SỬ DỤNG STEROIDS TRONG ĐỢT CẤP COPD: Tại Sao và Như Thế Nào? Nguyễn Như Vinh ĐHYD Tp. Hồ Chí Minh

Nội dung Đợt cấp là gì? 1. Tại sao cần SCS? 2. Khi nào cần? 3. Liều như thế nào? 4. Thời gian dùng bao lâu? 5. Đường dùng? 6. Tác dụng phụ ra sao? 7. ICS có vai trò không? Kết luận

Đợt cấp Định nghĩa Một tình trạng nặng hơn của các triệu chứng hô hấp 1 Nặng hơn sự thay đổi hằng ngày Cần phải thay đổi điều trị Chẩn đoán Dựa vào tam chứng: 1 Khó thở Ho Thay đổi đàm Điều trị (mục tiêu) Giảm thiểu hậu quả của đợt cấp hiện tại và ngăn chặn đợt cấp kế tiếp 1 Giảm tần số và độ nặng của đợt cấp có thể giảm tử vong liên quan đến COPD 2 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. http://www.goldcopd.org/. Last accessed July 2016 2. Marks A. US Pharmacist 2009;34(7):HS-11-HS-15

Sinh bệnh học Wedzicha JA & Seemungal TA. Lancet 2007;370:786 96 O Donnell DE, et al. COPD Research and Practice 2015;1:4

Phân tầng điều trị 12. Hosp Physician. 2009;38:9 16.

Tại sao sử dụng Corticoid trong đợt cấp? COPD has pulmonary and systemic components Inhaled substances + Genetic susceptibility Airway inflammation Mucociliary dysfunction Structural changes Breathlessness Bronchitis: coughing, sputum production Emphysema: hyperinflation, wheezing 2017 Global Initiative for Chronic Obstructive Lung Disease Skeletal muscle wasting & Cachexia Comorbidities (e.g. diabetes, cardiovascular disease, osteoporosis)

Tại sao sử dụng Corticoid trong đợt cấp? Tình trạng viêm xảy ra mạnh mẽ trong đợt cấp của BPTNMT Tình trạng viêm gia tăng ở bệnh nhân BPTNMT so với người hút thuốc lá không bị BPTNMT hay không hút thuốc lá. Một khi đã hình thành, quá trình viêm sẽ tiếp diễn dù ngưng hút thuốc lá và viêm xảy ra nhiều hơn khi bệnh nhân có đợt cấp do vi trùng hay virus

Tại sao sử dụng Corticoid trong đợt cấp? Cơ chế viêm theo hướng tăng BCAT thường xảy ra khi bệnh nhân mắc BPTNMT vào đợt cấp. Các nghiên cứu về sinh thiết niêm mạc đường hô hấp cho thấy BCAT ở niêm mạc phế quản tăng 30 lần trong đợt cấp

Tại sao sử dụng Corticoid trong đợt cấp? Các nghiên cứu cho thấy sử dụng corticosteroid toàn thân trong đợt cấp COPD rút ngắn thời gian hồi phục và cải thiện chức năng hô hấp (FEV1). Corticosteroid toàn thân còn giúp cải thiện: Độ bão hòa oxy Nguy cơ tái phát sớm Thất bại điều trị Thời gian nằm viện

Management of Exacerbations Acute Maintenance Objective Relieve dyspnea Reduce airway inflammation Improve lung function Eradicate infections Reduce risk of new exacerbation Anzueto A. Am J Med Sci. 2010 Jul 9 Strategy SABA +/- short acting anticholinergic Systemic corticosteroids Systemic corticosteroids Antibiotics Smoking cessation Pharmacotherapy Salmeterol +/- fluticasone Formoterol +/- budesonide Tiotropium Immunizations Influenza Pneumonia Pulmonary rehab Self-management support

Outcomes Treatment failure Need to intensify therapy/ ED or hospital admission Follow-up:3-30days Relapse Treatment for AE of COPD or hospital re-admission Follow-up:1-4months Improvement in lung function -early effect FEV1(L) as absolute or change Follow-up:3days Decreased breathlessness -early effect Borg scale or VAS Follow-up:3days Adverse drug effect Follow-up:2-26weeks Hyperglycaemia Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD001288. Relative effect (95%CI) OR 0.48 (0.35-0.67) OR 0.77 (0.51-1.17) 0.14L higher (0.09-0.20) 0.35 SD higher (0.05-0.64) OR2.33 (1.59-3.43) OR2.79 (1.86-4.19) No of participants (studies) Quality of the evidence 917 (9studies) high 596 (5studies) moderate 649 (7studies) high 178 (3studies) moderate 736 (8studies) high 804 (6studies) high Patient or population: acute exacerbations COPD Settings: outpatient, inpatient and people in ICU Intervention: systemic corticosteroid

Systemic corticosteroids in acute exacerbation of COPD: a metaanalysis of controlled studies with emphasis on ICU patients OR = 1.72 Annals of Intensive Care 2014 4:32 Primary endpoint: treatment success

Do Systemic Corticosteroids Improve Outcomes in Chronic Obstructive Pulmonary Disease Exacerbations? Annals of Emergency Medicine Volume 67, no. 2 : February 2016

When should acute exacerbations of COPD be treated with systemic corticosteroids and antibiotics in primary care: a systematic review of current COPD guidelines NPJ Prim Care Respir Med. 2015; 25: 15002.

Nội dung Đợt cấp là gì? 1. Tại sao cần SCS? 2. Khi nào cần? 3. Liều như thế nào? 4. Thời gian dùng bao lâu? 5. Tác dụng phụ ra sao? 6. ICS có vai trò không? Kết luận

Liều dùng Pulm Pharmacol Ther. 2014 Apr;27(2):179-83. doi: 10.1016/j.pupt.2013.03.004. Epub 2013 Mar 18. Comparison of two systemic steroid regimens for the treatment of COPD exacerbations. RATIONALE: Systemic steroids shorten recovery time, improve lung function and hypoxemia in COPD exacerbations. Although several studies have shown that both parenteral and oral steroids are effective and GOLD guideline recommends use of oral steroids at a dose of 30-40 mg/day, very little data exists as to whether any route of admininstration (parenteral vs oral) or any dose is more effective and/or safer. METHODS: This was a randomized, parallel-group study aiming to compare the effectiveness and safety of orally administered lower dose of steroids with parenteral administration of higher doses. Thus, a total of 40 patients were included; one group (Group 1, n = 20) received methylprednisolone (MP) as recommended by the GOLD guideline (PO 32 mg/day for seven days) and the other (Group 2, n = 20) was given IV MP at 1 mg/kg/day for four days and 0.5 mg/kg/day for three days. RESULTS: The two groups were similar with regards to age (69.0 ± 10.5 vs 67.1 ± 8.4 years), duration of COPD (11.8 ± 8.3 vs 9.7 ± 7.7 years), FEV1 (41.3 ± 17.3 vs 34.0 ± 12.0%), PaO2 levels (55.5 ± 9.9 vs 59.1 ± 11.0 mmhg) and dyspnea scores (9.4 ± 1.1 vs 10.0 ± 1.0). Worsening hypercapnic respiratory failure developed in two patients from Group 1 on days 1 and 2, these were intubated and thus excluded from the study. At day 7, both groups showed significant improvements in FEV1 levels (50.8 ± 19.4 and 43.8 ± 21.4%, respectively) (Table 2), PaO2 levels (66.5 ± 12.5 and 65.3 ± 10.6 mmhg, respectively) (Table 3) and dyspnea scores (3,5 ± 2,8 and 4.2 ± 2.8) (Fig. 1). The length of hospital stay was similar for the two groups (11.0 ± 3.9 vs 12.7 ± 6.4). Regarding adverse events, four patients in Group 1 vs 11 patients in group 2 developed hyperglycemia. Besides, three patients in group 2 had worsening of previously controlled hypertension. All events were treated and controlled with administration of proper medications. All patients were followed up for three months. Eight patients in group 1 and 15 patients in group 2 had unplanned visits to their physicians or to the emergency rooms for recurring exacerbations. Four patients in group 1 and five patients in group 2 were readmitted to hospital for recurrence (p = NS). During the follow-up two patients from group 1 died. CONCLUSION: These data show that oral administration of MP at a dose 32 mg/day for seven days significantly improves lung function, symptom scores and oxygenation in patients admitted to the hospital for COPD exacerbation and is as effective as and possibly safer than parenteral admininistration of higher doses.

Liều dùng

Liều dùng Clin Respir J. 2013 Oct;7(4):305-18. doi: 10.1111/crj.12008. Epub 2012 Nov 28. Systemic corticosteroid for COPD exacerbations, whether the higher dose is better? A meta-analysis of randomized controlled trials. Cheng T 1, Gong Y, Guo Y, Cheng Q, Zhou M, Shi G, Wan H. Abstract BACKGROUND: Systemic corticosteroids (SCS) have been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the optimal dose remains controversial. OBJECTIVES: We performed a meta-analysis to evaluate whether high-dose SCS is better. METHODS: We searched PubMed, EMBASE, CPCI-S and CENTRAL databases, and references of reviews or meta-analyses to identify randomized controlled trials using SCS in AECOPD. We performed a routine meta-analysis to evaluate the effects of SCS on treatment failure rate and forced expiratory volume in 1 s (FEV1) improvement compared with placebo in AECOPD. Subgroup analysis was performed by dividing the studies into a high-dose group [initial dose 80 mg prednisone equivalent (PE)/day] and a low-dose group (initial dose 30-80 mg PE/day) in all patients and in only inpatients. Meta-regression was performed using initial dose as an independent factor. We classified the suspected adverse effects into several groups and combined them separately. RESULTS: Our search yielded 12 studies involving 1172 patients. SCS use was associated with a significant reduction in the treatment failure rate [risk ratio 0.58; 95% confidence interval (CI): 0.46-0.73] and improvement in FEV1 (0.11 L; 95% CI: 0.08-0.14 L). The high-dose regimen did not show superiority to the low-dose regimen. No obvious correlation was found between the SCS effect and the initial dose. SCS led to an obvious increase in hyperglycemia risk. However, the high-dose group did not show obviously higher risk of adverse effects. CONCLUSION: SCS can reduce treatment failure rate and improve lung function in AECOPD. The low-dose regimen (initial dose 30-80 mg/day PE) is proper for treating AECOPD.

Liều dùng Ngoại trú: GOLD & Uptodate # 40 mg prednisone uống x 5 ngày; NICE 30 mg prednisone uống x 7-14 ngày. Nội trú: Chưa rõ liều tối ưu GOLD: 40 mg prednisone uống x 5 ngày; NICE 30 mg prednisone uống x 7-14 ngày Uptodate: 30-60 mg prednisone (1 lần/ngày) 60-125 methylprednisone (2-4 lần/ngày) Corticosteroid Tác dụng ngắn Liều tương đương Hoạt tính kháng viêm tương đối Thời gian hoạt động (giờ) Hydrocortisone 20 1 8-12 Cortisone acetate 25 0,8 8-12 Tác dụng tức thì Prednisone 5 4 12-36 Prednisolone 5 4 12-36 Methylprednisolone 4 5 12-36 Triamcinolone 4 5 12-36 Tác dụng dài Dexamethasone 0,75 30 36-72 Betamethasone 0,6 30 36-72 GOLD 2018 Uptodate 2018 - NICE 2010 Liều tương đương của các thuốc corticosteroid.

J Fam Pract. 2014 January;63(1):29-30,32

Thời gian dùng thuốc JAMA. 2013 Jun 5;309(21):2223-31. doi: 10.1001/jama.2013.5023. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. IMPORTANCE: International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE: To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers ( 20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS: Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE: Time to next exacerbation within 180 days. RESULTS: Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P =.006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P =.005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P <.001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.

From: Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: The REDUCE Randomized Clinical Trial JAMA. 2013;309(21):2223-2231. doi:10.1001/jama.2013.5023

Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease ( 7 days vs. >7 days) Outcomes Relative effect (95% CI) Number of participant s (studies) Quality of the evidence (GRADE) Treatment failure Need for additional treatment Follow-up: 10 to 14 days OR 0.72 (0.36 to 1.46) 457 (4 studies) Moderate Relapse New acute exacerbation or COPD-related admission Follow-up: 14 to 180 days OR 1.04 (0.7 to 1.56) 478 (4 studies) Moderate Adverse drug effect - hyperglycaemia Follow-up: 3 to 14 days OR 0.99 (0.64 to 1.53) 345 (2 studies) Moderate Adverse drug effects Gastrointestinal tract bleeding, symptomatic gastrointestinal reflux, symptoms of congestive heart failure or ischaemic heart disease, sleep disturbance, fractures, depression Follow-up: 10 to 180 days OR 0.88 (0.46 to 1.7) 503 (5 studies) Low a,b Mortality OR 0.91 336 Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No.: CD006897.

With regards to duration of treatment, a meta-analysis by Walters et al (Walters 2014b) concluded that a shorter course of corticosteroids (around 5 days) is unlikely to lead to worse outcomes compared with a longer course. In 2013, Leuppi et al (Leuppi 2013) reported on the largest randomised controlled trial in this area. The authors found that a five day course of corticosteroids (one 40mg dose of intravenous methylprednisolone followed by four days of prednisolone 40mg) was non-inferior to treatment for 14 days (one IV dose plus 13 days of 40 mg prednisolone) regarding subsequent exacerbations and mortality over six months of follow-up. In light of the evidence above, it would appear that a 5 day course of oral prednisolone of 30mg to 50mg is adequate. In patients who have been on oral corticosteroids for longer than 14 days, tapering may be necessary. Patients on long-term oral corticosteroid therapy (> 7.5 mg prednisolone daily for more than 6 months) are at risk of developing osteoporosis. Prevention and treatment of corticosteroid-induced osteoporosis should be considered.

Management of Exacerbations - Summary 2017 Global Initiative for Chronic Obstructive Lung Disease

Oral vs. IV Steroids de Jong et al. (2007) 4 5 days of 60 mg prednisolone daily either IV (n=107) or po (n=103) Evaluated treatment failure: death, ICU admission, readmission to ICU due to COPD, or intensification of therapy within 90 days of treatment Oral (56.3%) non-inferior to IV (61.7%) Overall treatment failure higher than 2 week regimen in Niewoehner trial (38%) 1 First three days of Niewoehner trial featured steroid doses 2.6 times higher 5 No data reported on adverse events Ceviker, Sayiner (2013) 6 7 days of 32 mg methylprednisolone po daily (n=20) 4 days 1 mg/kg/day methylprednisolone IV then 3 days of 0.5 mg/kg/day (n=20) Both groups showed improvement in FEV 1 (49.1% oral vs. 40.0% IV) Less incidence of hyperglycemia in oral (22.2% vs. 55%) Did not compare equipotent steroid doses

Intravenous corticosteroid compared with oral corticosteroid for acute exacerbations of COPD Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD001288

Đường dùng GOLD, ERS/ATS: Uống (nếu đường tiêu hóa không có vấn đề) Mặc dù 90% BS Mỹ thích dùng đường TM OCS được hấp thụ nhanh với nồng độ huyết thanh đạt đỉnh sau 1h, sinh khả dụng đạt gần như hoàn toàn và có hiệu quả # IV trong điều trị hầu hết các đợt cấp COPD Hiệu quả điều trị tương đương IV: thời gian nằm viện lâu hơn, chi phí cao hơn

Do Corticosteroids Provide Benefit to Patients With Community-Acquired Pneumonia? Systematic Review Snapsho Annals of Emergency Medicine, 2016: Volume 67, Issue 5, 640-642

ICS vs. SCS J Aerosol Med Pulm Drug Deliv. 2017 Oct;30(5):289-298. doi: 10.1089/jamp.2016.1353. Epub 2017 Mar 16. Comparative Efficacies of Inhaled Corticosteroids and Systemic Corticosteroids in Treatment of Chronic Obstructive Pulmonary Disease Exacerbations: A Systematic Review and Meta-Analysis. BACKGROUND: Corticosteroids play an important role in the treatment of chronic obstructive pulmonary disease (COPD) exacerbations, and a global initiative has suggested the use of inhaled corticosteroids (ICSs) as an alternative to systemic corticosteroids (SCs). Here, we report results of a meta-analysis performed to systematically compare the efficacies of ICSs and SCs in the treatment of COPD exacerbations. METHODS: PubMed, EMBASE, and the Cochrane databases were searched for relevant human clinical trials describing the use of ICSs compared with SCs in the treatment of COPD exacerbations. We compared the results of FEV1%pred and blood gas analyses that had been calculated. Weighted mean differences and fixed effects models were applied by using Revman 5.2. RESULTS: Five original studies satisfied our inclusion criteria, and no significant heterogeneity was shown. Three studies evaluated the increase of FEV 1 %pred after treatment for 7 days. There were three and four studies, respectively, that evaluated the increase of SaO 2 and PaO 2, and three reported the decrease of PaCO 2 at 24 hours control, 2-4 days control, and 7-10 days control. All the results showed that both ICSs and SCs were effective in the treatment of COPD exacerbations. CONCLUSION: ICSs were not inferior to SCs when used in the treatment of COPD exacerbations.

Kết luận Corticoid đường toàn thân là thuốc kháng viêm hiệu quả cho nhiều bệnh nhân vào đợt cấp của BPTNMT Liều điều trị ngoại trú là 30-40 mg/ ngày. Sử dụng đường uống được ưu tiên hơn tĩnh mạch vì hiệu quả tương đương nhưng dễ sử dụng và kinh tế hơn. Thời gian sử dụng 5-7 ngày được nhiều khuyến cáo vì sử dụng dài ngày hơn chưa có bằng chứng hiệu quả hơn.