1、以病程分期為依據之兒童腸病毒重症治療 The Stage Based Therapy of Critically Ill Children with EV 71 Infection,林口長庚兒童醫院兒童加護科 夏紹軒 吳昌騰 兒童心臟科 黃茂盛 鍾宏濤 兒童神經科 林光麟 王傳育 兒童呼吸胸腔科 黃健燊 兒童感染科 張鑾英 黃玉成 邱政洵 林奏延,A Cardiopulmonary disaster requiring multidisciplinary treatment,I. Outbreaks II. 臨床分期及其表現 III. 呼吸衰竭的病生理學 IV. 治療的考量 V. 結論,Out
2、breaks (1),民國八十七年五月初一個一歲兩個月大的小女孩被帶到門診，主訴是 fever with oral ulcers and vesicles on hands, feet and knees. 母親對於小朋友的高燒不退、躁動不安、食慾減退、入睡困難、無力站立非常擔心。,Outbreaks (2),醫生說：這是典型手足口病症狀，只要吃一些退燒藥，多休息、多喝水就好了。 第二天，小女孩被帶回急診，已經發生意識不清、發紺等症狀，當時，急診醫師為她插上氣管內管，大量粉紅色泡沫狀液體從氣管內冒出。,Outbreaks (3),小女孩被送到 PICU. 發生心肺衰竭，CPR無效後，被宣布死亡
3、。 此後一個月，共有七名兒童因同一症狀死在本院，醫師立即通報疾病管制局，並發現幾乎全台灣各大醫學中心都有類似案例。,Enetrovirus type 71 腸病毒七十一型分別在糞便、咽喉、及腦脊髓液檢體中被培養出來。,EV 71 Outbreaks,Enterovirus type 71 was firstly isolated from the stool of an infant with encephalitis in US in 1969 1975, 44/705 were killed in Bulgaria 1997, 30 were killed in Malaysia 1998
4、, 78 were killed in Taiwan 1999, 8 were killed in Hong-Kong,1998 腸病毒流行之統計,估計約一百萬至兩百萬人口被感染？！ 查有實據者129106人為EV71感染 405人為重症 78人死亡 80%死於肺水腫與肺出血,腸病毒的傳染途徑,飛沫傳染 唾液與呼吸道分泌物在痊癒之後2-3 weeks仍可分離出EV71病毒 糞口傳染 糞便在痊癒之後6-8 weeks仍可分離出EV71病毒 病毒離開人體可存活8小時左右,I. Outbreaks II. 臨床分期及其表現 III. 呼吸衰竭的病生理學 IV. 治療的考量 V. 結論,EV71(17
5、4) non71 EV(241),Uncomlicated cases HFMD/herpangina Viral exanthem Febrile illness Others Comlicated cases Meningitis Encephalitis/myelitis Polio-like syndrome Pulmonary Oedema Fatal cases Survivors with severe neurological sequela,119(68%) 108(63%) 2(1.1%) 7(4%) 2(1.1%) 55(32%) 13(7.5%) 26(14.5%)#
6、4(2.3%) 12(6.9%)# 14(8.0%)# 5(2.8%)#,187(78%) 105(43%) 5(2%) 18(7.4%) 59(24%) 54(22%) 44(18%) 5(2.1%) 0(0%) 0(0%) 0(0%) 0(0%),#:p0.001, Chang et al.,Table 1:Demographic and clinical characteristics of 154 patients,Group Pulmonary CNS cases Uncomplicatedoedema(N=11) (N=38) cases (N=105),Sex(M/F) 5/6
7、24/14 56/49 Age(months) 20(21) 29(21) 30(33) Fever 11(100%) 38(100%)* 93(89%) Peak BT(C) 39.8(0.6)# 39.3(0.7) 39.1(0.8) WBC(109/L) 27.1(8.9) 14.2(5.8) 13.4(4.5) Glucose 22.4(12.7) 7.0(3.5)# 5.6(1.0) (mmol/L) CRP(mg/L) 13.9(14.3) 15.1(24.8) 16.6(27.6),Compared cases of pulmonary edema/CNS involvement
8、 with uncomplicated cases , *:p=0.03; #:p=0.01; :p=0.004; : p=0.001. Chang et al. Lancet 354(9191): 1682, 1999,Table 4: Risk factors associated with pulmonary oedema,Pulmonary CNS cases OR PRisk Factors oedema(N=11) (N=38) (95%CI)Glu150 9(82%) 4(11%) 38(6-211) 0.001 * Leukocytosis 9(82%) 12(32%) 9.7
9、(2.9-34) 0.003 # Upper limb 4(36%) 4(11%) 4.9(2.6-9.2) 0.04 weakness Lower limb 7(64%) 11(29%) 4.3(2.0-9.2) 0.04 weakness,Chang et al. Lancet 354(9191): 1682, 1999,Skin and Mucosa Lesions,Oral ulcers distributed not on soft palate only as typical hand-foot mouth disease Vesicles on hand and foot wer
10、e smaller (pin-point) than typical HFM disease Sometimes the skin lesion consisted of petechiae-like clusters,Phases Based Therapy of Critical EV-71 Infection 腸病毒重症之臨床分期,第一期：上呼吸道感染手足口病 第二期：神經症狀腦膜腦脊髓炎 第三A期：高血壓肺水腫出血自主神經失調 第三B期：低血壓心臟衰竭？心肌炎？SIRS? 第四期：逐漸恢復神經後遺症,分期標的,Stage 1: Oral ulcer, skin rash, fever
11、Stage 2: Neurological symptomsmyoclonic jerk, limb weakness, seizure, consciousness disturbance Stage 3A: Elevated BP Stage 3B: Decreased BP, use of catecholamines Stage 4: Cessation of catecholamines.,Results,We observed a majority of patients (58% 14/24) presented different five clinical phases. T
12、wo patients developed PE without a HFM prodrome One patient developed PE without previous CNS involvement signs In six patients, hypertension phases were not observed Three patients did not develop hypotension phenomenon,Table A Severe Hypertension Criteria by Age,Modified from Hycan et al Task Forc
13、e on Blood Pressure control in Children. Pediatrics 79:1, 1987.,Table B. Normal Blood Pressure by Age,Hazinski MF: Nursing Care of the Critically Ill Child, 2nd ed. St.Louis, Mo: Mosby Year Book; 1992,第一期：手足口病,持續約數天 可能發高燒 類手足口病Hand-Foot-Mouth disease 類皰疹性咽峽炎Herpangina 大多數病人可自然痊癒，無後遺症 手足水泡較典型手足口病小約針尖
14、大小 高危險群可能向後期發展,重症病例之前趨症狀及危險因子 I,重症病例前趨症狀四肢反射性抖動 (myoclonic jerk)嘔吐嗜睡,中樞神經受侵犯之危險因子年齡小於三歲高燒超過39度燒超過3天嗜睡、抽筋、頭痛嘔吐高血糖(150mg/dl),重症病例之前趨症狀及危險因子 II,重症病例中肺水腫之危險因子年齡小於三歲高血糖(150mg/dl)肢體無力 白血球升高 重症包含中樞神經受侵犯及肺水腫,第二期：腦膜腦炎,持續數天 包括睡眠易驚醒startling、手足抖動myoclonic jerk、肢體無力weakness 可能嘔吐、嗜睡 可能發生痙攣 腦脊髓液可能有發炎跡象亦可能無 到此仍可能自
15、然痊癒，或許有後遺症,第三A期：高血壓肺水腫出血自主神經失調？,持續約數小時至一天左右，民國八十七年肺水腫出血為最主要死因 血壓上升為最早徵兆、高燒、心搏過快200/min以上、呼吸急促、出冷汗。 高血糖(200mg/dl) 肺水腫、肺泡出血、血氧含量降低 神經症狀持續惡化，昏迷指數降低、四肢更無力,Lungs are congested,Red blood cells are found in small airways and alveoli,Parameters Sequence Around PE,Parameters Sequence (2),第三B期：低血壓：心臟衰竭,持續約二至七
16、天 心搏速率漸降但血壓可能更低 肺水腫出血漸好轉但仍需呼吸器，自呼能力差 血糖正常化 神經症狀之變化：垂直眼震顫、斜視、肢體無力、抽筋等，此期間腦灌流可能變差造成缺氧缺血性腦病變。,第四期：逐漸恢復,持續？月？年 心臟功能幾乎完全恢復 肺功能可能不好但足堪負擔換氣，然而病人自呼、吞嚥功能不好有嚴重影響，所以仍需呼吸器支持。 漸漸甦醒，神經可能有嚴重後遺症 可能發生反覆性肺炎。,I. Outbreaks II. 臨床分期及其表現 III. 呼吸衰竭的病生理學 IV. 治療的考量 V. 結論,Pathophysiology of Pulmonary Oedema,Starlings formula
17、 Flow=K(PcPis) (OncplOncis),Interstitium,Alveolus,Lymphatics,Pulmonary capillary,Pc,Pis,K,Oncpl,Oncis,O2,Hypotheses of the Mechanism of pulmonary oedema,SIRS/ARDS Neurogenic pulmonary edemaCardiogenic,Capillary permeability Systemic/pulmonary vasculer resistence LV systolic dysfunction LV diastolic
18、dysfunction,Evidence Supporting SIRS,Lin et al.,Evidences Related to Neurogenic Pulmonary Oedema,CNS involvement preceeds pulmonary oedema Increased cortisol level and clinical evidences suggested an autonomic nervous system dysfunction(increased sympathetic tone) Lack of study of pulmonary capillar
19、y permeability Systemic vascular resistence does not increase significantly.,Diffuse inflammatory cell infiltration in Cerebrum, midbrain and brain stem,Perivascular cuffing was also common,Cortisol Level vs. Vital Signs,Evidences Related to Cardiogenic,Increased pulmonary artery wedge pressure? Ech
20、o revealed systolic and diastolic dysfunction Hypertension associated Inappropriate tachycardia associated Increased cardiac enzymes However, autopsy findings are against myocarditis,Initial Swan-Ganz Monitor Data,Echocardiography Evidences,Systolic dysfunction: The initial ejection fraction: 18-75%
21、(meanSE=51.5 3.6%)(n=18) Diastolic dysfunction: Mitral flow velocities: E/A, DT, IVRT,E=peak velocity of the early filling wave, A=peak velocity of the late filling wave due to atrial contraction, DT=deceleration time, IVRT=isovolumic relaxation time Mitral annulus velocities: E/E, E=early diastolic
22、 annulus velocity(the rate of change in long-axis dimension and LV volume),Diastolic Function,PE: pulmonary oedema, HF: heart failure, HT: hypertension,Cardiac Enzymes,CKMB (normal16U/L): 4-92U/L, meanSE=31.177.73(n=12) Troponin I (normal2ng/ml): 0.4-50ng/ml, meanSE=21.924.36(n=17),Grossly, the hear
23、t is hypertrophic,Under microscope, there is no inflammatory change,I. Outbreaks II. 臨床分期及其表現 III. 呼吸衰竭的病生理學 IV. 治療的考量 V. 結論,When Patient Becomes Very Critical,Neurological deteriorates GCS9 Apnea, choke Unable to protect airway Paradoxical respiration Pulmonary oedema/hemorrhage develops Cardiovasc
24、ular system malfunctions: hypertension, tachycardia,Virus,SIRS,Cytokines,RV,LV,Neuromediator?,Change capillary permeability,Catecholamines,Diastolic dysfunction,Systemic vascular resistence,?Hypervolemia,?Systolic function,congestion,Virus,SIRS,Cytokines,RV,LV,Neuromediator?,Changed capillary permea
25、bility,Catecholamines,Diastolic dysfunction,Systemic vascular resistence,?Hypervolemia,?Systolic function,IVIG,diuretics,Dobutamine, milrinone,?vasodilator,Vaccine?,PPV,congestion,Steroid?,?clonidine,Stage Hand, foot & mouth disease and treatment,Characterized by fever, oral ulcer and skin rash Symp
26、tomatic treatment Aware high risk factors: age 39 lethargic vomiting limb weakness, seizure including myoclonic jerk hypertension? 4. Admit suspicious children,Stage CNS Involvement General Treatment,1. Admit to PICU p.r.n. 2. Monitor BP, HR, sugar, ABG, e, coma scale 3. Intubate patient and provide
27、 mechanical ventilator for GCS9 or significant IICP 4. IVIG: dosage? 5. Fluid restriction:1/2-2/3 maintenance, 6. Furosemide for patients with high CVP 7. Invasive monitorings: CVP ABP?,Stage CNS Involvement Specific Treatment for CNS,Anticonvulsants to control seizure Keep head in midline position
28、with 15-30 tilt Aggressively control body temperature Watch Increased ICP signs and give Mannitol or glycerol as needed Sedatives? midazolam, morphine or propofol Consult neurologists Monitoring: GCS, TCD, NIRS, ICP?, SjvO2?,Stage A: Treatment,Ristrict preload: Fluid restriction, diuretics Reduce af
29、terload cautiously?: BP ,with normal cardiac contractility : vasodilator or -blocker: XNitroprusside? 0.5-4mcg/kg/min XEsmolol? 50-300mcg/kg/min Milrinone 0.25-0.75 mcg/kg/minSedatives? midazolam, morphine or propofol Augment myocardium contractility Milrinone 0.25-0.75 mcg/kg/min Dobutamine 5-20 mc
30、g/kg/min,Stage A: Treatment,Mechanically Ventilated with PEEP:6-8cmH2O Consider HFOV when hypoxemia and hemorrhage persist despite PEEP 8cm H2O or MAP 15cm H2O Change IVF to NS when glucose 200mg%, and shift to D2.5HS when glucose drops to 200mg% Anticipate the drop of BP when hyperglycemia corrects
31、. Steroids? Central Antisympathetics?,0 0.2 0.4 0.6 0.8 1.0 1.2 1.4,Seconds,30 25 20 15 10 8 6,Airway pressure(cmH2O),oscillator,PPV,Mean airway pressure,PIP,PEEP,P,Stage B Hypotension: treatment,Maintain adequate cerebral and vital organ perfusion during hypotension, optimize preload, afterload and
32、 myocardium contractilityInotropesdopamine 5-20mcg/kg/minepinephrine 0.05-0.4(?)mcg/kg/min Due to intrinsic catecholamine depletion, HIGH infusion rate of inotropes may be needed to keep adequate BP 2. ECMO and ventricular assist device?,Stage B Hypotension: treatment,Wean ventilator as tolerated, s
33、witch back to conventional ventilator when MAP15cmH2O CNS evaluation: cerebral perfusion? Add glucose in IVF when sugar drops to about under 200mg%,Stage Convalescence-Treatment,Wean off inotropes Tracheostomy for ventilator dependent patients Chest care is mandatory to avoid aspiration pneumonia Sw
34、allowing disturbancetube feeding (gastric or duodenum) Rehabilitation Refer to respiratory care center or home care,Outcome(2000-2001),*died or vegetate state, withdrawn, *moderate sequela, ventilator dependent, *mild to moderate sequela, partial ventilator dependent, *minimal sequela, RCC: respirat
35、ory care center, RCW: respiratory care ward.,Gr 1 2 3 4 p-value,CPR ever Age(M) Neutral Ab CSF WBC CKMB Troponin I EF% 0 GCS 0 IE Resuscitate Fluid(ml/kg),7/8 1/5 0 0 0.01,36.411.8 15.62.4 12.33.7 9.02.2 0.05,88 11.7 70.4 15.7 53.3 37.3 102 17 0.17,140.4 30.3 84 32.1 9.3 3.3 16.2 6.4 0.05,49.7 25.5
36、34.7 15.3 15 5 22.8 7.5 0.5,42.3 6.8 20.9 6.0 9.9 3.3 8.1 2.8 0.001,44.8 9.4 40.2 5.0 64 1.7 59.2 5.1 0.05,9.3 1.3 12.6 0.9 8.6 0.7 10.2 1.28 0.21,the first value around admission to PICU or ER, IE(inotrope equivalent)=infusion rate of dopamine+dobutamine+100xepinephrne+10xmilrinone mcg/kg/min,38.95
37、.68 56.93.8 33.35.8 10.33.4 0.001,42.1 10.1 53.8 15.6 63.7 6.8 45 19.3 0.74,Gr 1 2 3 4 p-value,BP 0 3A hours 3B hours Sugar 0 Sugar200(h) HR 0 HR180h P/F 0 P/F min P/F300h,2.4 1.2 5.6 2.0 4.3 2.8 76.4 30.7 0.05,93.6 42.3 200.9 34.4 149.1 35.7 35.6 14.3 0.05,2.6 0.8 5.1 1.4 2.8 1.5 5.7 2.4 0.5,21.3 1
38、3.6 38.7 8.2 10.1 3.2 10.4 3.1 0.24,53.1 20.9 106.35 53.5 27.33 1.5 51.0 30.6 0.5,93.9 4.0 118 14.2 118 9.0 124 10.2 0.05,373.1 58.9 281.6 47.5 226 29.2 233.7 38.7 0.05,171.5 16.0 158.8 20.0 176.7 21.2 174.3 15.7 0.9,134 33.2 329.0 61.9 167.4 31.3 203.6 27.9 0.05,the first value around admission to
39、PICU or ER, P/F=PaO2FiO2, *P=0.055,83.7 18.1* 128.6 37.7 99 47.6 203 27.9 0.05,Conclusions(1),Most EV71 infected critically ill children presented a clinical course with clear-cut stages. Different stages may need different therapeutic considerations and monitoring. The prognosis of EV71 infected ch
40、ildren is related with the damages of respiratory, cardiovascular and cerebral systems. An early intensive care maybe the major cause in that patients of 2000-2001 had a better outcome than of 1998,Conclusions(2),Almost all patients ever experienced CPR died eventually. The mean duration before CPR
41、occurred is 7.12.4hours which is too short to wait for all risk factors present. ECMO or LVAD should be considered in the beginning for patients with evidence of severe heart injury such as Troponin40, significantly compromised systolic/diastolic function and shock.,Conclusion(3),The following actio
42、ns are important in managing the respiratory failure on children with EV 71 infection Hospitalize children with risky clinical signs. Early identification of the development of pulmonary oedema and hemorrhage Anticipation of heart failure and optimize the use of inotropes Prevent recurrent pneumonia in convalescent stage. Vaccination may be the way out to avoid repeated tragedies every year.,
