新光醫院感染科敗血症標準作業流程 severe sepsis and septic shock 黃建賢

SEPSIS DEFINITIONS microbes involves a rapidly amplifying polyphony of signals and responses that may spread beyond the invaded tissue.

1. 敗血症的定義 敗血症的定義 1.1宿主因微生物感染大量繁殖並造而造成全身性症狀，臨床上可表現出發燒，低體溫，寒顫，呼吸加速，心搏加速，宿主因為微生物的侵犯而表現出”系統性發炎反應症候群”(systemic inflammatory response syndrome，SIRS) 1.2 ”系統性發炎反應症候群”定義為包函下列或兩者以上 1.2.1 體溫38度C以上或36度C以下 1.2.2 心跳速度超越每分鐘90下 1.2.3 呼吸速率超越每分鐘20下 1.2.4 血液中白血球大於每毫升12000或小於每毫升4000或含百分之10以上之不成熟白血球(bands)

ETIOLOGY gram-negative and gram-positive bacteria fungi, mycobacteria, rickettsiae, viruses, or protozoans… Positive blood cultures : 30 to 60 % of patients with sepsis 60 to 80 % of patients with septic shock

Sepsis

Definitions Used to Describe the Condition of Septic Patients Bacteremia Systemic inflammatory response syndrome (SIRS) Sepsis Severe sepsis Septic shock Multiple-organ dysfunction syndrome (MODS) Presence of bacteria in blood Fever, tachypnea, tachycardia, leukocytosis/leukopenia SIRS has a proven or suspected microbial etiology Sepsis with ≥1 signs of organ dysfunction Sepsis with hypotension or need for vasopressor Dysfunction of ≥1 organ

Epidemiology of Sepsis in the United States from 1979-2000 N Engl J Med 2003; 348: 1546-54.

EPIDEMIOLOGY 2/3: in hospitalized patients. Risk Factors to GNB bacteremia diabetes mellitus lymphoproliferative diseases cirrhosis of the liver burns invasive procedures or devices drugs that cause neutropenia

EPIDEMIOLOGY Risk factors for GPC bacteremia Fungemia : vascular catheters, indwelling mechanical devices, burns, intravenous drug injection. Fungemia : immunosuppressed patients neutropenia broad-spectrum antimicrobial therapy TPN Intestinal perforation

PATHOPHYSIOLOGY Endotoxin Gram negative bacilli Lipopolysaccharide (LPS, also called endotoxin)

PATHOPHYSIOLOGY Microbial signals Gram positive cocci peptidoglycan and lipoteichoic acids extracellular enzymes

敗血症的症狀 Fever or hypothermia (low body temperature) Hyperventilation Chills Shaking Warm skin Skin rash Rapid heart beat Confusion or delirium Decreased urine output

CLINICAL MANIFESTATIONS S/S: fever, chills, tachycardia, tachypnea, altered mental status, and hypotension. afebrile common in neonates, in elderly patients and in persons with uremia or alcoholism.

CLINICAL MANIFESTATIONS Llaboratory finding: C-reactive protein fibrinogen complement components transferrin inhibits albumin synthesis Leukocytosis, left shift

LABORATORY FINDINGS Early sepsis leukocytosis with a left shift Respiratory alkalosis Thrombocytopenia Hyperbilirubinemia proteinuria. neutrophils may contain toxic granulations, Dohle bodies, or cytoplasmic vacuoles

LABORATORY FINDINGS Progressing of sepsis: thrombocytopenia worsens prolongation of the thrombin time decreased fibrinogen presence of D-dimers, suggesting DIC) Azotemia, hyperbilirubinemia become prominent Elevated GOT GPT

LABORATORY FINDINGS Progressing sepsis: hyperventilation induces respiratory alkalosis. accumulation of lactate, metabolic acidosis (with increased anion gap) hyperglycemia, severe infection may precipitate diabetic ketoacidosis(DKA)

Multiple organ dysfunction syndrome MOF: Dysfunction or failure of multiple organs reflecting widespread vascular endothelial injury associated with high fatality rates. Mortality and morbidity correlate with the number of organs affected.

DIAGNOSIS S/S --Progressing sepsis tachypnea, tachycardia, altered mental status, The septic response can be quite variable systemic inflammatory response syndrome SIRS

DIAGNOSIS Definitive diagnosis isolation of the microorganism from blood or a local infected site Gram's stain culture of the primary site of infection.

TREATMENT Sepsis may be fatal quickly. Successful management urgent measures to treat the local site of infection, hemodynamic and respiratory support eliminate the offending microorganism Therapy of acidosis and DIC, other complications

TREATMENT Outcome influenced by the patient's underlying disease aggressively treated. Antimicrobial agents

PROGNOSIS Mortality: More than 25 % 1/3 within the first 48 h mortality can occur 14 or more days later. Late deaths poorly controlled infection complications of intensive care multiple organs failure

2.敗血症初期之緊急處理 2.1 敗血症最初七小時之緊急處理措施著眼於恢復因敗血症所引起的低血流灌注，恢復組織功能，應包含以下所有之緊急處理 2.1.1 中心靜脈壓維持8-12mmHg 2.1.2 平均動脈壓維持大於等於65 mmHg 2.1.3 小便量維持大於等於每小時每公斤體重0.5毫升 2.1.4 中心靜脈氧飽含量維持大於等於70﹪

2.敗血症初期之緊急處理 2.2 臨床檢驗 2.2.1由周邊靜脈至少抽取2至3套血液培養後盡快給予抗生素治療 2.2.2盡快找尋可能之感染部位並取得檢體，如導管相關之感染，呼吸器相關之肺炎等 2.2.3在抗生素使用前須取得可能感染部位之培養檢體，如尿液，腦脊髓液，傷口，呼吸道檢體或其他部位之組織液 2.2.4必要時可作血清學檢查、檢測抗體及抗原或檢測尿液中退伍軍人菌抗體

2.敗血症初期之緊急處理 2.2 臨床檢驗 2.2.5如有液狀檢體，可作染色鏡檢如葛蘭氏染色，抗酸菌染色等 2.2.6軟組織感染時，除了做血液培養外，盡可能取得檢體做染色鏡檢 2.2.7必要時可在主治醫師同意下對病灶施行超音波檢查，電腦斷層或核 磁共振檢查以確立病灶及嚴重程度 2.2.8必要時可對病灶做抽吸或切片檢查以取得檢體 2.2.9如病灶有明顯積液、必要時可施以抽吸引流或外科治療

3.抗生素療法 3.1抗生素治療必須在取得適當檢體後盡快給予 3.2當病患有嚴重敗血症或敗血性休克時，要盡速給予體液補充，除非有相當禁忌症(如急性肺水腫等) 3.3抗生素經驗療法必須依社區或院內感染，感染部位、菌種、抗生素穿透能力及疾病人實際狀況來給予(參考本院每半年出版之菌種及抗生素敏感試驗表) 3.3.1抗生素治療以一種抗生素為原則 3.3.2必要時可以合併抗生素使用以治療混合型感染或加強抗生素療效 3.3.3抗生素之選擇依病人過去病史，過敏史，合併疾病，合併症及臨床抗生素敏感性做選擇

3.抗生素療法 3.4抗生素治療必須在使用48小時至72小時後重新評估 3.4.1依細菌培養及抗生素敏感性試驗之結果做調整 3.4.2以窄效性抗生素為原則 3.4.3為避免抗藥性產生，抗生素之選擇以低毒性及同類藥中價廉為原則 3.4.4治療以7-10天為原則，必要時可延長之 3.4.5抗生素之使用及停用以培養結果及臨床醫師判定為原則

4 控制病源 4.1臨床上所有敗血症病患均盡量查出並除去感染源 4.1.1必要時以引流、清創或外科手術行之 4.1.2病患有外科手術需求時，必須在完成初步急救並解釋病情之後、在家屬同意下、盡速施行之

5 輸液治療 5.1輸液治療包括自然血漿，人工血漿及一般輸液 5.2 個人體液需求量依個體及疾病狀況不同依臨床狀況做調整 5.1.1人工輸液較血漿易出現水份積蓄及水腫 5.1.2輸液速度以每30分鐘輸人工輸液300至1000毫升、或血漿以每30分鐘300至500毫升為主 5.1.3輸液速度及輸液量以臨床反應、血壓及尿液量做調整 5.1.4密切監視病患以避免出現肺水腫及其他併發症 5.2 個人體液需求量依個體及疾病狀況不同依臨床狀況做調整

6 血管收縮劑 6.1 當病患經輸液治療後仍無法維持適當的血壓及組織灌流時得使用血管收縮劑治療 6.2 當低血壓足以危及生命時，血管收縮劑得以和輸液治療同時給予 6.3 Nor-epinephrine或dopamine須以中心靜脈方式給予 6.4 使用血管收縮劑病患得施行動脈血壓監測 6.5 Nor-epinephrine起始劑量以0.01至0.04 units/分為原則 6.6 Cardiac index在2.5 L.min-1.m2以下者不宜使用血管收縮劑

7 升壓劑(Dobutamine) 7.1 病患在經適當輸液治療後仍無法維持正常之輸出量時得以使用升壓劑，必要時得合併血管收縮劑使用

8 類固醇 8.1 休克病患在適當補充輸液，使用血管升壓劑後，仍無法維持正常血壓時得以使用類固醇 8.2 劑量以每天hydrocortisone200至300毫克，分3至4次給予，使用7天為原則、必要時得延長之 8.3 病患在檢測ATCH前得以使用dexamethasone取代hydrocortisone以免影響血中cortisol濃度檢測值 8.4 敗血症病患未合併休克時，不建議使用類固醇

9 人類活性C蛋白使用 9.1 高死亡率之多重器官衰竭、敗血性休克、成人呼吸窘迫症病患，無出血傾向時、APACHEII score>=25、在主治醫師同意下得以使用人類活性C蛋白(rhAPC)

10 血類製劑 10.1 無特殊禁忌症之敗血症病患在血色素7.0g/dl以下時得以輸血 10.2 輸血目標值為血色素7.0至9.0g/dl 10.3 病患無明顯出血時、不建議以冷凍新鮮血漿來改善血液中之凝血值 10.4不論有無出血現象，嚴重敗血症病患得以輸用血小板以維持血小板值在5000/mm3以上(5×10-9/L)

11 呼吸器使用 11.1 呼吸器使用依本院呼吸器使用原則，及成人呼吸窘迫症呼吸器使用原則行之

12 鎮靜劑麻醉藥品及肌肉鬆弛劑使用 12.1 嚴重敗血症病患合併呼吸衰竭及呼吸器使用時、得依本院藥物使用規範使用鎮靜劑麻醉藥物及肌肉鬆弛劑 12.2 必要時得以會診麻醉科、以進行藥物調整及避免藥物副作用

13 血中葡萄糖控制 13.1 敗血症病患須嚴密監測並控制血糖 13.2 血中葡萄糖控制以200 mg/dl以下為原則(有嚴格監測時得控制在140 mg/dl以下) 13.3 必要時得以使用胰島素取代口服降血糖藥控制血糖

14 碳酸鹽治療 14.1 碳酸鹽治療得以使用於敗血症合併血流灌注所引起之酸中毒 14.2 碳酸鹽治療酸中毒以pH值7.3以下為原則 14.3 嚴重敗血症病患得使用低劑量肝素或低分子量肝素預防深部靜脈血栓形成 14.4 病患有出血傾向或其他禁忌症時應避免使用肝素

15 預防壓力性腸胃道潰瘍 15.1 所有敗血症病患均應預防壓力性潰瘍之產生 15.2 以使用H2 receptor抑制劑為原則，有禁忌症或不適用者除外

16 褥瘡之預防 16.1 敗血症合併活動能力降低之病患、應預防褥瘡之產生 16.2 臨床上依預防褥瘡形成臨床技術手冊行之 16.3 褥瘡之治療、必要時可給予抗生素及施行清創手術

Epidemiology of Sepsis in the United States from 1979-2000 Causative Organisms Gram-positive bacteria 52.1% Gram-negative bacteria 37.6% polymicrobial infections 4.7% anaerobes 1.0% fungi 4.6% Specific organisms causing sepsis were recorded in 51% of all discharge records over the 22-year period. N Engl J Med 2003; 348: 1546-54.

Antimicrobial Agents in the Management of Sepsis Two blood culture one percutaneous one from each vascular access >48 hrs one or more drugs active against likely bacterial or fungal pathogens consider microbial susceptibility patterns Begin IV antibiotics within the first hr of recognition of severe sepsis microbial and clinical data narrow-spectrum antibiotics non-infectious cause identified prevent resistance, reduce toxicity and reduce cost Reassess antimicrobial regimen at 48-72 hrs Evaluate patient for a focused infection Crit Care Med 2004; 32: 858-73.

Vasopressor and Inotropics Norepinephrine 4 mg/4 ml/amp (diluted by D5W) - 0.03~3.3 μg/kg/min (2~200 μg/kg/hr) Epinephrine 1 mg/1 ml/amp - 0.06~0.47 μg/kg/min (3.6~30 μg/kg/hr) Dopamine 200 mg/5 ml/amp 2~55 μg/kg/min (0.12~3.3 mg/kg/hr) Dobutamine 250 mg/20 ml/amp 2~28 μg/kg/min (0.12~1.68 mg/kg/hr) Vasopressin 20 U/1 ml/amp 0.01~0.04 U/min (0.6~2.4 U/hr) Crit Care Med 2004; 32: 1928-48.

Role of Corticosteroid in the Management of Septic Shock Treat patients who still require vasopressors despite fluid replacement with hydrocortisone 200-300 mg/day for 7 days divided in 3-4 doses or by continuous infusion (Grade C) High dose of corticosteroids (> 300 mg/day) should NOT be used in severe sepsis or septic shock. (Grade A) Crit Care Med 2004; 32: 858-73.

Role of Corticosteroid in the Management of Septic Shock In the absence of shock, corticosteroids should NOT be administrated for the treatment of sepsis (Grade E) The use of ACTH stimulation test to identify responders (>9 μg/ml increase in cortisol 30-60 mins post-ACTH administration) and to continue therapy is optional. Should NOT wait for ACTH stimulation results to administer corticosteroids Crit Care Med 2004; 32: 858-73.

Mechanical Ventilation of Sepsis-induced ALI/ARDS High tidal volume that are coupled with high plateau pressures should be avoided in ALI/ARDS. reduce tidal volume over 1-2 hrs to 6 ml/kg predicted body weight maintain inspiratory plateau pressure <30 cmH2O maintain SaO2/SpO2 88-95% anticipated PEEP settings at various FiO2 requirements FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 PEEP 5 5 8 8 8 10 10 12 14 14 14 16 18 20-24 (Grade B) Crit Care Med 2004; 32: 858-73.

Intensive Insulin in Critical Ill Patients After initial stabilization of patients with severe sepsis maintain glucose <150 mg/dl by continuous infusion of insulin monitor blood glucose every 30-60 mins and then q4h (Grade D) In patients with severe sepsis, a strategy of glycemic control should include a nutrition protocol with the preferential use of the enteral route. (Grade E) Crit Care Med 2004; 32: 858-73.

Intensive Insulin in Critical Ill Patients prospective, randomized, controlled trial adults admitted to SICU (N= 1,548) who were receiving MV adults admitted to MICU (N= 1,200) who were considered to need ICU care for at least 3 days 50 IU actrapid HM/ 50 ml NS infused by pump (max. dose 50 IU/hr) intensive insulin (blood glucose ~80-110 mg/dl) conventional treatment (blood sugar ~180-200 mg/dl) primary endpoint: ICU mortality/in-hospital mortality N Engl J Med 2006; 354: 449-61.

Intensive Insulin in Critical Ill Patients Mortality 8.0% vs 4.6% 10.9% vs 7.2% 26.8% vs 24.2% 38.1% vs 31.3%* 40.0% vs 37.3% 52.5% vs 43.0%* RRR 42.5% 33.9% 9.7% 17.8% 6.8% 18.1% ARR 3.4% 3.7% 2.6% 6.8% 2.7% 9.5% NNT 29 27 - 14 10 P value <0.04 0.01 0.31 0.05 0.33 0.009 Surgical ICU ICU death In-hospital death Medical ICU N Engl J Med 2001; 345: 1359-67. N Engl J Med 2006; 354: 449-61. * patients who stayed in the ICU ≥3 days

Advances in Therapy for Severe Sepsis and Septic Shock Time-sensitive intervention Early goal-directed therapy Drotrecogin alfa (activated) for high-risk patients Low-dose steroids Low tidal volume ventilation Tight blood sugar control Mortality reduction (ARR) 16% (P= 0.009), NNT= 6 13% (P= 0.001), NNT= 8 10% (P= 0.023), NNT= 10 10% (P= 0.005), NNT= 10 3.4% (P= 0.005), NNT= 29 JAMA 2002; 288: 862-71. N Engl J Med. 2000; 342: 1301-8. N Engl J Med. 2001; 345: 1359-67. N Engl J Med. 2001; 345: 1368-77. N Engl J Med. 2001; 344: 699-709.

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