has been widely recognized as a significant cause of illness, accounting for between 1% and 5% Obstructive sleep apnea Syndrome Obstructive sleep apnea is characterized by the whole or part of the upper respiratory tract that is blocked when sleeping for more than 10 seconds, causing hypoxia and the birth of acidified radicals, which if not diagnosed and treated early will have serious health consequences and socio-economic burdens Especially in children, OSAS causes hypoxia at night distance and also causes biomedical disorders on hemolysis, transformation, and psycho-motor In particular, the consequences of OSAS in children on mental development are very harmful because it can cause them to slow down psychological development, reduce learning ability and memory In addition, children with OSAS may suffer from depression or hyperactivity Therefore, the harmful effects of OSAS on children need to be diagnosed and treated promptly Obstructive sleep apnea in people with asthma which has been interested in and researched the last few years has shown that obstructive sleep apnea is a co-contractive disease and is more common in asthma patients since in these patients there has been frequent and rehabilitation of the airways if asthma is not well controlled In children with asthma, OSAS needs to be diagnosed and treated at a time when children show signs of suspicion However, until now in Viet Nam, there has been very little research on OSAS in children reported, especially OSAS in children with asthma Therefore, we conduct the topic: "Study on clinical and subclinical features and evaluation of treatment results for sleep apnea syndrome in children with asthma" with the following objectives: Evaluate the incidence of sleep apnea syndrome in children with asthma Research on some clinical and subclinical characteristics of children with asthma-related to sleep apnea syndrome Evaluate the degree of improvement of sleep apnea syndrome and treatment outcomes for asthma with sleep apnea by medical treatment (mainly with anti-leukotriene drugs) NEW CONTRIBUTIONS OF THE THESIS The topic has identified the frequency of sleep apnea syndrome in children with asthma Describe the clinical, subclinical features and respiratory polygraphy of sleeping asthma children with obstructive sleep apnea To evaluate the degree of improvement of apnea syndrome in children with asthma and OSAS by antiLeukotrienes drugs through clinically altered evidence and changes in ventilatory polygraphy STRUCTURE OF THE THESIS The thesis consists of (125 pages), include: statements of the problems (2 pages), overview (35 pages), subjects and research methods (25 pages), results (31 pages), discussions (29 pages), conclusions (2 pages), suggestions (1 page) The thesis has 17 tables, 12 pictures, 27 charts, appendixes 237 references Chapter OVERVIEW 1.1 Previous studies review 1.1.1 In the World In 1976 Guilleminault was the first person who studied OSAS in children Hudgel and Shrucard (1979) studied the first case of asthma and OSAS Larsson (2001): OSAS-related symptoms in asthma patients Goldbart AD (2012) used Montelukast within 12 weeks for children with OSAS 1.1.2 Vietnam Nguyen Xuan Bich Huyen (2009): OSAS incidence of snoring and sleep disorders of Vietnamese patients at the Respiratory Department - Cho Ray Hospital relies on Polysomnography and ventilatory polygraphy In 2011, Bach Mai Hospital implemented recording techniques of respiratory polygraphy In 2012, Nguyen Thanh Binh: clinical characteristics, Polysomnography and effectiveness of CPAP breathing in the treatment of OSAS syndrome In 2013, Duong Quy Sy announced the frequency of OSA in adults In 2017, Nguyen Hoang Yen stated the incidence of OSAS in children with asthma In 2018, Nguyen Thi Van: OSAS condition in Children with asthma at The National Children's Hospital 1.2 Epidemiology, associated pathogenesa and consequences of sleep apnea syndrome in children The incidence of OSAS in children is estimated to be 2% (1% 5%) OSAS is found at any age, at the highest age of 2-8 years, the incidence is higher in male children, who have a family history of OSAS Asians and blacks are at higher risk for OSAS than whites Tonsillitis is the most common cause of OSAS in children Obesity is an important risk factor for OSAS at any age but is particularly dominant in adolescence OSAS and asthma are two co - diseases, both of which share the same symptoms because they are associated with airflow limits and increased respiratory exertion, as a result of narrowing the airways during sleeping In patients with asthma, OSAS acts as a contributing mechanism to worsen asthma because decreased airway at night is associated with sleeping distribution, having sleeping troubles, early waking, and daytime drowsiness Increased abdominal pressure throughout the OSAS period contributes to gastroesophageal reflux, increased reactivity of the bronchi, and bronchitis Patients with hard-tocontrol asthma may have an increase in the number of stages with OSAS and a decrease in blood oxygen saturation, especially during sleep phases with rapid eye movement In children, OSAS causes nocturnal hypoxia due to apnea and decreased breathing, is the cause of pathogenetic disorders on hemodynamics and metabolism, and the risk of cardiovascular diseases such as heart failure, high blood pressure, and pulmonary hypertension Especially, serious consequences of OSAS on the mental, motor, and physical development of children because it can affect the process of physical and psychological development, cause cognitive impairment, impaired concentration, decreased learning and memory ability In addition, children with OSAS can cause behavioral disorders, depression, or hyperactivity Hence, it reduces the child's quality of life and increases the need for health care 1.3 Diagnosis of obstructive sleep apnea syndrome in children Clinical: Relying on a thorough history to detect clinical symptoms including nighttime symptoms (snoring, difficulty sleeping, restless sleep, frequent waking up, sweating and urination ) and daytime symptoms such as daytime sleepiness, as well as OSASrelated illnesses such as cognitive impairment, abnormal behavior, and growth retardation Clinical examination and assessment of the general state of the body, growth, respiratory conditions: rhinitis, overgrowth of tonsils -VA, cardiovascular symptoms Subclinical: Polysomnography and ventilatory polygraphy are diagnostic criteria Diagnostic criteria: OSAS diagnosis based on diagnostic standards of American Sleep Association: Patients with criterion A and/or B+ criterion C A Symptoms of excessive daytime drowsiness cannot be explained by any other factor B At least two of the following criteria: Severe snoring, nocturnal breathing, constant waking up during the night, sleep without rest, daytime fatigue, change in concentration C Polysomnography and ventilatory polygraphy with apneahypnosis index (AHI ≥1 times/hour) and diagnosis of degree: + Minor: 1≤ AHI < + Average: ≤ AHI < 10 + Severe: AHI ≥ 10 1.4 Treatment of obstructive sleep apnea syndrome Managing patients with OSAS requires a multidisciplinary approach and a variety of treatments The decision on treatment and selection of treatments is carried out on each pediatric patient Anti-inflammatory therapy: Leukotriene antagonist, used to treat asthma and allergic rhinitis, and obstructive sleep apnea Syndrome A daily 4mg Singulair treatment for children under years old and 5mg Singulair per day for children years old or elder for 12 weeks is also effective in remission and contributes to control asthma in patients with OSAS and unmanaged asthma In addition, the combination of Montelukast and topical corticosteroids is also effective in treating OSAS in children Surgical tonsillectomy - VA curettage: indicated in OSAS in children with hypertrophy of tonsillitis -VA Other treatments including weight loss, positive pressure breathing, orthopedic surgery on the jaw area, and control of the child's habitat Chapter SUBJECTS AND METHODS OF RESEARCH 2.1 Subjects of study: Patients over years old who have been diagnosed with asthma are examined and treated at the Department of Immuno -Allergy – Joints of The National Children's Hospital from December 2015 to the end of December 2018 2.1.1 Criteria for selecting pediatric patients in the study: - Patients over years old who were diagnosed with asthma according to GINA 2014 - Patients had acute asthma attacks - Patients and their parents agreed to participate in the study 2.1.2 Exclusion standard: one of the following standards - Patients with acute asthma attacks - Patients and their parents disagree to participate in the study 2.2 Research methods 2.2.1 Research design: Objectives and 2: Cross-sectional and progressive descriptive research Objective 3: Non-controlled clinical intervention study 2.2.2 Sample size Goal 1: 139 patients Goal 2: 99 patients Goal 3: 92 patients are monitored within months and 53 patients are monitored within months 2.2.3 Research content – key indicators - Patients are allowed to exploit age, gender, height, weight, BMI - History of asthma prevention treatment, history of allergies of themselves and their family: - Clinical symptoms: Night and daytime symptoms of asthma patients with OSAS - Subclinical: blood formula, total blood IgE quantification, prick test, respiratory function measurement, exhaled air NO concentration measurement, measurement of ventilatory polygraphy * The characteristics of ventilatory polygraphy: The severity of OSAS according to the AHI index: bouts/hour Other indicators of ventilatory polygraphy in sleeping: attacks/hour (obstructive apnea, central apnea, mixed apnea, oxygen index, percutaneous oxygen saturation, lowest number of desaturated oxygen, number of snoring times Correlations and risk indices of OSAS in children with asthma - Correlation between the severity of asthma, FEV1 index, FENO index and AHI index; BMI with snoring index - The night and daytime symptoms of asthma patients with risk of OSAS - Evaluation after months and months of treatment based on changes in asthma level variables and asthma control according to GINA, ACT score, night and daytime symptoms, respiratory function and ventilatory polygraphy of asthma patients with OSAS after 3month treatment and – month - treatment compared to the original 2.2.4 Research instruments of study Sample medical records, German Seca scales, measurement of Respiratory function with Koko meter (Inspire, Hertford, UK) AFENO measurement by using Hypair NO meter (Medisoft, Sorinnes, Belgium) and NObreath meter (Bedfont Scientific Ltd, UK) ventilatory polygraphy are performed by using Apnea Link Plus machine (ResMed, USA) 2.2.5 Data processing: Using by SPSS22.0 software, use the appropriate statistical algorithms 2.2.6 Research Ethics Comply with the ethics in the study and have been passed the Ethics Council in Biomedical Research at Hanoi Medical University under Decision No 187/HDĐĐĐHYHN Chapter RESEARCH RESULTS 3.1 Frequency of obstructive sleep apnea in asthma children The results of the study showed that the incidence of obstructive sleep apnea syndrome (OSAS) in asthma pediatric patients was very high, accounting for 71.2% in 139 subjects involved in the study In which, male patients accounted for 73.4%, higher than female patients 2.8 times; the average age of the study patients was 9.3 years (the youngest was years and the oldest was 15 years) with an average BMI of 17.4 kg/m2 3.2 Clinical and sub-clinical characteristics of children with obstructive sleep apnea 3.2.1 General characteristics of asthma patients who have sleep apnea Table 3.1: General characteristics of subjects of study Patient characteristics Age, year Females (male), % Height, cm Weight, kg BMI, kg/m2 Allergy, % Eczema,% Allergic rhinitis,% Conjunctivitis,% Drug allergies, % Food allergies, % Has a family history of allergies, % Gastroesophageal reflux % Asthma severity level % Level Level Level Level Level of asthma control % Total controlled Partial controlled Uncontrolled ACT Score No 99 9,26 ± 0,19 25,3 (74,7) 132,8 ±1,13 31,1 ±0,85 17,4 ± 2,8 91,9 34,34 85,86 42,42 3,03 13,13 64,7 14,14 10,10 44,44 41,41 4,04 9,09 32,32 58,59 19.0 ± 3.4 10 Comments: IgE and leukocyte levels highly increased in the study patients The respiratory function of the FEV1 was low: 85.1%, other indicators are within the normal limit (FVC 92.1%; FEV1/FVC 92.3%) The concentration of nitrite oxide in the exhaled gas of the bronchi on average of the asthma group is 22.1 ppb higher than the normal limit, and higher than the asthma group without OSAS, as recommended by the ATS, normal FENO value < 20ppb CaNO is 7.4 ppb, increased up compared to normal values, while nasal nitrite oxide concentration increases by 1505.9ppb Among Children with asthma with OSAS, 61.6% were mild (AHI14/hour), 25.3% moderate (AHI5-9/hour), and 13.1% severe (AHI ≥10/hour) Average AHI: 4.8 times/hour (Lowest time/hour, highest 21 hours/hour) Average SpO2 (78,48%) measured during sleeping lower normal children (92%) 3.2.4 Link between asthma and obstructive sleep apnea 3.2.4.1 Correlation between severe asthma and FEV1 index with AHI index in sleeping Figure 3.1 Correlation between ASTHMA at severe levels and sleep AHI index Figure 3.2 Correlation between FEV1 and sleep AHI Comments - There is no meaningful correlation between asthma at severe levels with apnea - decreased breathing index (AHI) with p > 0.05 - No statistically significant correlation between FEV1 and apnea index (AHI) when sleeping with p > 0.05 11 3.2.4.2 Correlation between BMI and snoring index in asthma patients with obstructive sleep apnea Figure 3.3 Correlation between BMI and snoring index in asthma patients with OSAS Comments: There is a statistically significant correlation between the BMI body mass index and the snoring index with R = 0.189 and p = 0.027 (p< 0.05) 3.2.4.3 Correlation between bronchial FENO and nasal FENO with sleep AHI Figure 3.4 Correlation between the bronchial FENO index and the AHI index 12 Figure 3.5 Correlation between the nasal FENO index and the AHI index Comments: There is a statistically significant correlation between bronchial FENO and nasal FENO with apnea index (AHI) with R = 0.046 and p = 0.00 (p< 0.05) and R = 0.037 and p = 0.00 (p< 0.05) 3.2.4.4 Night and daytime symptoms of asthma children at risk of obstructive sleep apnea Table 3.5: Night and daytime symptoms of Children with asthma at risk of OSAS Patient characteristics Night symptoms Symptoms of snoring Difficulty falling asleep Difficulty breathing while sleeping Restless sleep Wake up regularly Sweat thieves Enuresis Daytime symptoms Abnormal behavior Irritable Agitated Daytime drowsiness Relative risk value (95% confidence interval) 3,75 (1,7 – 8,23) 2,50 (1,1 – 5,67) 1,41 (0,67 – 2,98) 2,44 (1,12 – 5,34) 1,45 (0,67 – 3,20) 1,22 (0,59 – 2,55) 0,88 (0,29 – 2,7) 3,04 (1,09 – 8,53) 1,80 (0,83 – 3,90) 1,46 (0,6 – 3,37) 2,5 (0,89 – 7,04) p 0,01 0,028 0,365 0,025 0,352 0,592 0,816 0,034 0,134 0,417 0,085 13 Comments: - The group of children with asthma with OSAS has daytime symptoms such as abnormal behaviors, or irritability, being prone to agitation, impaired perception, and drowsiness during the day, accounting for a higher proportion than the asthma group but not OSAS - Abnormal behavior symptoms in asthma patients are 3.04 times more likely to have OSAS than asthma patients without OSAS (p=0.034) - Symptoms such as irritability, agitated, daytime drowsiness in asthma patients made the risk of statistically meaningless OSAS increase (p > 0.05) 3.3 Characteristics of asthma patients with obstructive sleep apnea after months and months of Singulair treatment in combination with asthma treatment 3.3.1 Characteristics of severe asthma levels after months - months of treatment 70% Ban đầu First-line After months Sau tháng After months Sau tháng 60,4% 60% 48,4% 44,4% 50% 40% 37,6% 41,4% 34,0% 30% 20% 14,0% 10,1% 10% 5,7% 4,0% 0% 0% Level Bậc 11 Level Bậc 22 Level Bậc 33 Level Bậc 44 Chart 3.1 Development of asthma at the severe level after months of treatment Comments - After months, the number of first-level asthma patients increased to 60.4% compared to the original of 10.1% and the number of 3rd level asthma patients decreased from 41.4% to 5.7% - After months, level asthma patients decreased to 34.0% compared to 48.4% after months and 44.4% at the beginning - After months there are no severe asthma patients 14 3.3.2 The characteristics of control level of asthma after months Ban đầu First-line Sau 3tháng After months After months Sau 6tháng 80% 70% 60% 58,6% 67,9% 58,1% 50% 40% 35,5% 32,3% 28,3% 30% 20% 10% 6,5% 9,1% 3,8% 0% Uncontrolled Chưa kiểm soát Partialsoát controlled Kiểm phần Totalsoát controlled Kiểm hoàn toàn Chart 3.2 Development of asthma control level after months of treatment Comments - After months of treatment, the level of unman-controlled asthma decreased from 58.6% at the beginning to 3.8% - The level of complete asthma control from 9.1% at first increased to 35.5% after months and increased to 67.9% after months 3.3.3 Change Control Point of ASTHMA ACT after months 30 22,6 25 20 24,2 19,2 15 10 BAN ĐẦU First-line SAU After33THÁNG months SAU After 66 THÁNG months Chart 3.3 Control levels under ACT after months of treatment Comments - ACT score increased from 19.2 to 22.6 points after months and 24.2 points after months of treatment 15 3.3.4 Characteristics of Respiratory function after months 120% 100% 99,1% 93,5% 85,1% 103,4% 95,9% 98,8% 92,1% 92,3% 95,6% BAN ĐẦU(n=99) (n=99) First-line After3 3THÁNG months (N=92) (n=92) SAU After6 6THÁNG months (N=53) (n=53) SAU 77,8%79,7% 68,8% 80% 60% 40% 20% 0% FEV1 FVC FEV1/FVC PEAK FLOW Chart 3.4 Changes in respiratory function after months of treatment Comments: After and months of treatment of FEV1, FVC, FEV1/FVC, peak flow has increased markedly 3.3.5 Characteristics of Bronchial FENO after months of treatment 25 22,19 20 15,1 14,38 SAU After33THÁNG months (N=92) SAU THÁNG After 66 months (N=53) 15 10 BANFirst-line ĐẦU (N=99) Chart 3.5 Bronchial FENO characteristics after months of treatment 16 Comments - The initial concentration of exhaled gas nitrite oxide (FENO) is 22.19ppb higher than the normal threshold, after months the concentration of FENO inflammatory score has decreased gradually from 22.19ppb at first to 15.1ppb and after months stable at the normal level of 14.38ppb 3.3.6 Features associated with obstructive sleep apnea in asthma patients after months of treatment 3.3.6.1 Night symptoms in asthma patients with obstructive sleep apnea after months BAN ĐẦU (n=99) (N=99) First-line SAU THÁNG(n=92) (N=92) AfterBA months After6 6THÁNG months (N=53) (n=53) SAU 90% 76,8% 74,2% 80% 70% 61,6% 60% 50% 56,6% 44,1% 52,5% 48,5% 45,5% 38,4% 40% 30% 18,3% 20% 18,3% 11,3% 10% 5,4% 5,7% 0% 8,6% 0% 11,1% 1,9% 0% 0% 0% TRIỆU Snoring CHỨNG NGÁY KHÓ ĐI Difficulty VÀO GIẤC falling NGỦ asleep KHÓ THỞ Difficulty KHI NGỦ breathing NGỦ THỨC GIẤC ĐỔ MỒ HÔI ĐÁI DẦM Restless Wake up Sweat Enuresis KHÔNG TRỘM sleep thieves YÊN GIẤC regularly Chart 3.6 Changes in night symptoms after months of treatment Comments: After months of treatment, all the initial symptoms of the patient have improved markedly 17 3.3.6.2 Daytime symptoms in asthma patients with obstructive sleep apnea after months 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% BAN ĐẦU (n=99) (N=99) First-line SAU BA THÁNG(n=92) (N= 92) After months After months (N=53) (n=53) SAU THÁNG 46,5% 36,6% 30,3% 26,4% 29,3% 26,3% 17,2% 9,4% HÀNH VI BẤT Abnormal THƯỜNG behavior CÁU GẮT Irritable KÍCH ĐỘNG Agitated 12,9% 5,4% 5,1% 3,8% 7,5% 0,0% 3,8% GIẢM NHẬN Decreased THỨC awareness BUỒN NGỦ Daytime BAN NGÀY drowsiness Chart 3.25 Daytime symptoms after months of treatment Comments: After months of treatment, agitation decreased from 29.3% at the beginning to 0% Symptoms of daytime drowsiness dropped from 26.3% at first to 3.8% Abnormal behaviors decreased from 30.3% at first to 9.4% 3.3 Change in severe obstructive sleep apnea after months of treatment 80% BAN ĐẦU (n=99) (99) First-line SAU THÁNG After months(92) (n=92) After months(53) (n=53) SAU THÁNG 69,8% 70% 61,6% 60% 57,6% 50% 40% 30% 29,3% 28,3% 25,3% 20% 13,0% 10% 1,9% 0% 13,1% 0% 0% 0% KHÔNG BỊ SAOS Normal MỨC ĐỘ NHẸ Mild MỨC ĐỘ TRUNG Moderate BÌNH MỨC ĐỘ NẶNG Severe Chart 3.26 Change severe OSAS after months Comments: OSAS at severe levels have decreased after treatment of months and months ... 5,7% 0% 8,6% 0% 11,1% 1,9% 0% 0% 0% TRIỆU Snoring CHỨNG NGÁY KHÓ ĐI Difficulty VÀO GIẤC falling NGỦ asleep KHÓ THỞ Difficulty KHI NGỦ breathing NGỦ THỨC GIẤC ĐỔ MỒ HÔI ĐÁI DẦM Restless Wake up... had acute asthma attacks - Patients and their parents agreed to participate in the study 2.1.2 Exclusion standard: one of the following standards - Patients with acute asthma attacks - Patients... levels after months - months of treatment 70% Ban đầu First-line After months Sau tháng After months Sau tháng 60,4% 60% 48,4% 44,4% 50% 40% 37,6% 41,4% 34,0% 30% 20% 14,0% 10,1% 10% 5,7% 4,0%