Hiệu quả và chi phí thở khí nitric oxide ở trẻ sơ sinh suy hô hấp nặng

BỘ GIÁO DỤC VÀ ĐÀO TẠO BỘ Y TẾ ĐẠI DPHỐ HỒ CHÍ MINH ĐẠI HỌC Y DƯỢC THÀNH -  - CAM NGỌC PHƯỢNG HIỆU QUẢ VÀ CHI PHÍ THỞ KHÍ NITRIC OXIDE Ở TRẺ SƠ SINH SUY HÔ HẤP NẶNG LUẬN ÁN TIẾN SĨ Y HỌC TP Hồ Chí Minh - Năm 2014 BỘ GIÁO DỤC VÀ ĐÀO TẠO BỘ Y TẾ ĐẠI HỌC Y DƯỢC THÀNH PHỐ HỒ CHÍ MINH -  - CAM NGỌC PHƯỢNG HIỆU QUẢ VÀ CHI PHÍ THỞ KHÍ NITRIC OXIDE Ở TRẺ SƠ SINH SUY HÔ HẤP NẶNG CHUYÊN NGÀNH : NHI – SƠ SINH MÃ SỐ : 62 72 16 01 LUẬN ÁN TIẾN SĨ Y HỌC Người hướng dẫn khoa học: PGS TS Vũ Minh Phúc PGS TS Phạm Thị Minh Hồng TP HỒ CHÍ MINH - NĂM 2014 LỜI CAM ĐOAN Tơi xin cam đoan cơng trình nghiên cứu riêng Các số liệu luận án trung thực chưa công bố cơng trình khác Ký tên Cam Ngọc Phượng MỤC LỤC Trang phụ bìa Lời cam đoan Mục lục Danh mục chữ viết tắt Bảng đối chiếu từ chuyên môn Việt – Anh Danh mục bảng Danh mục biểu đồ Danh mục sơ đồ Danh mục hình Trang ĐẶT VẤN ĐỀ MỤC TIÊU NGHIÊN CỨU Chương 1: TỔNG QUAN TÀI LIỆU 1.1.Cơ sở sinh học phân tử cao áp phổi 1.2 Khí Nitric oxide 1.3 Áp dụng lâm sàng thở khí Nitric Oxide 27 1.4 Tác dụng phụ khí Nitric Oxide 38 Chương 2: ĐỐI TƯỢNG VÀ PHƯƠNG PHÁP NGHIÊN CỨU 2.1 Đối tượng nghiên cứu 41 2.2 Phương pháp nghiên cứu 41 Chương 3: KẾT QUẢ NGHIÊN CỨU 3.1 Đặc điểm dân số nghiên cứu………………… 55 3.2 Kết điều trị thở khí Nitric oxide 64 3.3 So sánh đặc điểm lâm sàng, cận lâm sàng nhóm thở NO đáp ứng hồn tồn khơng đáp ứng 70 3.4 Hậu thở NO ……… 72 3.5 Kết điều trị chung- Tỉ lệ tử vong, di chứng lúc 30 ngày tuổi… 75 3.6 Chi phí điều trị trung bình………………………………… 80 Chương 4: BÀN LUẬN 4.1 Đặc điểm dân số nghiên cứu………………… 83 4.2 Kết điều trị thở NO 89 4.3 So sánh đặc điểm lâm sàng, cận lâm sàng nhóm thở NO đáp ứng hồn tồn khơng đáp ứng 92 4.4 Hậu thở NO ……… 96 4.5 Kết điều trị chung- Tỉ lệ tử vong, di chứng lúc 30 ngày tuổi… 97 4.6 Chi phí điều trị trung bình………………………………… 100 KẾT LUẬN 102 KIẾN NGHỊ 104 DANH MỤC CÁC CƠNG TRÌNH NGHIÊN CỨU TÀI LIỆU THAM KHẢO PHỤ LỤC DANH MỤC CÁC CHỮ VIẾT TẮT TIẾNG VIỆT ĐT Điều trị SA Siêu âm SHH Suy hô hấp SS Sơ sinh TBS Tim bẩm sinh TIẾNG ANH ALK Activin-like kinase type1 ALI Acute lung injury (Tổn thương phổi cấp) ARDS Acute respiratory distress syndrome (Hội chứng suy hô hấp cấp) ASQ Ages and Stages Questionaire ( Bộ câu hỏi tuổi giai đoạn) BMPR-II Bone morphogenetic protein type II receptor (Thụ thể protein tạo hình xương nhóm II) [Ca2+]I concentration of myoplasmic Ca2+ (Nồng độ Ca2+trong tương cơ) [Ca2+]in Intracellular Ca2+ concentration (Nồng độ Ca2+ nội bào) Ca2+ L channel L-type Ca2+ channel (Kênh Ca2+ loại L) Ca2+ T channel T-type Ca2+ channel (Kênh Ca2+ loại T) cAMP Adenosine 3',5' -cyclic monophosphate (Adenosine 3',5' monophosphate vòng) cGMP Guanosine 3',5' -cyclic monophosphate (Guanosine 3',5' monophosphate vòng) CI Confidence Interval (Khoảng tin cậy) Cl−Ca channel Ca2+ -activated Cl− channel (Kênh Cl− hoạt hóa Ca2+) ECMO Exchange Corporeal Membrane Oxygenation (Trao đổi oxy màng thể) EDRF Endothelium Derived Relaxing Factor (Yếu tố giãn mạch có nguồn gốc nội mô) eNOS endothelial Nitric oxide synthetase (Men tổng hợp Nitric Oxide nội mô) ERK Extracellular signal regulated kinases (Kinases điều hịa tín hiệu ngoại bào) FiO2 Fraction of inspired Oxygen (Phân suất Oxy khí hít vào) GSNO S-nitrosoglutathione 5-HT 5-hydroxytryptamine iNO Inhaled Nitric Oxide (Nitric Oxide hít vào) IP3 inositol 1,4,5 triphosphate IRAG IP3 receptor associated PKG substrate (Thụ thể IP3 kèm chất PKG) IP3 R channel IP3 -sensitive channel (Kênh IP3 nhạy cảm) K+ATP channel ATP-dependent K+ channel (Kênh K+ phụ thuộc ATP) K+Ca channel Ca2+ -dependent K+ channel (Kênh K+ phụ thuộc Ca2+) K+dr channel Delayed rectifier K+ channel (Kênh K+ chỉnh lưu muộn) K+ir channel Inward rectifier K+ channel (Kênh K+ chỉnh lưu hướng nội) MAP Mean Airway Pressure (Áp lực trung bình đường thở) MetHb MetHemoglobin MLCP myosin light chain phosphatase nicotinamide (myosin chuỗi nhẹ phosphatase) NADP adenine dinucleotide phosphate NNT Number need to treat (Số ca cần điều trị) NO Nitric oxide NOS Nitric Oxide Synthetase (Men tổng hợp Nitric Oxide) NTG Nitroglycerin OI Oxygenation Index (Chỉ số Oxy hóa máu) PaO2 Arterial Oxygen tension (Áp suất phần Oxy máu động mạch) PAOP Pulmonary artery occlusion pressure (Áp lực động mạch phổi bít) ODQ H-(1,2,4) oxadiazole (4,3-a) quinoxallinone PDGF Platelet-derived growth factor (Yếu tố tăng trưởng có nguồn gốc tiểu cầu) PEEP Positive end expiratory pressure (Áp lực dương cuối kỳ thở ra) PKA cAMP-dependent protein kinase (protein kinase phụ thuộc cAMP) PLC phospholipase C PPHN Persistent Pulmonary Hypertension of the Newborn (Cao áp phổi tồn trẻ sơ sinh) ppm Parts per million (Phần triệu) PR Prevalence Risk (Tỷ số tỷ suất mắc) RR Relative risk (Nguy tương đối) RSNOs S-nitrosothiols RTK Receptor tyrosine kinases (Thụ thể tyrosine kinases) RyR channel Ryanodine-sensitive channel (Kênh nhạy cảm Ryanodine) SERCA Sarcoplasmic-endoplasmic reticulum Ca2+ -ATPase (Ca2+ ATPase lưới nội bào tương) sGC soluble guanylyl cyclase (guanylyl cyclase hòa tan) SIN-1 3-Morpholino-sydnonimine SMC Smooth muscle cell (Tế bào trơn) SNAP S-nitroso-N-acetylpenicillamine SN Sodium nitropruside SNC S-nitrosocysteine SOC channel store-operated channel Sarcoplasmic (Kênh điều hòa dự trữ) SR reticulum (Lưới tương) TIE2 Endothelial specific tyrosine kinase (tyrosine kinase nội mô đặc hiệu ) DANH M C BẢNG ng Tên b ng Trang Bảng 1.1 Đặc điểm đồng phân NOS 11 Bảng 1.2 K ch th ch thể dịch yếu tố vận mạch tế b o nội mô 19 Bảng 1.3 So s nh tỷ lệ tử vong nhu cầu ECMO nh m thở khí NO so với nh m chứng điều trị suy hô hấp trẻ đủ th ng v gần đủ th ng 30 So s nh tỷ lệ tử vong nh m thở NO v nh m chứng điều trị suy hô hấp trẻ sanh non 32 So s nh tỷ lệ tử vong nh m thở NO so với nh m chứng điều trị hội chứng nguy kịch hô hấp cấp v tổn thương phổi cấp trẻ em v người lớn 37 Phân loại giá trị biến số……………………………………… 48 Đặc điểm dân số nghiên cứu…………………………………… 56 Triệu chứng lâm sàng 57 Phân bố hình ảnh Xquang ngực theo OI………………………… 57 Giá trị OI………………………………………………………… 58 Đặc điểm siêu âm tim màu 59 Nguyên nhân suy hô hấp…………… 62 Thay đổi khí máu động mạch, OI, dấu hiệu lâm sàng sau thở NO giờ………………………………………………………… 64 Kết sau thở NO theo OI…………………………… 65 Ba mức độ đáp ứng thở khí NO………………………………… 67 So sánh đặc điểm lâm sàng, cận lâm sàng nhóm thở NO đáp ứng hồn tồn khơng đáp ứng 71 Tỉ lệ tử vong theo trị số OI trước thở khí NO……………… 75 Bảng 3.18 Tỉ lệ tử vong theo mức độ đáp ứng thở khí NO………………… 75 Chẩn đốn lâm sàng nguyên nhân suy hô hấp tử vong……… 76 Di chứng lâu dài 77 Tái khám thần kinh……………………………………………… 78 Bảng 1.4 Bảng 1.5 Bảng 2.6 Kết chẩn đoán, điều trị tử vong dân số nghiên cứu… 79 Chi phí điều trị trung bình cho bệnh nhi thở NO (Việt nam đồng)…………………………………………………………… 81 Chỉ số hô hấp trước thở NO………………………………… 86 Bảng 4.25 Nguyên nhân suy hô hấp………………………………………… 88 Bảng 4.26 Hậu lâm sàng trước mắt……………………………………… 97 Bảng 4.27 Di chứng đến 12 tháng theo dõi 99 103 so với nhóm trẻ cao áp phổi tồn tại, bệnh màng Thời gian điều trị thở NO trung bình 25,1 ± 11 thời gian thở máy trung bình 12 ngày Thời gian nằm viện trung bình 24 ngày Chi phí - hiệu sống cịn trung bình nghiên cứu 45.121.323 VNĐ, với hiệu sống cịn xuất viện 68%, chi phí khí NO trung bình 28.402.000 VNĐ /một bệnh nhi, chiếm 62,9% tổng viện phí 104 KIẾN NGHỊ Qua nghiên cứu 50 trường hợp trẻ sơ sinh đủ tháng non tháng muộn suy hô hấp giảm oxy máu nặng, điều trị thở khí Nitric oxide, chúng tơi mạn phép đưa kiến nghị sau: Xây dựng hướng dẫn chi tiết điều trị thở khí Nitric oxide suy hô hấp sơ sinh nặng: Chiến lược điều trị trước thở NO Ổn định bệnh nhi FiO2 100% Kiềm hoá máu (pH > 7,45) Dịch truyền/ Vận mạch An thần Huy động phế nang Thở máy rung tần số cao Surfactant thay Liều điều trị NO Thở NO liều khởi đầu 20 ppm Khi bệnh nhi đáp ứng với thở khí NO, cố gắng giảm MAP FiO2 dần để hạn chế tổn thương phổi Chiến lược cai NO - Khởi đầu thở NO liều 20 ppm - Nếu bệnh nhi đáp ứng thở NO, giảm FiO2 5% Khi FiO2 60%, giảm liều NO, thường vòng - Cố gắng giảm FiO2 giảm liều NO tình trạng lâm sàng bệnh nhi ổn định với tiêu chuẩn sau : (1) SpO2 trước ống động mạch > 92% ; (2) PaO2 > 60 mmHg (3) độ khác biệt SpO2 trước sau ống động mạch < 5% - Nên cố gắng cai NO tối thiểu 24 - Có thể giảm liều NO ppm 15 phút đạt liều ppm - Từ liều NO ppm xuống ppm: Nên giảm liều NO ppm 105 - Có thể tăng FiO2 15% đến tối đa 75% nhằm mục đích ngưng NO Khi ngưng NO, có khả độ bão hồ oxy động mạch giảm, thường tăng FiO lên 10 – 20 % Nói cách khác, khơng nên thở NO lại phải tăng FiO2 vừa phải - Sau ngưng thở NO, nên đánh giá lại bệnh nhi sau 60 phút, định thở lại NO (1) Cần FiO2 > 75% để trì PaO2 > 60 mmHg SpO2> 92% ; (2) Tình trạng huyết động xấu Nên làm siêu âm tim màu bệnh nhi cai NO thất bại dù áp dụng phác đồ thở NO chuẩn, diễn tiến lâm sàng bệnh nhi nặng trình điều trị thở NO Biện pháp an tồn bệnh nhi mơi trường: - Biện pháp an tồn bệnh nhi: Để loại bỏ độc tính NO trình điều trị cần theo dõi nồng độ NO, NO2 khí hít vào, nồng độ MetHb Trong trình điều trị NO, cần thu thập số liệu q trình điều trị, độc tính, thất bại điều trị, sử dụng phương pháp điều trị thay kết trước mắt Ngoài ra, trung tâm điều trị thở NO nên tổ chức theo dõi tái khám phát triển thần kinh thính lực cho tất trẻ xuất viện - Biện pháp an tồn mơi trường: Đường thở máy thở nối với hệ thống hút trung tâm, tránh khí NO NO2 đường thở thải vào phòng bệnh Kiểm tra hệ thống cung cấp NO, đảm bảo khơng có dị rỉ khí trước cho bệnh nhi thở NO Trang bị hệ thống thở khí NO nên tập trung trung tâm sơ sinh tuyến cuối, có khả theo dõi hỗ trợ hô hấp, bao gồm thở máy rung tần số cao cho trẻ sơ sinh suy hô hấp nặng Chi phí điều trị thở khí NO cần bảo hiểm y tế tốn, phương pháp điều trị cấp cứu cho trẻ sơ sinh suy hô hấp nặng Bước đầu áp dụng kỹ thuật thở khí NO cho thấy hiệu cải thiện oxy hóa máu an tồn, khơng có tác dụng phụ Vì vậy, chúng tơi mạnh dạn đề xuất tiếp tục nghiên cứu đa trung tâm, với cở mẫu lớn hơn, đặc biệt quan tâm chi phí hiệu sống trước định triển khai kỹ thuật Việt nam TÀI LIỆU THAM KHẢO TIẾNG ANH 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DỤC VÀ ĐÀO TẠO BỘ Y TẾ ĐẠI HỌC Y DƯỢC THÀNH PHỐ HỒ CHÍ MINH -  - CAM NGỌC PHƯỢNG HIỆU QUẢ VÀ CHI PHÍ THỞ KHÍ NITRIC OXIDE Ở TRẺ SƠ SINH SUY HÔ HẤP NẶNG CHUYÊN NGÀNH : NHI – SƠ SINH. .. 1.44) Thở khí NO có hiệu sử dụng trẻ suy hô hấp mức độ trung bình nặng Hai nghiên cứu so sánh hiệu thở khí NO cho nhóm trẻ suy hơ hấp trung bình nhóm trẻ suy hơ hấp nặng [152] Nghiên cứu không... đáp PHỤ LỤC PHIẾU LẤY CHẤP THUẬN CỦA THÂN NHÂN BỆNH NHÂN HIỆU QUẢ CHI PHÍ THỞ KHÍ NITRIC OXIDE Ở TRẺ SƠ SINH SUY HƠ HẤP NẶNG Chấp thuận từ bệnh nhân người bảo hộ Tôi thông tin đầy đủ nguy có