SEPSIS & SEPTIC SHOCK DIDI CANDRADIKUSUMA
Divisi Penyakit Tropik - Infeksi Lab/SMF Ilmu Penyakit Dalam
Terminologi • Infeksi : beradanya microorganisme seperti bakteri, jamur, virus, protozoa, dengan disertai respon inflamasi dan multiplikasi dari organisme tersebut, pada jaringan Host yang dalam keadaan normal seharusnya steril • Bakteremia : adanya bakteri “viabel”dalam darah
Terminologi • SIRS (Systemic Inflammatory Response Syndrome) : Respon Inflamasi Sistemik terhadap berbagai clinical insult yang berat, ditandai oleh dua atau lebih gejala-gejala berikut : » Suhu tubuh > 38o C atau < 36o C » Denyut jantung > 90 / menit » Respirasi > 20 / menit atau PaCO2 < 32 mm Hg » Sel darah putih > 12.000 / mm3 atau < 4000 / mm3, atau > 10% bentuk imatur (stab = band) • Sepsis : SIRS yang penyebabnya karena infeksi
Terminologi • Severe Sepsis : Sepsis yang disertai gangguan fungsi organ, hipoperfusi atau hipotensi • Septic Shock : Sepsis dengan hipotensi (sistolik < 90 mm Hg atau penurunan 40 mm Hg dari data dasar), setelah pemberian cairan resusitasi yang adekwat, disertai tanda-tanda hipoperfusi • MODS (Multiple Organ Dysfunction Syndrome) : Gangguan fungsi organ pada seorang yang sakit berat, dimana homeostasis tidak dapat dipertahankan tanpa intervensi
Hubungan SEPSIS dan SIRS
Surgical Sepsis
Infection
DM
Severe Sepsis MOF
Pancreatitis
SIRS
Trauma Burn
SEPSIS: DEFINING A DISEASE CONTINUUM
Infection/ Trauma
SIRS
A clinical response arising from a nonspecific insult, including 2 of the following: – – – –
Sepsis Severe Sepsis SIRS related to infection (suspected or confirmed)
Temperature ≥38oC or ≤36oC HR ≥90 beats/min Respirations ≥20/min WBC count ≥12,000/mm3 or ≤4,000/mm3 or >10% immature neutrophils
SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644.
SEPSIS: DEFINING A DISEASE CONTINUUM
Infection/ Trauma
SIRS
Sepsis Severe Sepsis
Sepsis with organ failure (one or more) Cardiovascular (hypotension) Renal Respiratory Hepatic Hematologic CNS Unexplained metabolic acidosis Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.
Injury
Infection Non Infection
LPS
( lipopolysaccharide )
Complement System Phagocyte cells
Rapid Inflammatory Reaction
Monocytes and Macrophages Sitokine pro inflammatory secretion Inflammatory Cascade (Mediator, Neutrofil, Endothel Platelet, Fibroblast)
Delayed Inflammatory Response
P H Y S I O L O G I C P A T H O L O G I C
Injury
Local Inflammatory Restricted Systemic
Exaggerated Systemic Sepsis / SIRS
Tahap-tahap SEPSIS / SIRS 1 • Tahap I Injury Sitokin proinflamasi mediator dan sel melawan organisme patogen • Tahap II Sebagian sitokin ke sirkulasi merekrut makrofag dan platelet stimulasi growth factor rapid inflammatory reaction. Sampai tahap II ini fisiologik, dikendalikan oleh sitokin anti inflamasi
Tahap-tahap SEPSIS / SIRS • Tahap III Clinical insult terlalu besar Sistem pengendalian tubuh tidak normal homeostasis tak dapat dipertahankan efek sitokin destruktif kerusakan organ yang jauh dari tempat infeksi MODS MOFS Perubahan yang terjadi Progressive endhotelial dysfunctions permeabilitas pembuluh darah meningkat. Platelet sludging gangguan sirkulasi maldistribusi aliran darah, iskemia dan reperfusion injury Aktivasi sistem koagulasi Vasodilatasi, transudasi cairan dan maldistribusi aliran darah syok
Tahap-tahap SEPSIS / SIRS • Tahap IV Terjadi kompensasi reaksi anti inflamasi yang berlebihan imunosupresi / immune paralysis / CARS ( Compensated Anti inflammatory Response Syndrome) CARS ditandai : Penurunan ekspresi HLA – DR < 30% pada permukaan monosit penurunan sekresi TNF dan IL-6 anergi mudah terkena infeksi. • Tahap V
Tahap akhir dari MODS immunologic dissonance Penyebabnya : Inflamasi yang berlebihan Depresi imun yang persisten
Pro-inflammatory response
Initial insult (bacterial, viral, traumatic, thermal)
Systemic spillover of pro-inflammatory mediators
anti-inflammatory response
Systemic spillover of anti-inflammatory mediators
Systemic Reaction SIRS (pro-inflammatory) CARS (antipro-inflammatory) MARS (mixed)
Cardiovascular Compromise (shock) SIRS Predominates
Homeostais
Apoptosis (cell death)
Organ dysfunction
CARS and SIRS Balanced
Death with minimal inflammation
SIRS Predominates
Suppression of the immune system CARS Predominates
Treatment of Sepsis
SEVERE SEPSIS: EARLY RECOGNITION • SIRS Criteria: – – – –
Fever Tachypnea Tachycardia Leukocytosis or leukopenia
• Organ Failures: – Respiratory • paO2:FiO2 < 300
– Cardiovascular • SBP < 90 mm Hg after IVF
– Renal • U/O < 30 mL/hr
– CNS • Delirium
– Metabolic • Lactate > 4 mmol/L, or anion gap metabolic acidosis
HOMEOSTASIS IS LOST IN SEPSIS
Proinflammatory mediators
Endothelial injury
Tissue factor expression
Thrombin production
Homeostasis
Increased PAl-1
Increased TAFIa
Reduced Protein C (endogenous Activated Protein C inhibits PAI-1)
PAI-1= plasminogen activator inhibitor-1;TAFIa= thrombin activatable fibrinolysis inhibitor. Carvalho and Freeman. J Crit Illness. 1994;9:51; Kidokoro et al. Shock. 1996;5:223; Vervloet et al. Semin Thromb Hemost. 1998;24:33.
SEVERE SEPSIS: A VICIOUS CYCLE OF INFLAMMATION AND COAGULATION
Infection
Inflammation
Ischemia
Organ Failure Coagulation
Endothelial Dysfunction
Death
Inflammation Coagulation
Inflammation
Inflammation Coagulation Esmon. Immunologist. 1998;6:84.
INTERVENTIONS IN SEVERE SEPSIS
• What is harmful? • What doesn’t work? • What might / probably works? • What does work?
Initial Resuscitation (first 6 hours) • Begin resuscitation immediately in patients with hypotension or elevated serum lactate >4mmol/l; do not delay pending ICU admission • Resuscitation goals: - Central venous pressure (CVP) 8–12 mm Hg* - Mean arterial pressure ≥ 65 mm Hg - Urine output ≥ 0.5 mL.kg-1.hr-1 - Central venous (superior vena cava) oxygen saturation ≥ 70%, or mixed venous ≥ 65% • If venous O2 saturation target not achieved: consider further fluid transfuse packed red blood cells if required to hematocrit of ≥ 30% and/or dobutamine infusion max 20 μg.kg-1.min-1 • A higher target CVP of 12-15 mmHg is recommended in the presence of mechanical ventilation or pre-existing decreased ventricular compliance
Diagnosis • Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration - Obtain two or more blood cultures (BCs) - One or more BCs should be percutaneous - One BC from each vascular access device in place >48 hours - Culture other sites as clinically indicated • Perform imaging studies promptly in order to confirm and sample any source of infection (if safe to do so)
Antibiotics Begin intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis and septic shock – Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source – Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity & minimize costs
Antibiotics • Consider combination therapy in Pseudomonas infections • Consider combination empiric therapy in neutropenic patients • Combination therapy no more than 3-5 days and deescalation following susceptibilities • Duration of therapy typically limited to 7–10 days; longer if response slow, undrainable foci of infection, or immunologic deficiencies • Stop antimicrobial therapy if cause is found to be noninfectious
Source Infection and Control • A specific anatomic site of infection should be established as rapidly as possible and within the first 6 hours of presentation • Formally evaluate patient for a focus of infection amenable to source control measures (e.g. abscess drainage, tissue debridement) • Implement source control measures as soon as possible following successful initial resuscitation • Exception: infected pancreatic necrosis, where surgical intervention best delayed • Choose source control measure with maximum efficacy and minimal physiologic upset • Remove intravascular access devices if potentially infected
Fluid Therapy • Fluid-resuscitate using crystalloids or colloids • Target a CVP of ≥ 8mmHg (≥12mmHg if mechanically ventilated) • Use a fluid challenge technique while associated with a hemodynamic improvement • Give fluid challenges of 1000 ml of crystalloids or 300– 500 ml of colloids over 30 minutes. More rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion • Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement
Vasopressors • Maintain MAP ≥ 65mmHg • Norepinephrine or dopamine centrally administered are the initial vasopressors of choice • Epinephrine, phenylephrine or vasopressin should not be administered as the initial vasopressor in septic shock • Vasopressin 0.03 units/min maybe subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone • Use epinephrine as the first alternative agent in septic shock when • blood pressure is poorly responsive to norepinephrine or dopamine • Do not use low-dose dopamine for renal protection • In patients requiring vasopressors, insert an arterial catheter as soon as practical
Inotropic Therapy • Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output • Do not increase cardiac index to predetermined supra-normal levels
Steroids • Consider intravenous hydrocortisone for adult septic shock when hypotension remains poorly responsive to adequate fluid resuscitation and vasopressors - ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone - Hydrocortisone is preferred to dexamethasone - Fludrocortisone (50 μg orally once a day) may be included if an alternative to hydrocortisone is being used which lacks significant mineralocorticoid activity - Steroid therapy may be weaned once vasopressors are no longer required - Hydrocortisone dose should be <300mg/day
• Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s endocrine or corticosteroid history warrants it
Recombinant Human Activated Protein C (rhAPC) • Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II ≥ 25 or multiple organ failure) if there are no contraindications
• Adult patients with severe sepsis and low risk of death (typically, APACHE II <20 or one organ failure) should not receive rhAPC
Blood Product Administration • Give red blood cells when hemoglobin decreases to <7.0 g/dl (<70 g/L) to target a hemoglobin of 7.0 – 9.0 g/dl in adults. • A higher hemoglobin level may be required in special circumstances (eg: myocardial ischemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease or lactic acidosis) Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures
• Do not use anti-thrombin therapy • Administer platelets when: Counts are <5000/mm3 (5 X 109/L) regardless of bleeding. Counts are 5000 to 30,000/mm3 (5–30 X 109/L) and there is significant bleeding risk. Higher platelet counts ≥ 50,000/mm3 (50 X 109/L) are typically required for surgery or invasive procedures
Mechanical Ventilation of Sepsis-induced Acute Lung Injury (ALI)/ARDS • Target a tidal volume of 6ml/kg (predicted) body weight in patients with ALI/ARDS • Target an initial upper limit plateau pressure ≤30cmH2O. Consider chest wall compliance when assessing plateau pressure • Allow PaCO2 to increase above normal, if needed to minimize plateau pressures and tidal volumes • Positive end expiratory pressure (PEEP) should be set to avoid extensive lung collapse at end-expiration o Consider using the prone position for ARDS patients requiring potentially injurious levels of FiO2 or plateau pressure, provided they are not put at risk from positional changes • Maintain mechanically ventilated patients in a semi-recumbent position unless contraindicated • Suggested target elevation 30 - 45 degrees o Non invasive ventilation may be considered in the minority of ALI/ARDS patients with mild-moderate hypoxemic respiratory failure. The patients need to be haemodynamically stable, comfortable, easily arousable, able to protect/clear their airway and expected to recover rapidly
Mechanical Ventilation of Sepsis-induced Acute Lung Injury (ALI)/ARDS • •
•
• •
Use a weaning protocol and a spontaneous breathing trial (SBT) regularly to evaluate the potential for discontinuing mechanical ventilation SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T-piece. Before the SBT, patients should: Be arousable Be hemodynamically stable without vasopressors Have no new potentially serious conditions Have low ventilatory and end-expiratory pressure requirement Require FiO2 levels that can be safely delivered with a face mask or nasal cannula Do not use a pulmonary artery catheter for the routine monitoring of patients with ALI/ARDS Use a conservative fluid strategy for patients with established ALI who do not have evidence of tissue hypoperfusion
Sedation, Analgesia, and Neuromuscular Blockade • Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients • Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily interruption/lightening to produce awakening. Re-titrate if necessary
• Avoid neuromuscular blockers where possible. Monitor depth of block with train-offour when using continuous infusions
Glucose Control • Use IV insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU • Aim to keep blood glucose 150 mg/dL (<8.3 mmol/L) using a validated protocol for insulin dose adjustment • Provide a glucose calorie source and monitor blood glucose values every 1-2 hours (4 hours when stable) in patients receiving intravenous insulin • Interpret with caution low glucose levels obtained with point of care testing, as these techniques may overestimate arterial blood or plasma glucose values
Renal Replacement o Intermittent haemodialysis and continuous veno-venous haemofiltration (CVVH) are considered equivalent o CVVH offers easier management in hemodynamically unstable patients
Bicarbonate Therapy • Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-induced lactic academia with pH ≥ 7.15
Deep Vein Thrombosis (DVT) Prophylaxis • Use either low-dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH), unless contra-indicated • Use a mechanical prophylactic device, such as compression stockings or an intermittent compression device, when heparin is contra - indicated
o Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for DVT o In patients at very high risk LMWH should be used rather than UFH
Stress Ulcer Prophylaxis • Provide stress ulcer prophylaxis using H2 blocker or proton pump inhibitor • Benefits of prevention of upper GI bleed must be weighed against the potential for development of ventilator-associated pneumonia
Consideration for Limitation of Support • Discuss advance care planning with patients and families • Describe likely outcomes and set realistic expectations
KASUS 1 • Seorang laki-laki, 60 tahun, datang ke IRD dengan keluhan tidak sadar. Kesadaran menurun sejak sehari sebelum Masuk RS. Sebelumnya sejak 2 minggu ini kaki kanan penderita bengkak kemerahan dan nyeri setelah mengalami luka akibat kecelakaan lalu lintas. Pada pemeriksaan didapatkan kesadaran somnolens, Tekanan Darah 85/50 mmHg, Nadi 112 x / menit, tempertur axilla 39˚C, pernafasan Kussmaul dengan RR 32x/menit. Pemeriksaan laboratorium: Hb 12.4, lekosit 15.800, trombosit 174.000, stab 80%, asidosis metabolik, penurunan fungsi ginjal, icterus (+).
• Problem apa saja yang terjadi pada pasien ini? • Apa kemungkinan diagnosis penderita ini dan diferensial diagnosisnya • Bagaimana patofisiologi terjadinya kondisi pada pasien ini? • Bagaimana penatalaksanaan pasien ini? • Apa saja kemungkinan yang bisa terjadi pada pasien ini?
KASUS 2 • Seorang laki-laki, 45 th, datang ke IGD dengan keluhan nyeri perut sejak sehari sebelumnya. Nyeri di perut atas, mual, muntah. Pada pemeriksaan didapatkan KU lemah, GCS 4-5-6, T 90/60, N 106x/mnt, nyeri epigastrium (+), tampak jejas di perut kiri atas. Lab: Hb 13,5, leko 13.200, Tr 180.000, kadar amilase dan lipase meningkat 5x
• Problem apa saja yang terjadi pada pasien ini? • Apa kemungkinan diagnosis penderita ini dan diferensial diagnosisnya • Bagaimana patofisiologi terjadinya kondisi pada pasien ini? • Bagaimana penatalaksanaan pasien ini? • Apa saja kemungkinan yang bisa terjadi pada pasien ini?
KASUS 3 • Wanita 60 tahun datang ke RS dengan keluhan kesadaran menurun, tidak mau makan 3 hari ini, batuk berdahak (+),mual, muntah, panas (+). DM (+), HT (+). Pemeriksaan fisik: Kes somnolens, T 100/70, N 108, t 38, Rh +/+, wh -/-, H/L ttb. Lab: Hb 11,8, leko 12.100, Tr 208.000, GDA 435
• Problem apa saja yang terjadi pada pasien ini? • Apa kemungkinan diagnosis penderita ini dan diferensial diagnosisnya • Bagaimana patofisiologi terjadinya kondisi pada pasien ini? • Bagaimana penatalaksanaan pasien ini? • Apa saja kemungkinan yang bisa terjadi pada pasien ini?
TERIMA KASIH
