sepsis is a major cause of mortality world wide, it need to raise the awareness about early detection of patients at risk

1. SEPSIS
THE SERIAL KILLER
DR.MAGDY KHAMES ALY
CRITICAL CARE MEDICINE
ZMH AL BATAYEH

2. INTRODUCTION
• SEPSIS and the multiorgan failure that often
accompanies the systemic inflammatory response
syndrome (SIRS) is a leading cause of mortality in the
intensive care unit. Over 750,000 patients develop sepsis
annually in the United States accounting for about 10%
of all intensive care unit (ICU) admissions
• In UAE no solid statistics but roughly about 7% died
from infectious diseases in 2013 according to
http://global-health.healthgrove.com/l/314/United-Arab-
Emirates

3. DEFINITIONS
SEPSIS:
Life-threatening acute organ dysfunction caused by a dysregulated host
response to infection. Organ dysfunction: acute change in SOFA score ≥ 2
points from infection.
SEPTIC SHOCK:
Sepsis with hypotension requiring vasopressors to maintain MAP ≥ 65
mmHg and having a serum lactate level > 2mmol/dL despite adequate
volume resuscitation.
• Further refinements in sepsis terminology may be possible when rapid
diagnostic techniques become available to assess the immune status of
septic patients. Functional genomics and proteomics may assist in
characterizing septic patients in the future.

4. PATHOGENESIS
• MICROBIAL FACTORS:
• Bacterial endotoxin and other bacterial components:
Bacterial endotoxin, or lipopolysaccharide (LPS) in the
circulation
provokes a vigorous systemic inflammatory response.
Humans are especially susceptible to the profound
immunostimulant properties of endotoxin; even minute
doses may be lethal.
bacterial lipoteichoic acid, lipopeptides and even
sequences of bacterial and viral DNA can be detected by
the immune system and activate innate immune
responses.

5. PATHOGENESIS
• MICROBIAL FACTORS:
• Bacterial superantigens
Bacterial superantigens comprise a diverse group of
protein-based exotoxins from streptococci,
staphylococci, and other pathogens that all share the
capacity to bind to specific sites on major
histocompatibility class II molecules on antigen
presenting cells and activate large numbers of CD4+ T
cells, bypassing the usual mechanism of antigen
processing and presentation.

6. PATHOGENESIS
• MICROBIAL FACTORS:
• Other microbial mediators
Translocation of microbial components such as bacterial
endotoxin occurs from the GI tract to the circulation
during periods of severe stress and hypoperfusion of the
GI mucosa. Bacterial endotoxin and perhaps other gut-
derived microbial mediators might play a pathogenic
role in the ongoing inflammatory process after systemic
hypotension produced by infectious or noninfectious
insults.

7. PATHOGENESIS
• HOST-DERIVED MEDIATORS:
• Cytokines
Inflammatory cytokines play a pivotal role in sepsis pathogenesis. The
major proinflammatory cytokines, TNF-α and IL-1β, induce their
hemodynamic and metabolic effects in concert with an expanding
group of host-derived inflammatory mediators that work in a
coordinated fashion to produce the systemic inflammatory response.
The cytokine system functions as a network of communication signals
between neutrophils, monocytes, macrophages, and endothelial cells.
The endocrine-like effect of systemic cytokine and chemokine release
drives the inflammatory process and causes coagulation activation
throughout the body.

8. PATHOGENESIS
• HOST-DERIVED MEDIATORS:
• CD4+ T helper cells
• The coagulation system
Activation of the coagulation cascade and generation of a
consumptive coagulopathy and diffuse microthrombi are well-
recognized events in sepsis.
• Neutrophil–endothelial cell interactions
Activated neutrophils degranulate, exposing endothelial surfaces
and surrounding structures to reactive oxygen intermediates, nitric
oxide, and a variety of proteases. This process contributes not only
to microbial clearance but also to diffuse endothelial injury in the
setting of systemic inflammation.

9. PATHOGENESIS
• HOST-DERIVED MEDIATORS:
• Nitric oxide
• Nitric oxide is the major endothelial-derived relaxing factor that
initiates the vasodilation and systemic hypotension observed in
septic shock. Nitric oxide activates guanylate cyclase, which
increases cyclic guanosine monophosphate levels inside vascular
smooth muscle cells. This results in systemic vasodilation and
decreased vascular resistance. Excessive and prolonged release
of nitric oxide results in generalized vasodilatation and systemic
hypotension. In the presence of superoxide anion, nitric oxide
leads to the formation of peroxynitrite and highly cytotoxic
molecules, such as hydroxyl radicals and nitrosyl chloride,
which then initiate lipid peroxidation and cause irreversible
cellular damage.

10. PATHOGENESIS
• HOST-DERIVED MEDIATORS:
• Late host-derived mediators:
Macrophage migration inhibitory factor is a late mediator that
activates immune cells, upregulates TLR4 expression, and
contributes to lethal septic shock. This corticosteroid-regulated
mediator promotes inflammation and has become a target for
therapeutic agents in sepsis. The nuclear protein high-mobility
group box–1 protein is released into the extracellular space with
cell injury and necrosis and also participates in late-onset
inflammatory phase of septic shock.

11. ORGAN DYSFUNCTION
• CAUSES:
• Inadequate tissue blood supply and repeated episodes of ischemia-
reperfusion
• Failure of the microcirculation to support tissue maintenance may
result from capillary bed hypoperfusion, blood flow redistribution
within vascular beds, functional arteriovenous shunting, blood flow
obstruction from microthrombi, platelet or white blood cell
aggregates, or abnormal red blood cell deformability.
• Nitric oxide, reactive oxygen intermediates, inflammatory cytokines,
and apoptosis inducers may directly damage endothelial surfaces.
• Endothelial swelling shifts intravascular fluid into extravascular and
intracellular spaces, mechanically obstructing capillary lumens and
further limiting microvascular blood flow.
• Myocardial performance and pulmonary function also diminish over
the course of septic shock and may contribute to the development of
MODS.

12. PATHOGENESIS

13. PATHOGENESIS

14. APPROACH TO SEPSIS
• “Hectic fever [meaning sepsis] at its inception
is difficult to recognize but easy to treat; left
unattended, it becomes easy to recognize but
difficult to treat.” Machiavelli 1505

15. • Fully developed septic shock is a readily
apparent clinical syndrome that is seldom
confused with other pathologic states.
However, the early phases of septic shock may
be quite subtle even in carefully monitored
patients. Although fever is characteristic,
hypothermia may occur and connotes a poor
prognosis.
• Early recognition of sepsis and septic shock
risk factor is a challenge

16. SOFA
• The updated international guidelines use the Sequential [Sepsis-
Related] Organ Failure Assessment Score to define sepsis
(SOFA).
Laboratory criteria included in the SOFA focus on the presence of:
• Coagulopathy
• Hepatic dysfunction
• And/or renal dysfunction.
Other nonspecific laboratory criteria, such as peripheral white
blood cell count can aid in the general diagnosis of infection but are
no longer used to define sepsis or septic shock.

17. SOFA

18. QSOFA

19. • qSOFA & SOFA are mortality predictors, not
tests for sepsis
• The SOFA score is an illness-severity score

20. SIRS VS SOFA AND QSOFA
• Although qSOFA may be valuable in predicting sepsis-
related mortality, it performed poorly as a screening
tool for identifying sepsis in the ED.
• As the time to meet qSOFA criteria was significantly
longer than for SIRS, relying on qSOFA alone may delay
initiation of evidence-based interventions known to
improve sepsis-related outcomes.
• SIRS might indeed be too sensitive to diagnose sepsis,
and as such, it would be better to exclude SIRS from the
sepsis diagnostic criteria entirely. It should be
emphasized, however, that removal of SIRS from the
diagnostic criteria does not equate the end of SIRS as a
concept.

21. • Comparison with SIRS
• In the data set used to retrospectively validated the
Sepsis 3 criteria:
• In ICU patients with suspected infection, SOFA (AUROC = 0.74;
95% CI, 0.73-0.76) was superior to SIRS (AUROC = 0.64; 95%
CI, 0.62-0.66) for predicting hospital mortality
• In patients outside of the ICU, SOFA (AUROC = 0.79; 95% CI,
0.78-0.80) or change in SOFA score (AUROC = 0.79; 95% CI,
0.78-0.79) was similar to that with SIRS (AUROC = 0.76; 95%
CI, 0.75-0.77) for predicting hospital mortality
• Therefore, SIRS is indeed not yet dead, but it will remain permanently
NEEDED ESPCIALY IN ED

22. Acute phase
reactants/biomarkers
• C-reactive protein (CRP):
-CRP is helpful when normal but is not specific for infection when
elevated. CRP can be elevated for days following surgery and will also be
elevated in rheumatologic and neoplastic illnesses.
-Very high CRP levels (> 85 mg/L) is useful in distinguishing infection
from non-infectious causes of acute systemic inflammation.
• Serum procalcitonin (PCT):
-PCT is an FDA approved test to aid in the risk assessment of patients
with sepsis. A recent meta-analysis of studies examining confirms the
value of PCT to distinguish sepsis for noninfectious causes of systemic
inflammation. Levels of PCT more than 2 ng/mL is the best cutoff value
in the early diagnosis of bacterial sepsis.

23. Management of septic shock

24. • The management of a patient with septic shock
begins with prompt recognition of the condition and
the rapid administration of appropriate antibiotic
therapy as well as source control of infection.
• Attention is simultaneously given to failing organs
with institution of measures including fluid
resuscitation, vasopressors, blood transfusions, and
inotropic agents as needed to maximize oxygen
delivery.
• Patients with ARDS are managed with low tidal
volume ventilator strategies to minimize damage
induced by overstretching the alveoli.

25. • Current sepsis bundles
• Sepsis bundles to be completed within the first 3-hour
- Measure lactate level
-Obtain blood cultures prior to administration of antibiotics
-Administer broad spectrum antibiotics
-Administer 30 mL/kg crystalloid for hypotension or lactate ≥4
• Sepsis bundles to be completed within the first 6-hour
-Apply vasopressors (for hypotension that does not respond to
initial fluid resuscitation) to maintain a MAP ≥65 mmHg
-When persistent hypotension after initial fluid administration
(MAP <65 mmHg) or if initial lactate was ≥4 mmol/L, re-assess
volume status and tissue perfusion (repeat focused exam, measure
CVP or ScvO2, bedside cardiovascular ultrasound, dynamic
assessment of fluid responsiveness)
• Re-measure lactate if initial lactate elevated

26. • Pitfalls of current sepsis bundles
• Measurement of ScvO2 no longer a first line
goal therapy.
• Measurement of central venous pressure to
assess volume status.
• Administration of large volume of crystalloid.
• Delayed administration of vasopressors.

27. • Static fluid status measurements (i.e. Central Venous
Pressure) No longer recommended as lone
guiding principles as they carry limited value for
measuring fluid responsiveness
• 2017 guidelines recommend the use of dynamic
variables over static variables to predict fluid
responsiveness (ie passive leg raise, pulse pressure
variation, stroke volume variation)

28. Hemodynamic Management of
Patients with Septic Shock
• Hemodynamic management includes:
1. Making the diagnosis of septic shock (as one
differential diagnosis of circulatory shock),
2. Assessing the hemodynamic status (volume status,
fluid responsiveness, need for vasopressor, or
inotropic agent) including the identification of
therapeutic conflicts (e.g., intravascular hypovolemia
in the presence of pulmonary fluid overload)
3. Guiding therapeutic interventions.

29. • The hemodynamic management of septic shock
patients remains a complex challenge. There are
no SSC guideline recommendations on the
hemodynamic management for the period
following the initial 6 hours of treatment in septic
shock. A consensus conference report of the
European Society of Intensive Care Medicine
(ESICM) can provide guidance on how to perform
hemodynamic monitoring in critically ill patients
with circulatory shock

30. SEPSIS BUNDLE VS EGDT
• Sepsis bundles after multicenter randomized
clinical trials on EGDT:
Three recent multicenter randomized studies (ProCESS, ARISE
and ProMISe) have shown that EGDT using ScvO2 did not reduce
all-cause mortality.
• EGDT for Sepsis, Seen Through PRISM:
The PRISM analysis included a total of 3,723 patients at 138
hospitals in seven countries, with a subgroup analysis of the sickest
patients included in the three trials.

31. PRISM AND EGDT
• Investigators found:
-90-day mortality was statistically identical for EGDT (24.9%) and
usual care (25.4%)
-EGDT was associated with more ICU days (mean 5.3 days vs. 4.9
days) and vasoactive drug use (1.9 days vs. 1.6 days)
-There were higher costs with EGDT
-No benefit from EGDT for patients with worse septic shock (higher
lactate levels, predicted mortality, or with combined hypotension and
hyperlactatemia)
-PRISM's sickest one-third of patients by risk scoring had a 45%
mortality in both the EGDT and usual care arms, and was 4x the size of
the entire 2001 EGDT trial.

32. • Beyond the sepsis bundles, the prognosis of septic shock is
tightly linked to the earliness of both appropriate antibiotic
therapy and early aggressive hemodynamic
resuscitation.
• This includes administration of fluids and of vasopressors in
order to target a MAP >65 mmHg, which remain the
cornerstone of the management of septic shock patients.
Nevertheless, the implementation of sepsis bundles results in a
decrease in mortality and to better outcomes in septic shock
patients. These benefits mainly depend on the compliance with
the sepsis bundles, highlighting the importance of dedicated
educational programs.

33. KEY POINTS
• Early recognition of sepsis and patient at risk is the major
challenge
• Early administration of antibiotic and control of infection is the
most important
• Early aggressive hemodynamic resuscitation also the main
factor in improving patients outcome.
• Fluids vs vasopressors which one first or both together in
aggressive hemodynamic resuscitation need more study to
validate
• Amount of fluids given how much? How to assess?
• SIRS still needed, qSOFA not enough to assess SEPSIS in ED
• No single biomarker is enough to diagnose SEPSIS, combined
biomarkers and developing score for diagnosis is needed