SEPSIS
from the intensivist point of view
Vladimír Šrámek
ARK, FN u svaté Anny v Brně
Basics of Clinical Medicine, LF MU 2018
structure of the lecture
• Difference in the terms
• Sepsis definition – past and present
• Epidemiology/economics
• DG (clinics, lab, scores: qSOFA, SOFA)
• Th (ATB, resuscitation protocol, Th acc.
pathophysiology). Personalised/presicion
medicine
TERMS
• Infection – presence of the allien
microorganism eliciting counteraction
(local/systemic)
• Bacteriemia – presence of the bacteria in the
blood (viremia/fungemia/parasitemia)
• Inflammation – defence mechanism against
the infection (local/systemic; short-longterm;
+/- (imunodepression)
• Sepsis
published – ICM/CCM January 2017, 4. revision
SEPSIS definition
• Consensual conference ACCP/SCCM, held in 1991, defined sepsis as
activation od the systemic inflammatory reaction (SIRS) as a reaction on
presence of the allien (micro)organism and stratified its clinical course
(sepsis severe sepsis septic shock) (1).
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American
College of Chest Physicians/Society of Critical Care Medicine. Chest 1992 Jun;101(6):1644-55.
SIRS (al least 2 out of 4 marks)
Temperature  38oC, or  36oC
HR  90 beats/min
Respirations  20/min
WBC count 12,000/mm3, or 4,000/mm3, or >10% immature Neu
SIRS elicited by microorganism = SEPSIS
SEPSIS + 1 organ dysfunction (e.g. Hypotension corrected by fluids) =
SEVERE SEPSIS
SEVERE SEPSIS + shock (vasopressors) = SEPTIC SHOCK
DG sepsis (Sepsis-3)
3rd Sepsis konference, held by SCCM/ESICM in 2015 suggested fundamental
reclassification: no SIRS and newly to define sepsis in the ICU as a change in
organ function ICU (defined as dSOFA > 2) which is caused by (suspected)
infection. Septic shock is newly defined as hypotension (MAP > 65 mmHg)
reacting only on vasopressors and simultaneously signs of tissue
hypoperfusion (lakctate > 2 mmol/l).
Singer M, Deutschman CS, Seymour CW et al (2016) The Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3). JAMA 315(8):801–810
SEPSIS epidemiology
incidence of Severe Sepsis
†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association.
2000. ‡Angus DC et al. Crit Care Med. 2001.
0
50
100
150
200
250
300
AIDS† ColonBreast
Cancer§
CHF* Severe
Sepsis‡
Cases/100,000
800
1,000
1,200
1,400
1,600
1,800
2001 2025 2050
Year
300
400
500
600
SepsisCases(x103)
TotalUSPopulation(million)
Angus DC, et al. JAMA 2000;284:2762-70.
Angus DC, et al. Crit Care Med 2001;29:1303-10.
Severe Sepsis - incidence raising
Severe Sepsis Cases
US Population
mortality Severe Sepsis
†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association.
2000. ‡Angus DC et al. Crit Care Med. 2001.
0
50 000
100 000
150 000
200 000
250 000Deaths/Year
AIDS † Severe
Sepsis‡
AMI *Breast
Cancer§
Treating seniors, severely ill, males …
… extreme costs…
Mortality related to severe sepsis and septic shock among critically ill
patients in Australia and New Zealand, 2000-2012.
Kaukonen KM1, Bailey M2, Suzuki S3, Pilcher D4, Bellomo R5.
JAMA. 2014;311(13):1308-1316. doi:10.1001/jama.2014.2637
+
diagnostics SEPSIS I
• clinics
triage of the patients
Questions:
Is he/she ill at all?
Can be treated as an out-patient?
Stay in the hospital?
Stable/unstable? Admitted to a monitored bed?
SHOCK – term definition
Situation when CV system is not capable to deliver nutrients (O2)
to the peripheral tissues. This leads to energeticfunctional
morphological cell failure. Failure of micro (macro)circulation
HEMODYNAMIC compromise
inbalance of OXYGEN (O2) consumption (VO2)
and delivery (DO2)
shunt
Na+K+ATPase
M
venula
capillary leak
shock state
- 3 gates to the body
JL Vincent:
• CNS – qualitative/quantitative
• Skin
• Kidney
quick SOFA
(2 out of 3 criteria)
CardioVascular (CV) signs of instability
A) Hypotension:
• a) systolic arterial pressure (SAP) < 90 mm Hg or its sudden drop of
30-40 mmHg or
• b) mean arterial pressure (MAP) < 60 mm Hg.
• CAVE: shock state can be present without hypotension (so called
hidden/compensated shock) – mortality is high
B) Tachycardia – heart beats > 100/min.
• CAVE: tachycardia not present in patients on beta-blockers.
hypotension
MAP = SV x SVR
MAP
Problem?
ECHO
(tamponade, tension PNO)
Problem?
CRT
Skin
• Spots on the skin
(mottled skin)
• Nail bed perfusion
(capillary refill time)
• Cold periphery
(Tcent – Ttoe; Tforearm – Tthumb)
diagnostics SEPSIS II
• lab
availibity of acute
biochemisty/haematology results
POC analysators:
3 in St. Anna
Centrál lab
- Building D
lab
Severity of the case:
• PaO2 (> 13 kPa, > 8 kPA)
• SaO2 (comparion with SpO2)
• PaCO2 (> 6…8 kPa, simultaneously with pH)
• pH (7,36 – 7,44; logaritmic scale)
• BE (only MAc has neg BE, degress of + in RAc –
ability to compensate (kindney), chronicity)
Sepsis (sensitivity > specificity)
• Leu, CRP, PCT….
glucose
pyruvate
KREBS
cycle
III - lactate clearance (liver….)
I - anaerobic metabolism
II - aerobic metabolism
lactate
BLOOD LACTATE LEVEL
H+
2e + O. + 2H+
Lab – lactate
marker „anaerobic metabolism“
therapy SEPSIS
• ATB
• Supportive care
(gas exchange (lungs) + perfusion (CV system) +
failing organ replacement/support)
• Acc. to pathophysiology
DIGESTIVE TRACT INTERNAL ORGANS
ACQUISITION
CARRIAGE
OVERGROWTH
COLONIZATION
INFECTION
SURVEILLANCE SAMPLES
(throat, rectum)
DIAGNOSTIC SAMPLES
LOWER AIRWAY,BLOOD,BLADDER
To treat??? (interaction microb – organism)
1 hod in Septic Shock
Effective:
a) ATB acc. microbiolgy results within 48 hrs
b) ATB empirically acc. given clinical syndrome
Garnacho-Montero J, CCM 2003
adequate ATB – Septic Shock
excess survival
1 hour ???
3 hr ED triage 1 hr hypotension
RIVERS protocol
Publication in NEJM in 2001 presented results of „Chicago ED trial“ by
Emanuel Rivers (absolute mortality reduction by 16 %), agressive
(CVC, ScvO2 measurement, RBC, dobutamine) – concept of EGDT
in ED/ICU conditions was born.
RIVERS, E., NGUYEN, B., HAVSTAD, S., ET AL. Early goal-directed therapy in the
treatment of severe sepsis and septic shock. N Engl J Med, 2001, 345, p. 1368–1377.
Test: kontinuální monitorace ScvO2, protokolizace
tekutina + vasopresor + dobutamin + RBC
2012 RECOMMENDATIONS
A. INITIAL RESUSCITATION
1. Protocolized, quantitave resuscitaon of
patients with sepsis-induced tissue
hypoperfusion (defined in this document as
hypotension persisting after initial fluid
challenge or blood lactate concentration 4
mmol/L). Goals during the first 6 hr
resuscitation:
• a. Central venous pressure 8–12 mm Hg
• b. Mean arterial pressure ≥ 65 mm Hg
• c. Urine output ≥ 0.5 mL/kg/hr
• d. Central venous (superior vena cava)
or mixed venous oxygen saturation 70%
or 65%, respectively (grade 1C).
2. In patients with elevated lactate levels,
targeting resuscitation to normalize lactate
(grade 2C).
2016 RECOMMENDATIONS
A. INITIAL RESUSCITATION
1. Sepsis and septic shock are medical emergencies, and we
recommend that treatment and resuscitation begin immediately (BPS).
2. We recommend that, in the resuscitation from sepsis-induced
hypoperfusion, at least 30 mL/kg of IV crystalloid fluid
be given within the first 3 hours (strong recommendaon, low quality of
evidence).
3. We recommend that, following initial fluid resuscitation, additional
fluids be guided by frequent reassessment of hemodynamic status
(BPS).
Remarks: Reassessment should include a thorough clinical examinaon
and evaluation of available physiologic variables (heart rate, blood
pressure, arterial oxygen saturation, respiratory rate, temperature,
urine output, and others, as available) as well as other noninvasive or
invasive monitoring,as available.
4. We recommend further hemodynamic assessment (such as assessing
cardiac funcon) to determine the type of shock if the clinical
examination does not lead to a clear diagnosis (BPS).
5. We suggest that dynamic over static variables be used to predict
fluid responsiveness, where available (weak recommendation, low
quality of evidence).
6. We recommend an initial target MAP 65 mmHg in patients
with septic shock requiring vasopressors (strong recommendaon,
moderate quality of evidence).
7. We suggest guiding resuscitation to normalize
lactate in patients with elevated lactate levels as a marker of
tissue hypoperfusion (weak recommendaon, low quality of evidence).
„SEPSIS TRILOGY“ (PROCESS, ARISE, PROMISE)
• ProCESS (hospital mortality at D60): n = 1351, 31 centers, mortality 21 % (EGDT),
18.2 % (modified protocol), 18.9 % (standard care).
• ARISE (comparison „all cause“ mortality at D90): n = 1600, 51 centers,
mortality 18.6 % (EGDT) and 18.8% (standard).
• ProMISe (comparison „all cause“ mortality at D90): n = 1260, 56 centers,
mortality 29.5 % (EGDT) and29.2 % (standard).
Metaanalysis: EGDT not superior, more costly.
Investigators TP. A randomised trial of protocolised care for early septic shock.
N Engl J Med, 2014, 370, p. 1683–1693.
ARISE Investigators. Goal-directed resuscitation for patients with early septic
shock. N Engl J Med, 2014, 371, p. 1496–1506. doi: 10.1056/NEJMoa1404380. Epub
2014, Oct 1.
MOUNCEY, PR., OSBORN, TM., POWER, GS. ,ET AL. Trial of early, goal-directed
resuscitation for septic shock. N Engl J Med, 2015, 372, p. 1301–1311. doi: 10.1056/
NEJMoa1500896. Epub 2015, Mar 17.
ANGUS, DC., BARNATO, AE., BELL, D., ET AL. A systematic review and meta-analysis
of early goal-directed therapy for septic shock: the ARISE, ProCESS and
ProMISe Investigators. Intensive Care Med, 2015, 41, p. 1549–1560. doi: 10.1007/
s00134-015-3822-1. Epub 2015, May 8.
2012 RECOMMENDATIONS
A. INITIAL RESUSCITATION
1. Protocolized, quantitave resuscitaon of
patients with sepsis-induced tissue
hypoperfusion (defined in this document as
hypotension persisting after initial fluid
challenge or blood lactate concentration 4
mmol/L). Goals during the first 6 hr
resuscitation:
• a. Central venous pressure 8–12 mm Hg
• b. Mean arterial pressure ≥ 65 mm Hg
• c. Urine output ≥ 0.5 mL/kg/hr
• d. Central venous (superior vena cava)
or mixed venous oxygen saturation 70%
or 65%, respectively (grade 1C).
2. In patients with elevated lactate levels,
targeting resuscitation to normalize lactate
(grade 2C).
2016 RECOMMENDATIONS
A. INITIAL RESUSCITATION
1. Sepsis and septic shock are medical emergencies, and we
recommend that treatment and resuscitation begin immediately (BPS).
2. We recommend that, in the resuscitation from sepsis-induced
hypoperfusion, at least 30 mL/kg of IV crystalloid fluid
be given within the first 3 hours (strong recommendaon, low quality of
evidence).
3. We recommend that, following initial fluid resuscitation, additional
fluids be guided by frequent reassessment of hemodynamic status
(BPS).
Remarks: Reassessment should include a thorough clinical examination
and evaluation of available physiologic variables (heart rate, blood
pressure, arterial oxygen saturation, respiratory rate, temperature,
urine output, and others, as available) as well as other noninvasive or
invasive monitoring,as available.
4. We recommend further hemodynamic assessment (such as assessing
cardiac funcon) to determine the type of shock if the clinical
examination does not lead to a clear diagnosis (BPS).
5. We suggest that dynamic over static variables be used to predict
fluid responsiveness, where available (weak recommendation, low
quality of evidence).
6. We recommend an initial target MAP 65 mmHg in patients
with septic shock requiring vasopressors (strong recommendaon,
moderate quality of evidence).
7. We suggest guiding resuscitation to normalize
lactate in patients with elevated lactate levels as a marker of
tissue hypoperfusion (weak recommendaon, low quality of evidence).
treatment of septic shock acc.
pythophysiology
noxa
Infekt
(LPS,PG)
nekrosa
hypoxie
I/R
Mono Leu
TNF IL1,IL6
IL10
NFkappaB
+ transkripční faktory
endothel, hladká svalovina cév
iNOS,COX2,iHO NO
TX,PG
CO
další systémy: koagulace, komplement, kininy...
ROC (OH.)
ONOO
elastáza
SOD, kataláza
Se,vit C,vit E
PAF
adhese
+ PARS
anticytokiny (antiTNF-alfa, TNF sol rec, IL-1ra, antiPAF…..
blokátory NOS (meth. Modř, L-NMMA), iNOS,
COX - ibuprofen, COX 2
antioxidační koktejly (NAC - broncholysin, pentoxyphilyn)
blokátory PARS (nikotinamid)
TXA1 - PgE2
coagulation: AT III, activated protein C – not on the market
complement: inhibitor C1 esterase
• hydrocortisone – most severe forms of SS
• vasopresine – YES (less severe SS?)
• mimotělní eliminační metody – ne (D.Payen)
• angiotensine II (sepsis + ARDS?)
Th acc. pathophysiology of septic
shock II
terapy SEPSIS conclusion
Algorithm leading to error elimination:
• Time to check the patient
• Consult
• Repeat/Monitor (clinics, lab)
• Neurology – „time is brain“
• Cardiology – time is muscle“
• Intensive care (SEPSIS) – TIME IS LIFE
Public: Education (sepsis…..)
Hospitals: Active search for unsbale patients -
RRT/METcall
CONCLUSION