Screening & Resuscitation bundle in Sepsis Yohanes George Emergency Room - ICU/ICCU – Pondok Indah Hospital Jakarta Departement of Anesthesia and Intensive Therapy – Faculty of Medicine Unversity of Indonesia

OUTLINE The evolution of the guideline The important of Screening Sepsis EGDT + Resuscitation Bundle (RB) from 2004-2015 Cases

The International Sepsis Guideline; Surviving Sepsis Campaign Phase 1: Barcelona Declaration (2002): Reduce mortality from severe sepsis and septic shock by 25% Phase 2: Development of Evidence-based Guidelines (2004) Second edition published 2008 Third edition released January 2013 Phase 3: Education and Implementation Development of Sepsis Bundles Evaluation

EVALUATION 1

First, put the early identification (sepsis screening) on resuscitation phase

SSC first edition 2004 SSC second edition 2008 SSC third edition 2012

SSC 2004 mfda

SSC 2008 mfda

What is the new!!

The importance of early recognition  the earliest better SSC 2012 mfda

B. Screening for Sepsis and Performance Improvement Routine Screening: We recommend routine screening of potentially infected seriously ill patients for severe sepsis to increase the early identification of sepsis and allow implementation of early sepsis therapy (grade 1C)

Validation of sepsis screening tools Moore LJ, Jones SL, Kreiner LA, et al: Validation of a screening tool for the early identification of sepsis. J Trauma 2009; 66:1539–46; discussion 1546 Subbe CP, Kruger M, Rutherford P, et al: Validation of a modified Early Warning Score in medical admissions. QJM 2001; 94:521–526 Evaluation for Severe Sepsis Screening Tool, Institute for Healthcare Improvement (IHI).http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Tools/ EvaluationforSevereSepsisScreeningTool.htm Evaluation for severe sepsis screening tool. http://www.survivingsepsis.org/files/Tools/evaluationforseveresepsissc reeningtool.pdf Decreased sepsis related mortality

How to do the sepsis screening!!

SCREENING SEPSIS Work up sepsis

SCREENING SEPSIS Infection √ + SIRS √ √ = Sepsis √ Work up sepsis

Multi-Organ Dysfunction Work up Sepsis √ √ Sepsis + Protokol EGDT & RB √ Multi-Organ Dysfunction 1 Organ Dysfunction √ = Sepsis Berat √ √

EVALUATION 2

THE SEPSIS BUNDLE

Compliance with bundle elements Compliance with each bundle element increased over time. Compliance with ALL elements increase over time, but remained low. Levy MM et al. CCM 38(2):367-374, February 2010.

Impact of bundle target on hospital mortality Xigris have eliminated Is the catheter still necessary? Not significant for CVP > 8 mmHg and ScvO2 > 70% Levy MM et al. CCM 38(2):367-374, February 2010.

Change in Compliance Over Time Levy MM et al. CCM 38(2):367-374, February 2010.

Change in Mortality Over Time Resuscitation bundle significant reduced mortality compare to Management bundle Levy MM et al. CCM 38(2):367-374, February 2010.

SSC Bundles need revise Analysis of large database confirm importance of early identification and resuscitation Initial resuscitation bundle To be initiated immediately upon identifying patients with severe sepsis and septic shock Septic Shock bundle To be initiated immediately and completed within 6 hours for patients with septic shock

First, eliminate the second bundles!! 1 bundle only (2012)

Second, change the component in the resuscitation bundle!!

(2004-2008) (2012) EGDT protocol still in the Bundle Use LACTATE as a end-point of resuscitation

THE NEW PROTOCOL = EGDT & RB 2012 Next 6 hours Blood lactate THE NEW PROTOCOL = EGDT & RB 2012 The first 3 hours Blood culture Broad spectrum antimicrobial Crystalloid 30 ml/kg Important thing; you don’t need CVC canulation to resuscitate septic patient in the first 3 hours Target of CVP 8-12 Fluid After transfusion ScvO2 >70%  Goal achieved Target of MAP 65-95 Vasopressor Target Tissue Oxygenation, the balance between DO2/VO2 If ScvO2 < 70 & Ht <30% give PRBC If lactate > 2 or ScvO2 still < 70%  check VO2 Dobutamine If after Dobutamine ScvO2 > 70%  Goal achieved After transfusion ScvO2 still <70%  Give Dobutamine Re-check lactate, if < 2  Goal-achieved

PROTOKOL RESUSITASI PADA SEPSIS BERAT DAN SEPTIC SHOCK I. WITHIN 3 HOURS Ambil darah untuk kultur dari akses perifer Check laktat darah Segera berikan antibiotik spectrum luas (gr + & -) Loading cystalloid 30 ml/kg II. HARUS SELESAI DALAM WAKTU 6 JAM Jika gagal nafas atau syok (hypotensive) segera berikan oksigen atau intubasi dan ventilasi mekanik Sedasi, dan pelumpuh otot jika dengan ventilasi mekanik PRELOAD TARGET: Pasang CVC dan ukur. Jika CVP < 8 mmHg segera berikan kristaloid. Jika kristaloid sdh mencapai 1.5l berikan koloid natural (albumin 5%) sampai TARGET CVP 8-12 mmHg. Jika CVP 8-12 mmHg, capai TARGET PRESSURE (MAP) MAP TARGET: Jika MAP < 65 mmHg berikan Vasopressor Jika MAP > 90 berikan Vasodilator Jika tercapai target MAP 65-90, capai TARGET TISSUE OKSIGENASI ScvO2 TARGET : Jika ScvO2 < 70% Transfusi PRC sampai target hematokrit > 30%. Jika Ht > 30% dan ScvO2 sudah > 70% maka TARGET TISSUE OKSIGENASI SUDAH TERCAPAI Jika Ht > 30% namun ScvO2 masih < 70% maka berikan Dobutamine titrasi. Jika ScvO2 sudah > 70% dengan dobutamine maka TARGET TISSUE OKSIGENASI SUDAH TERCAPAI Jika ScvO2 masih < 70% dengan dobutamine maka TARGET BELUM TERCAPAI, KEMBALI KE AWAL PROTOKOL UNTUK MENURUNKAN VO2 (MENAMBAH SEDASI, PELUMPUH OTOT, TURUNKAN DEMAM) Jika ScvO2 > 70% maka TARGET TISSUE OKSIGENASI TERCAPAI, CAPAI TARGET BERSIHAN LAKTAT TARGET BERSIHAN LAKTAT: Jika laktat turun > 20% dari nilai awal TARGET RESUSITASI TERCAPAI Jika laktat tidak turun maka TARGET RESUSITASI BELUM TERCAPAI, KEMBALI KE AWAL PROTOKOL PROTOKOL RESUSITASI PADA SEPSIS BERAT DAN SEPTIC SHOCK SSC GUIDELINE 2012

How to Implement the bundle!

Screening sepsis in ER Data history Pria 65 thn, ,masuk unit Gawat darurat karena keluhan demam dan sesak nafas, batuk2 sejak 2 hari yg lalu Pasien pernah dirawat di ICU sebelumnya (2 minggu yg lalu) dengan keluhan yg sama. Di ICU sempat dirawat 5 hari, 3 hari memakai ventilator. WD saat itu CAP dengan AB Ceftriaxone 2x1 gr plus Azithromycin 1x1. Hari ke 5 di ICU pasien pindah ruangan karena sudah sembuh dan bisa pulang rumah. Riwayat penyakit; DM dan PPOK.

Pem Fisik dan Diagnostik sepsis Saat ini di IGD; KU berat, sesak, keringat dingin. Kes apatis compos mentis. Tanda vital; Suhu 39.30C, TD 85/35, MAP 52 mmHg, HR 145 x/mnt, RR 40 x/mnt. PF paru; ronki +/+, wheesing +/+.SPO2 100% dgn NRM 15 L/mnt. Batuk2 dengan sputum kental kekuningan, tidak ada frotty sputum Diagnosa; septic shock Pneumonia MONITORING VITALS

145 85/35 (52) 40 NIBP Takikardia Hypotensive MAP < 65 Resp Failure, increase Work of Breathing Lung oxygenation with NRM 10 L/min 40 NEXT STEP

BEGIN RESUSCITATION EARLY RESUSCITATION THE FIRST 3 HOURS

EARLY RESUSCITATION; (3 jam pertama) Segera pasang IV-line perifer 20 G Ambil kultur darah perifer Cek kadar laktat darah Loading RL 1000 – 30 ml/kg selama 30-60 menit Intubasi dan ventilasi mekanik MONITORING

Assesment after loading RL 1000 cc: 130 NIBP 89/45 (60) 14 Masih takikardia 89/45 (60) Masih hipotensi MAP masih < 65 Intubation and Control Mechanical ventilation RESP 14 Laboratorium

Data tambahan : Laboratorium; Pneumonia Hb 9.0/L 19.0/Segment 95%/Ht 25/Trb 160. PCT 70/ Lactate 4.1 Ur/Cr: 71/2.1 Pneumonia Working Diagnostik:

Diagnostic definitif Septic shock ec Pneumonia Segera berikan Antibiotik Spectrum luas (meropenem 1 gram drip 3 jam) NEXT STEP

EGDT & LACTATE CLEARANCE RESUSCITATION BUNDLE EGDT & LACTATE CLEARANCE THE FIRST 6 HOURS

EGDT AND LACTATE CLEARANCE (6 jam pertama) : Pasang CVC, ambil kultur darah dari CVC Pasang arterial line untuk Invasive BP monitoring MONITORING

Assesment setelah pasang CVC & Invasive BP 110 ABP 95/45 (62) ( 3 ) 14 HR sudah turun 95/45 (62) MAP < 65 CVP ( 3 ) CVP masih rendah, <8  Intravascular volume masih kurang RESP 14 NEXT STEP

Ada tindakan berikut anda : Tambahan loading RL 500 lagi sampai target CVP 8-12 mmHg. Pasang NE 0.05 mikro untuk mencapai target MAP >65 mmHg MONITORING

Assesment after tambahan 500 cc + pemberian NE 0.05 100 ABP Heart rate normal 110/57 (65) MAP = 65 CVP ( 5 ) CVP naik 5 namun masih <8 RESP 14 NEXT STEP

Apa tindakan selanjutnya Setelah total kristaloid total 1500, namun CVP belum mencapai target 8-10 mmHg, diberikan tambahan loading koloid natural albumin 5% 30 cc/kg Naikkan dosis NE menjadi 0.1 mikro/kg/mnt untuk mencapai target MAP >65 mmHg Lactate 2.1 Start koloid natural Target MAP > 65 mmHg Target Lactate clearance > 10%  berhasil MONITORING

Assesment after albumin iso-oncotic + NE dosis: 100 ABP Heart rate normal 110/55 (67) MAP tercapai > 65 CVP ( 9 ) CVP tercapai > 8 RESP 14 NEXT STEP

Apa tindakan selanjutnya Ukur ScvO2 melalui vena sentral CVC; To determine the result of macrodynamic resuscitation  end point of tissue oxygenation Lactate 1.8 Next Target Lactate clearance > 10% berhasil MONITORING

Assesment of tissue oxygenation ScvO2 90 HR normal MAP tercapai ABP 120/65 (77) CVP tercapai > 8 CVP (10) ScvO2 low, <70% SvO2 53% RESP 14 NEXT STEP

Apa tindakan anda selanjutnya: ScvO2 53% pertanda belum mencapai target end point tissue oxygenantion sehingga berikan transfusi PRC 300 cc dengan target Ht >30% untuk menaikkan Delivery Oksigen MONITORING

Hematocrit 34% Assesment after 300 ml of PRC : 88 ABP 125/67 (79) (11) Hematocrit tercapai >30%, tapi ScvO2 masih <70% CVP (11) SvO2 63% RESP 14 NEXT STEP

Apa tindakan anda selanjutnya: Dobutamin 5 mikro/kg/mnt untuk meningkatkan flow (cardiac output) MONITORING

Assesment after dobutamin 5 mikro/kg/mnt 97 ABP 133/66 (88) CVP (13) ScvO2 tercapai > 70% SvO2 72% RESP 14 NEXT STEP

GOAL ACHIEVED; Target makrodinamik dan tissue oksigenasi tercapai  Ke ICU

Hari 5 di ICU KU membaik, tidak demam, kes compos mentis Tanda vital; suhu 36.90C, TD 127/72, HR 91 x/mnt, PF, akral hangat, paru; ronki -/-, wheesing -, foto toraks perbaikan, Hasil kultur 5 hari yg lalu; Sputum; klebsiela P sensitif terhadap ampicilin, ceftriaxone, meropenem, ciprofloxacin, cefoperazone-sulbactam, polymixin B Darah; no growth Laktat 0.9 Pasien pindah ruangan biasa

BUT TIME HAS CHANGE, NEW EVIDENCES HAS EMERGED

CRITIQUES OF EGDT (RIVERS STUDY)

Central Venous Pressure as a preload indicator Central Venous Pressure can not predict fluid responsiveness “Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares.” Marik PE, Baram M, Vahid B. Chest. 2008 Jul;134(1):172-8. doi: 10.1378/chest.07-2331. “Hemodynamic parameters to guide fluid therapy.” Marik et al. Annals of Intensive Care 2011, 1:1.

High ScvO2 is associated with increase mortality “High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality.” Textoris et al. Critical Care 2011, 15:R176.

No significantly different between Lactate clearance and ScvO2 Lactate vs ScVO2% From: Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy:  A Randomized Clinical Trial JAMA. 2010;303(8):739-746. doi:10.1001/jama.2010.158 No significantly different between Lactate clearance and ScvO2

TRISS Trial; Hemoglobin Threshold for Transfusion in Septic Shock Primary and Secondary Outcome Measures Outcome Lower Hemoglobin Threshold Higher Hemoglobin Threshold Relative Risk (95% CI) P Value Primary outcome: death by day 90 – no./total no/ (%) 216/502 (43.0) 223/496 (45.0) 0.94 (0.78-1.09) 0.44 Second outcomes   Use of life support- no./total no/ (%) At day 5 278/432 (64.4) 267/429 (62.2) 1.04 (0.93-1.14) 0.47 At day 14 140/380 (36.8) 135/367 (36.8) 0.99 (0.81-1.19) 0.95 At day 28 53/330 (16.1) 64/322 (19.9) 0.77 (0.54-1.09) 0.14 Ischemic event in the ICU – no./total no. (%) 35/488 (7.2) 39/489 (8.0) 0.90 (0.58-1.39) 0.64 Severe adverse reaction – no./total no. (%) 0/488 1/489 (0.2) - 1.00 Alive without vasopressor or inotropic therapy – mean % of days 73 75 0.93 Alive and out of the hospital – mean % of days 30 31 0.89 Transfusion if Hb < 7 Transfusion if Hb < 9 No significantly different Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock. Lars B. Holst, M.D, et al. N Engl J Med 2014; 371:1381-1391October 9, 2014.

Should we abandon the EGDT?

2014

ADDING FUEL TO THE FIRE… ARISE ProCESS Transfusion ? CVP ? ScvO2 ? Dobutamine ?

No significant different ARISE trial Goal-Directed Resuscitation for Patients with Early Septic Shock 51 center Australia/New Zealand 1600 patients, with 796 assigned to the EGDT group and 804 to the usual-care group No significant different “Goal-Directed Resuscitation for Patients with Early Septic Shock.” The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014;371:1496-506.

No significant different ProCESS trial A Randomized Trial of Protocol-Based Care for Early Septic Shock 31 tertiary US emergency departments 1341 enrolled patients, 439 assigned to EGDT, 446 to protocol based standard therapy, 456 to “usual-care.” No significant different “A Randomized Trial of Protocol-Based Care for Early Septic Shock.” The ProCESS Investigators. N Engl J Med. 2014;370:1683-93.

Surviving Sepsis Campaign Response 2014 The results of the ProCESS and ARISE trials have not demonstrated any adverse outcomes in the groups that utilized CVP and ScvO2 as end points for resuscitation. Therefore, no harm exists in keeping the current SSC bundles intact until a thorough appraisal of all available data has been performed. In light of the evidence from the ProCESS and ARISE trials, the SSC guidelines committee will immediately review the evidence and assess whether the guidelines need to be updated now.

FINALLY, 2015 EGDT Killed by the evidences WHAT WE HAVE LEARNED There is no single ‘magic of bullet’ in hemodynamic assesment CVP is not the only one parameter of volume status, we can use clinical and other tools We can replace ScvO2 meassurement with lactate to determine tissue oxygenation after macrodynamic done EGDT 2001-2015

Hypovolemic Normovolemic < 65 mmHg > 65 mmHg High > 2 Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION Administer 30 ml/kg crystalloid Supplemental oxygen, intubation, mechanical ventilation TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION VOLUME STATUS: Repeat focused exam of vitals sign, capillary refill, skin finding, pulse. OR TWO OF THE FOLLOWING: Measure CVP Measure ScvO2 IVC Inferior Vein Cava Collapsibiity/Distensibility (Bedside cardiovascular ultrasound) Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge Hypovolemic Normovolemic < 65 mmHg Mean Arterial Pressure Vasopressor > 65 mmHg High > 2 Lactate Updated Bundles in Response to New Evidence 2015 Normal < 2 GOAL ACHIEVED

Case 2

Day 1: Male 72 years old, admitted ICU from Emergency due to decreased of consciousness mfda

Physical exam: cellulitis of the left lower leg Day 1: Physical exam: cellulitis of the left lower leg Vitals HR 102, Resp Tachypnea (33/min), BP 123/55 UO decreased. ScvO2 65% CVC subclavian inserted, Ringer Fundin 500 ml + Alb 5% 250 ml. Norepinephrine 0.5 micros mfda

Meropenem 2 grams every 8 hours for 3 hours drip continyu Normal lung Meropenem 2 grams every 8 hours for 3 hours drip continyu Septic AKI mfda

Day 2: After 3 doses meropenem. Physical exam: cellulitis of the right leg start to improved. Vitals HR 83, Resp normal 17/min, BP 163/75 UO 0.8/kg/hr. Conscious. Without Norepinephrine

Lactate cleareance >10% Day 2: Laboratory results Septic AKI resolved ScvO2 normal Lactate cleareance >10% mfda

The most important in septic shock therapy are 3 pillars: No Rivers: Day 3: Improved Day 5: Moved to the ward Take home mesasage: The most important in septic shock therapy are 3 pillars: Early dectection Fluid resuscitation Empiric Antimicrobial treatment/Source Control No Rivers: No continyu fluid loading targeting CVP 8-12 No Transfusion targeting hematocrit No Dobutamine targeting ScvO2 mfda

Case 3

Non-invasive cardiac output monitoring Normal cardiac index Very low SVRI Vasopressor Normal preload No fluid loading Low Stroke Volume Normal index of contractility The cause of hypotension is vasoplegia not hypovolemia

They are cost absolutely nothing!!! Practical point The most important in septic shock therapy Early dectection/screening sepsis Fluid resuscitation/crystalloid solution Early Empiric Antimicrobial treatment They are cost absolutely nothing!!!

Conclusion Recognition Sepsis as medical emergency Screening/early recognition Broad spectrum antibiotic based on suspected source and local antibiogram Initial fluid administration 30ml/kg Lactate Cultures Vasopressors Assess fluid responsiveness and response to treatment

Thank you