SIMPOSIUM EMERGENCY FOR EVERY DOCTOR 2017

28 - 29 January 2017 - Hotel JW Marriott, Surabaya

Pokok Bahasan

Early Detection and Adequate

Treatment of Sepsis Apakah kita punya masalah dalam penanganan
sepsis?

Definisi-definisi sepsis & Pengenalan dini

Bambang Wahjuprajitno Pengelolaan dini (dalam 3 - 6 jam pertama)
Apakah cukup dengan resusitasi cairan saja?
Dept of Anesthesiology & Reanimation
Faculty of Medicine - University of Airlangga
Intensive Care Unit Dr. Soetomo General Hospital
Surabaya

Seberapa besar masalahnya di Indonesia?

Indonesia:
Populasi, derajat sepsis dan mortalitas tidak jelas
Mengapa perlu mengenal RS pendidikan di Surabaya (1996): 4.774 pasien MRS, 504
dan mengelola sepsis dgn pasien dgn sepsis, dengan mortalitas 70.2% 1,3

RS pendidikan di Yogyakarta (2007), 631 kasus sepsis, dengan

benar? mortalitas 48.96% 2,3

RS swasta di Bandung (January 2009-March 2012), 106 pasien

sepsis, 48 lelaki dan 58 wanita, dengan mortalitas 62.12%4

1. Hadi RU, et al. Folis Med Indones 1998;34:1420

2. Pradipta IS. M.Sc Thesis, Faculty of Pharmacy, Universitas Gadjah Mada, Indonesia. 2009
3. Pradipta IS, et al. N Am J Med Sci 2013 Jun; 5(6): 344352
4. Pradipta IS, et al. Int J Pharm Sci Rev Res 2013;19(2):24-29
4
 Seberapa besar masalahnya di Indonesia?
Asia overall (n = 1285):
Hospital mortality = 44.9%
Resuscitation bundle compliance = 7.6%
Management bundle compliance = 3.5%
International data:
Mortality = 20 - 50%
BMJ 2011;342:d3245 Compliance: around 20% (Europe & US)
Indonesia n = 33 dari 6 ICU (dari 30 ICU yg dikirimi):
Masalah Pengelolaan Severe Hospital mortality = 72.7%
Resuscitation bundle compliance = 0%
Sepsis di ICU-ICU di Asia
Management bundle compliance = 6.1% The MOSAICS Study Group. BMJ 2011;342:d3245
Rivers EP, Ahrens T. Crit Care Clin 2008;23:S1S47
6 Levy MM, et al. The Lancet Inf Dis 2012;12:919 - 924

Hubungan antara SIRS, sepsis dan infeksi

Others
Bacteriemia

Fungemia
Trauma

Definisi-definisi
Infection Sepsis SIRS
Parasitemia

Burns

Viremia

Others
Pancreatitis

8 Bone et al. Chest 1992;101:1644

 Perjalanan Sepsis Perkembangan Sepsis

Infection/ SIRS Sepsis Severe Sepsis Infection/ SIRS Sepsis Severe Sepsis
Trauma Trauma

A clinical response arising SIRS with a presumed or

confirmed infectious Sepsis with 1 sign of organ failure
from a nonspecific insult, Cardiovascular (refractory hypotension)
including 2 of the following: process
Renal
Temperature 38oC or 36oC unresponsive
HR 90 beats/min
Respiratory to fluid resuscitation
Respirations 20/min SIRS = Systemic Inflammatory Response Syndrome Hepatic
WBC count 12,000/mm3 or Hematologic
Shock

4,000/mm3 or >10% immature CNS

neutrophils
Metabolic acidosis

Adapted from: Bone RC, et al. Chest 1992;101:1644 Bone et al. Chest 1992;101:1644;
9
Opal SM, et al. Crit Care Med 2000;28:S81 10 Wheeler and Bernard. N Engl J Med 1999;340:207

SSC 2012: Diagnostic Criteria for Sepsis SSC 2012: Severe Sepsis
Infection, documented or suspected, and some of the following:

General variables
Fever (> 38.30C)
Hypothermia (core temperature < 360C)
Heart rate > 90/min1 or more than 2 SD above the normal value for age Severe sepsis definition = sepsis-induced tissue hypoperfusion or organ dysfunction (any of the
Tachypnea following thought to be due to the infection)
Altered mental status
Significant edema or positive fluid balance (> 20 mL/kg over 24 hr) Sepsis-induced hypotension
Hyperglycemia (plasma glucose > 140 mg/dL or 7.7 mmol/L) in the absence of diabetes
Lactate above upper limits laboratory normal
Inflammatory variables
Urine output < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation
Leukocytosis (WBC count > 12,000 L1) Acute lung injury with PaO2/FiO2 < 250 in the absence of pneumonia as infection source
Leukopenia (WBC count < 4000 L1)
Normal WBC count with greater than 10% immature forms Acute lung injury with PaO2/FiO2 < 200 in the presence of pneumonia as infection source
Plasma C-reactive protein more than two sd above the normal value Creatinine > 2.0 mg/dL (176.8 mol/L)
Plasma procalcitonin more than 2 SD above the normal value
Bilirubin > 2 mg/dL (34.2 mol/L)
Hemodynamic variables Platelet count < 100,000 L
Arterial hypotension (SBP < 90 mm Hg, MAP < 70mm Hg, or an SBP decrease > 40mm Hg in adults or less than two sd Coagulopathy (international normalized ratio > 1.5)
below normal for age)

Organ dysfunction variables

Arterial hypoxemia (PaO2/FiO2 < 300)
Acute oliguria (urine output < 0.5 mL/kg/hr for at least 2 hrs despite adequate fluid resuscitation)
Creatinine increase > 0.5 mg/dL or 44.2 mol/L
Coagulation abnormalities (INR > 1.5 or aPTT > 60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count < 100,000 L1)
Hyperbilirubinemia (plasma total bilirubin > 4 mg/dL or 70 mol/L)

Tissue perfusion variables

Hyperlactatemia (> 1 mmol/L)

11
Decreased capillary refill or mottling 12
 Sepsis-3 Masalah-masalah dengan definisi
Sepsis di-definisi-kan sebagai disfungsi organ yang mengancam nyawa yang disebabkan karena
disregulasi respons host terhadap infeksi Kesulitan antara kasus-kasus individual dengan gangguan
Baseline SOFA score = 0 (tidak diketemukan disfungsi organ) khusus dan vs. kasus-kasus untuk kepentingan epidemiologis
SOFA score 2 : overall mortality risk sekitar 10% pada populasi RS umum dengan kecurigaan infeksi
dapat menjelek menunjukkan kondisi serius perlu intervensi segera dan sesuai bila belum
dilakukan. Kasus individual: harus mudah digunakan; punya implikasi
terapetik langsung dan prognostik
Istilah awam, sepsis adalah kondisi yang mengancam nyawa yang timbul ketika respons tubuh pasien
Epidemiologic: kuat dan kokoh, rigorous; digunakan untuk
menimbulkan kerusakan pada jaringan dan organ tubuhnya sendiri
Pasien-pasien dengan kecurigaan infeksi yang mungkin memerlukan rawat inap lebih lama di ICU atau
meninggal di RS dapat di-identifikasi segera dengan qSOFA, yaitu berupa gangguan status mental, clinical trials
tekanan darah sistolik 100 mm Hg, atau respiratory rate 22/menit
Septic shock adalah suatu subset dari sepsis dimana abnormalitas sirkulasi dan seluler/metabolik cukup
berat untuk menyebabkan peningkatan mortalitas yang berarti
Definisi-definisi dianggap tidak tepat dan tidak adekuat
Pasien-pasien dengan septic shock: bila hipotensi tidak membaik meskipun telah mendapat resusitasi
dengan volume yang adekuat, sehingga memerlukan vasopressors utk mempertahankan MAP 65 mm
Diperlukan update dan revisi kriteria
Hg dan disertai serum lactate level > 2 mmol/L (18 mg/dL). Bila memenuhi kriteria ini, mortalitas di RS
mencapai lebih dari 40% Dipisahkan dari gangguan inflamasi non-infectious
13 Singer M, et al. JAMA 2016;315(8):801-810 14

Criteria Sepsis SOFA Score

SOFA Score 0 1 2 3 4

Respiration
PaO2/FiO2 or > 400 < 400 < 300 200 < 100
SaO2/FiO2 mmHg 221 - 301 142 - 220 67 - 141 < 67
Coagulation > 150 < 150 < 100 < 50 < 20

Liver
< 1.2 1.2 - 1.9 2.0 - 5.9 6.0 - 11.9 > 12.0
Bilirubin mg/dL
Cardiovascular No Dopamine 5 Dopamine > 5 Dopamine >
MAP < 70
Hypotension hypotension or any or NE 0.1 15 or NE > 0.1

CNS (GCS) 15 13 - 14 10 - 12 6-9 <6

Renal
3.4 - 4.9 or <
Creatinine (mg/dL) < 1.2 1.2 - 1.9 2.0 - 3.4 > 5.0 or < 200
5.0
or urine output

15 Seymour CW, et al. JAMA 2016;315(8):762-774 16

 Kesimpulan pilihan kandidat kriteria sepsis

Predictive validity untuk in-hospital mortality SOFA

LODS > SIRS & qSOFA Kriteria klinis sepsis
Infeksi diluar ICU: Predictive validity untuk in-
hospital mortality qSOFA > SOFA dan SIRS

2 points or more=10% mortality

18 Seymour CW, et al. JAMA 2016;315(8):762-774

Klarifikasi SSC Maret 2016 tentang qSOFA

qSOFA bukan definisi sepsis, tetapi suatu prediktor untuk baik

peningkatan mortalitas maupun lama rawat inap lebih dari 3 hari di
ICU maupun diluar ICU

Sepsis di-definisi-kan sebagai disfungsi organ yang mengancam

nyawa yang disebabkan karena disregulasi respons host terhadap
infeksi

Septic shock adalah sepsis dengan hipotensi yang persistent:

telah dilakukan resusitasi cairan yang adekuat
yang memerlukan vasopressors utk mempertahankan MAP of 65 mmHg, dan
disertai serum lactate > 2 mmol/L
We hope this editorial will clarify that the qSOFA is meant to be used to raise
suspicion of sepsis and prompt further actionit is not a replacement for SIRS
SIRS dan severe sepsis dihilangkan
and is not part of the definition of sepsis 20
 Algoritme aplikasi qSOFA
National Early Warning System (NEWS)

PHYSIOLOGICAL
3 2 1 0 1 2 3
PARAMETERS

Respiration rate 8 9 - 11 12 - 20 21 - 24 25

Oxygen saturation 91 92 - 93 94 - 95 96

Any supplemental
Yes No
oxygen

Temperature 35.0 35.1 - 36.0 36.1 - 38.0 38.1 - 39.0 39.1

Systolic BP 90 91 - 100 101 - 110 111 - 219 220

Heart rate 40 41 - 50 51 - 90 91 - 110 111 - 130 131

Level of
A V, P or U
consciousness

21 22

Perbandingan Sensitivity dan Specificity

Sensitivity Specificity

SIRS 2

qSOFA 2
91%

54%
13%

67%
Early Adequate Treatment
NEWS 7 77% 53% of Sepsis
NEWS 8 67% 66%

NEWS 9 54% 78%

qSOFA is an insensitive and late indicator of deterioration

23
 Sirkulasi pd Septic Shock Oxygen Delivery & Mortality in Septic Shock

100
100

Septic shock, pre-fluid resuscitation

Vasodilatation 75
Increased PVR 64

% Mortality
59
Decreased contractility
50
Capillary leak 50
43
33

25

Low Cardiac Output

The net result after fluid resuscitation:
Low CO Optimal CO 0
Low SVR 0-8.5 9.0-12.9 13.0-16.9 17.0-20.9 21.0-24.9 25.0+
Better prognosis OXYGEN DELIVERY (ML/MIN/KG)
N = 51 pts
Dellinger RP. Crit Care Med 2003;31:946-955 26 Tuchsmidt J, Fried J, Astiz M, Rackow E. Chest 1992; 102: 216-220

Treatment algorithm
Early Goal-Directed Therapy

Ini yang biasa kita Ini adalah Airway

DO2 = CO x Hb x SaO2 x 1.36
kerjakan di IGD pengukuran perfusi
Breathing

Volume
(preload)
Circulation

Pressors
(afterload)

Hb
Inotropes
(contractility)

27 Rivers E, et al. NEJM 2001;345:1368-1377 28 Rivers E, et al. NEJM 2001;345:1368-1377

 Tensi sering
normal
Tapi, pasien
sangat sakit

EGDT-ProCESS-ProMISe-ARISE
Apakah EGDT masih relevan?
Perkembangan setelah EGDT?

30
29

SSC 2004

Cry me a Rivers.
Single center trial bias
Jumlah pasien kecil 15 years

Representasi semua pasien sepsis?

Detroit Metro ED (lingkungan miskin, minoritas, status Kumar, describes
the importance of
early antimicrobial
Early recognition,
hemodynamic

kesehatan rendah, tidak ada jaminan asuransi) Pasien

resuscitation and
administration antibiotics means
EARLY SOURCE
lebih sakit mirip Indonesia? CONTROL

Nilai klinis pengukuran CVP (parameter hemodinamik

statis) dan ScVO2 kontinyu? mahal, ketersediaan
saat itu
31 32 Shankar-Hari M, et al. JAMA 2016;315(8):775-787 (modified)
 Studi-studi tentang resusitasi cairan setelah EGDT (2014)
(1)
Trial Name ProCESS ARISE ProMISe

A Randomized Trial of Protocol- Goal-Directed Resuscitation

Protocolised Management
Title Based Care for Early Septic for Patients with Early Septic
in Sepsis (ProMISe)
Shock Shock

U.S. Australia/New Zealand U.K.

Location
31 Emergency Departments 51 Emergency Departments Multi-Center

1600 adult sepsis subjects 1260 adult sepsis subjects

1935 adult subjects with septic with septic shock (refractory with septic shock
Population shock (refractory hypotension or
hypotension or LA 4mmol/ (refractory hypotension or
LA 4mmol/L)
L) LA 4mmol/L)

Intervention EGDT EGDT EGDT

Protocol-Based Care (no CVC)

Control Usual Care Usual Care
Usual Care

Primary Outcome 60 Day Mortality 90 Day Mortality 90 Day Mortality

Primary Outcome EGDT 21%

Result Protocol Based 18.1% EGDT 18.6% EGDT 29.5%
(relative risk) Usual Care 18.9% Usual Care 18.8% Usual Care 29.2%

Publication Date May 2014 October 2014 Mar 2014

Journal NEJM NEJM NEJM

Adapted from:
Yealy DM et al. A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med 2014; 370:1683-1693
Peake SL et al. Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med 2014; 371:1496-1506
33 Power GS et al., The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan. Crit Care Med; 2013 Dec;15(4):311-7 34 Yataco AC, et al. Crit Care Med 2017. DOI: 10.1097/CCM.0000000000002237

(2) (3)

35 Yataco AC, et al. Crit Care Med 2017. DOI: 10.1097/CCM.0000000000002237 36 Yataco AC, et al. Crit Care Med 2017. DOI: 10.1097/CCM.0000000000002237
 Konsep resusitasi pada EGDT
Early:
Early Recognition: kriteria SIRS SSC, qSOFA, Red Flag, Apakah resusitasi cairan sudah
NEWS
cukup pd pengelolaan
Early Diagnosis: Klinis, Lab, Dx invasif, kultur bakteria
Imaging, less/non-invasif hemodinamik pd sepsis?
Early Hemodynamic Resuscitation Management: EGDT (US) Pasti Tidak!
ProCESS (US), ARISE Australasia), ProMISe (UK)

Time sensitive, structured approach

Mencapai target tertentu (goal-directed)
37

Timing of antibiotic treatment & survival

Retrospective review of 2700 pts. with septic shock

Only 50% of patients with Septic Shock

received antibiotics within 6 hours

Each hour of delay

7.6% reduction in survival
39 Vallet B, Pinsky MR, Cecconi M. Intensive Care Med 2013 Sep;39(9):1653-5 40 Kumar A, et al. Crit Care Med 2006;34:1589-1596
 n = 1168 pts dari 3 IGD di Belanda

Tidak cukup hanya time

Time to Antibiotics

Getting it right Rivers Mayoritas dalam 6 jam

Right drugs Kumar Median pd 6 jam
Right time ProCESS Mayoritas dalam 3 jam
Right dose ARISE Median pd 70 menit
ProMISe Median pada 2,5 jam

41 de Groot et al. Critical Care 2015;19:194 42

Mortality Associated with Initial Inappropriate Therapy in Critically Ill Patients with VAP
Source Control (SSC 2016)
Inappropriate Appropriate

P=0.001
We recommend that a specific anatomic diagnosis of
P>0.2 infection requiring emergent source control be identified or
excluded as rapidly as possible in patients with sepsis or
P=0.06
septic shock, and that any required source control
P=0.001
intervention be implemented as soon as medically and
P>0.2 logistically practical after the diagnosis is made (BPS)
P>0.2
We recommend prompt removal of intravascular access
P>0.2 devices that are a possible source of sepsis or septic shock
after other vascular access has been established (BPS)
P<0.01

Crude Mortality Rates (%) BPS: Best Practice Statement ( the benefit or harm is unequivocal, but the evidence
43 44 is hard to summarize or assess using GRADE methodology)
 Time from admission to initiation of surgery
and 60-day outcome Ringkasan
n=154 patients of GI perforation with associated septic shock
EGDT, ProCESS, ProMISe, ARISE: semua dapat digunakan
Hanya beda dalam cara mencapai suatu target tergantung sumber daya yang
dipunyai
Kematian pada sepsis karena MSOF. Masalahnya apakah disfungsi organ
disebabkan karena mekanisme immunologis, hemodinamik, atau berkaitan
dengan masalah oksigenasi ditingkat jaringan dan sel?
Sampai sekarang penanganan sepsis dini (3 dan 6 jam pertama) :
Kenali dini (Early recognition): SSC 2012; qSOFA, NEWS, MNEWS
Resusitasi dini (Early resuscitation): EGDT, ProCESS, ProMISe, ARISE
Terapy antimikroba dini (Early antibiotics): Terapi de-eskalasi
Buang sumber infeksi dini (Early source control) 6 - 12 jam pertama
Dilanjutkan dgn menunjang fungsi organ di ICU
45 Azuhata T, et al. Critical Care 2014;18:R87 46

(time sensitive)

Early & Aggresive:

Recognition Resuscitation Remedy Removal
(antibiotics) (source control))
47 48
 Terima kasih

49