2. • Sepsis/septic shock is a life-threatening and
time-dependent condition that requires timely
management to reduce mortality.
• life-threatening organ dysfunction caused by a
dysregulated host response to infection.
• Circulatory, cellular, and metabolic
abnormalities contribute to a greater risk of
mortality
3. • Sepsis represents a spectrum of disease with
mortality risk ranging from moderate (eg,
10%) to substantial (eg, > 40%) depending on
various pathogen and host factors along with
the timeliness of recognition and provision of
appropriate treatment.
4. • Septic shock is a subset of sepsis with
significantly increased mortality due to severe
abnormalities of circulation and/or cellular
metabolism.
• Septic shock involves persistent hypotension
(defined as the need for vasopressors to maintain
mean arterial pressure ≥ 65 mm Hg, and a serum
lactate level > 18 mg/dL [2 mmol/L] despite
adequate volume resuscitation
5. SIRS
• Early sepsis: abnormalities of vital signs and
laboratory results.
• However, SIRS criteria have been found to lack
sensitivity and specificity for increased
mortality risk.
• The lack of specificity may be because the SIRS
response is often adaptive rather than
pathologic.
6. High incidence
• Advanced average age among patients
• Immunocompromised patients and patients with
chronic and debilitating diseases.
• DM
• Cirrhosis
• Leukopenia (especially that associated with
cancer or treatment with cytotoxic medications)
• Invasive devices (including endotracheal tubes,
vascular or urinary catheters, drainage tubes, and
other foreign materials)
7. • Prior treatment with antibiotics or
corticosteroids
• Recent hospitalization (especially in an
intensive care unit)
• Common causative sites of infection include
the lungs and the urinary, biliary, and
gastrointestinal tracts.
8. • Gram-positive bacteria are Staphylococcus
aureus and Streptococcus pneumoniae,
whereas among the Gram-negative bacteria,
those most commonly identified
are Escherichia coli, Klebsiella,
and Pseudomonas
• Rarely, it is caused by Candida or other fungi.
• A postoperative infection
9. • A unique, uncommon form of shock caused by
staphylococcal and streptococcal toxins is
called toxic shock syndrome.
• Sites of infection , respiratory tract/pulmonary
parenchyma (43%); the urinary system (16%);
the abdomen (14%); the head, which is
associated with a fever of unknown origin
(FUO) (14%); and other sites/causes (13%)
10. Pathophysiology of Sepsis and Septic
Shock
• A pathogenetic, sepsis-related cellular
modifications ,progression of microcirculation
from sepsis to septic shock
• The endothelium play a role in the regulation
of microcirculation and the modulation of
coagulation mechanisms and inflammatory
and anti-inflammatory signaling processes
11. • The glycocalyx is a component of the
endothelial membrane consisting of
proteoglycans and glycoproteins
• Construction of a mechanical barrier
regulating vascular permeability, the
activation of leukocytes and platelet adhesion,
and the modulation of the inflammatory/anti-
inflammatory response.
•
12. • Damage to the glycocalyx’s morpho-functional
integrity (known as “glycocalyx shedding”) can
occur due to oxidizing agents, cytokines,
exotoxins, and bacterial endotoxins.
• This event leads to leukocyte diapedesis and
increased vascular permeability with the
production of edema, which raises interstitial
pressure and worsens tissue perfusion
•
13. • Inflammatory stimulus (eg, a bacterial toxin)
triggers production of pro-inflammatory
mediators, including tumor necrosis factor (TNF)
and interleukin (IL)-1.
• These cytokines cause neutrophil–endothelial cell
adhesion, activate the clotting mechanism, and
generate micro thrombi.
• They also release numerous other mediators,
including leukotrienes, lipoxygenase, histamine,
bradykinin, serotonin, and IL-2.
14. • They are opposed by anti-inflammatory
mediators, such as IL-4 and IL-10, resulting in a
negative feedback mechanism.
• Initially, arteries and arterioles dilate, decreasing
peripheral arterial resistance; cardiac output
typically increases.
• This stage has been referred to as warm shock.
Later, cardiac output may decrease, blood
pressure falls (with or without an increase in
peripheral resistance), and typical features of
hypoperfusion
15. • Even in the stage of increased cardiac output,
vasoactive mediators cause blood flow to
bypass capillary exchange vessels (a
distributive defect).
• Poor capillary flow resulting from this
shunting, along with capillary obstruction by
micro thrombi, decreases delivery of oxygen
and impairs removal of carbon dioxide and
waste products.
16. • Hypoperfusion causes dysfunction and
sometimes failure of one or more organs,
including the kidneys, lungs, liver, brain, and
heart.
• Coagulopathy may develop because of
intravascular coagulation with consumption of
major clotting factors, excessive fibrinolysis
17. Symptoms and Signs of Sepsis and
Septic Shock
• history, physical examination, Sepsis is
suspected when a patient with a known
infection develops systemic signs of
inflammation or organ dysfunction
• mistaken for manifestations of other disorders
(eg, primary cardiac dysfunction, pulmonary
embolism, delirium), especially in
postoperative patients.
18. • fever, tachycardia, diaphoresis, and
tachypnea; blood pressure remains normal.
• Other signs of the causative infection may be
present As sepsis worsens or septic shock
develops, an early sign, particularly in older
people or the very young, may be confusion or
decreased alertness.
• Blood pressure decreases, yet the skin is
paradoxically warm.
19. • Later, extremities become cool and pale, with
peripheral cyanosis and mottling.
• Organ dysfunction causes additional
symptoms and signs specific to the organ
involved (eg, oliguria, dyspnea
20. Diagnosis of Sepsis and Septic Shock
• Clinical manifestations
• Blood pressure (BP), heart rate, and oxygen
monitoring
• CBC with differential, electrolyte panel and
creatinine, lactate
• CVP, PaO2, and central venous oxygen
saturation (ScvO2)
21. • Cultures of (blood, urine, cultures of other
suspect body fluids and other potential sites
of infection, including wounds in surgical
patients).
•
22. • Ultrasonography (eg, Rapid Ultrasound for
Shock and Hypotension (RUSH) Examination ),
CT, or MRI may be required, depending on the
suspected source.’’
• C-reactive protein and procalcitonin,presepsin
are often elevated in severe sepsis and may
facilitate diagnosis
• Ultimately, the diagnosis is clinical.
23. • Other causes of shock (eg,
hypovolemia, myocardial infarction [MI]) should
be ruled out via history, physical examination,
ECG, and serum cardiac markers as clinically
indicated.
• Hypoperfusion caused by sepsis may result in
ECG findings of cardiac ischemia including
nonspecific ST-T wave abnormalities, T-wave
inversions, and supraventricular and ventricular
arrhythmias.
24. Scoring systems
• The sequential organ failure assessment score
(SOFA score) and the quick SOFA score
(qSOFA) have been validated with respect to
mortality risk and are relatively simple to use
• The qSOFA score is based on the blood
pressure, respiratory rate, and the Glasgow
Coma Scale and does not require waiting for
lab results.
25. • Outside ICU, the qSOFA score is a better
predictor of inpatient mortality than the
systemic inflammatory response syndrome
(SIRS) and SOFA score.
• For patients with a suspected infection who
sare in the ICU, the SOFA,LODS scores are a
better predictor of in-patient mortality than
the systemic inflammatory response
syndrome (SIRS) and qSOFA score
26. • Patients with ≥ 2 of the following criteria meet
criteria for SIRS and should have further clinical
investigation:
• Temperature > 38° C (100.4° F) or < 36° C (96.8° F)
• Heart rate > 90 beats per minute
• Respiratory rate > 20 breaths per minute or
PaCO2 < 32 mm Hg
• White blood cell count > 12,000/mcL (12 × 109/L),
< 4,000/mcL (4 × 109/L) or > 10% immature
(band) forms
27. • Patients with ≥ 2 of the following qSOFA
criteria should have further clinical and
laboratory investigation:
• Respiratory rate ≥ 22 breaths per minute
• Altered mentation
• Systolic blood pressure ≤ 100 mm Hg
• The SOFA score is somewhat more robust in
the ICU setting, but requires laboratory testing
28. • CBC, ABGs, chest x-ray, serum electrolytes,
BUN ,creatinine, and liver function are
monitored.
• Serum lactate levels, central venous oxygen
saturation (ScvO2)
• WBC count may be decreased or increased
(4000-15000).
29. • During the course of sepsis, the WBC count
may increase or decrease, depending on the
severity of sepsis or shock, the patient's
immunologic status, and the etiology of the
infection.
• Concurrent corticosteroid use may elevate
WBC count and thus mask WBC changes due
to trends in the illness
30. • Hyperventilation with respiratory
alkalosis (low PaCO2 and increased arterial
pH) occurs early, in part as compensation for
lactic acidemia.
• Serum bicarbonate is usually low, and blood
lactate levels increase.
• As shock progresses, metabolic acidosis
worsens, and blood pH decreases.
31. • Early hypoxemic respiratory failure leads to a
decreased PaO2:FIO2 ratio and sometimes overt
hypoxemia with PaO2 < 70 mm Hg. Diffuse
infiltrates may appear on the chest x-ray due
to acute respiratory distress syndrome (ARDS).
• BUN and creatinine usually increase progressively
as a result of renal insufficiency.
• Bilirubin and transaminases may rise, although
overt hepatic failure is uncommon in patients
with normal baseline liver function.
32. • Hemodynamic measurements with a central
venous or pulmonary artery catheter can be
used when the specific type of shock is
unclear or when large fluid volumes (eg, > 4 to
5 L balanced crystalloid within 6 to 8 hours)
are needed.
• Bedside echocardiography in the ICU is a
practical and noninvasive alternative method
of hemodynamic monitoring.
33. • In septic shock, cardiac output is increased
and peripheral vascular resistance is
decreased, whereas in other forms of shock,
cardiac output is typically decreased and
peripheral resistance is increased.
• Neither CVP nor pulmonary artery occlusive
pressure (PAOP) is likely to be abnormal in
septic shock, unlike in hypovolemic,
obstructive, or cardiogenic shock
34. • Many patients with severe sepsis develop
relative adrenal insufficiency
• Adrenal function may be tested by measuring
serum cortisol at 8 AM; a level < 5 mcg/dL
(< 138 nmol/L) is inadequate.
35. Treatment of Sepsis and Septic Shock
• Perfusion restored with IV fluids&electrolytes
• Vasoactive Agents
• Oxygen support
• Broad-spectrum antibiotics
• Source control
• Sometimes other supportive measures (eg,
corticosteroids, insulin)
36. • Patients with septic shock should be treated in an ICU.
• The following should be monitored frequently (as often
as hourly):
• Volume status using central venous pressure (CVP),
pulmonary artery occlusion pressure (PAOP), serial
ultrasound and/or central venous oxygenation
saturation (ScvO2)
• Arterial blood gases (ABGs)
• Blood glucose, lactate, and electrolyte levels
• Renal function
37. • Arterial oxygen saturation should be
measured continuously via pulse oximetry.
• Urine output, a good indicator of renal
perfusion, should be measured
• The onset of oliguria (eg, < about 0.5
mL/kg/hour) or anuria, or rising creatinine
may signal impending renal failure..
38. • Following evidence-based guidelines and
formal protocols for timely diagnosis and
treatment of sepsis has been shown to
decrease mortality and length of stay in the
hospital
39. • Perfusion restoration
• IV fluids are the first method used to restore
perfusion. severe vasoplegia, which is
secondary to the shedding of the glycocalyx,
lead to distributive shock
• Balanced isotonic crystalloid is preferred than
chloride-rich solutions.
40. • Add albumin(debatable) to the initial fluid
bolus in patients with severe sepsis or septic
shock.
• Starch-based fluids are associated with
increased mortality and should not be
used(suspended in Europe)
• Microcirculation perfusion does not
necessarily improve with the stabilization of
cardiovascular parameters
41. • Moreover, glycocalyx abnormalities and
endothelial dysfunction can even be worsened
by aggressive fluid therapy.
42. • Initially, 1 L of crystalloid is given rapidly. Most
patients require a minimum of 30 mL/kg in the
first hour.
• However, the goal of therapy is not to administer
a specific volume of fluid but to achieve tissue
reperfusion without causing pulmonary edema
due to fluid overload.
• Estimates of successful reperfusion include ScvO2
and lactate clearance (ie, percent change in
serum lactate levels over 6 to 8 hours).
43. Target fluid therapy
• an individualized treatment targeted toward
“glycocalyx resuscitation” according to fluid
tolerance (FT) and fluid responsiveness (FR)
• FT can be expressed as the degree to which a
patient can tolerate the administration of
fluids without the onset of organ dysfunction
• FR is commonly defined as a stroke volume
(SV) increase of at least 10% following a fluid
bolus of 200–500 mL in 10–15 min
44. • Target ScvO2 is ≥ 70%. Lactate clearance target is
10 to 20%. Risk of pulmonary edema can be
controlled by optimizing preload; fluids should be
given until CVP reaches 8 mm Hg (10 cm water)
or PAOP reaches 12 to 15 mm Hg; however,
patients on mechanical ventilation may require
higher CVP levels.
• Monitor FR (e.g., passive leg raise SPLR), SV, and
the collapsibility index of inferior vena cava (CI-
IVC))
45. Emergency Physician’s Point of View
• General agreement among experts favors the use of
dynamic tools instead of static ones
• The main resuscitation endpoints are progressively evolving
toward restoring microcirculation
• In 2018, Perner et al. proposed an individualized fluid
treatment based on a repeated bolus of 250–500 mL of IV
crystalloids with the continuous monitoring of FR and the
early administration of vasopressors if circulation fails to
improve
• However, a recent RCT demonstrated that the restrictive vs.
liberal fluid strategies did not significantly differ in terms of
90-day mortality among patients with sepsis
46. • Balanced crystalloids. an individualized strategy
of resuscitation based on FT and FR is
preferable. Since the clinical evidence is
equivocal
• No differences have been shown with respect
to restrictive vs. liberal fluid strategies
• Small and repeated boluses (250–500 mL) of
crystalloids with continuous hemodynamic
monitoring to avoid fluid overload.
47. • The quantity of fluid required often far exceeds
the normal blood volume and may reach 10 L
over 4 to 12 hours. PAOP or echocardiography
can identify limitations in left ventricular function
and incipient pulmonary edema due to fluid
overload.
• Point-of-care ultrasound can also be used to
assess volume status, including inferior vena cava
(IVC) distention or collapsibility, cardiac function,
and presence of pulmonary edema
48. Vasoactive Agents
• If a patient with septic shock remains hypotensive
after CVP or PAOP has been raised to target
levels, norepinephrine (highly individualized
dosing) or vasopressin (up to 0.03 units/minute)
may be given to increase mean blood pressure
(BP) to at least 65 mm Hg.
• Epinephrine may be added if a second medication
is needed. However, vasoconstriction caused by
higher doses of these medications may cause
organ hypoperfusion and acidosis.
49. • Recent RCTs have proposed a “permissive
hypotension” (MAP 60–65 mmHg) in patients
≥65 years with septic shock showing no
differences in 90-day mortality, whereas
higher blood pressure values (≥65 mmHg) do
not seem to add further benefits
50. LEVOPHED
• NE is an α-1/β-1 adrenergic agonist enhancing
vascular filling pressure and redistributing blood
flow via its venoconstrictive effect
• Improves myocardial contractility and cardiac
output (increasing preload) while having a minor
impact on heart rate
• Ideally, an inotropic drug assessment should
occur within the first hour if fluid infusion alone is
not sufficient to reach the desired MAP
51. Vasopressin
• VP a second-line choice for septic shock
treatment
• It can be administered (at a dose of 0.25–0.5
μg/kg/min) in addition to NE to obtain the
target MAP by decreasing the dosage of the
latter and reducing the side effects due to
adrenergic overload
52. Epinephrine
• a third-line treatment for septic shock, and its
use should be limited to those cases with
inadequate MAP levels despite NE and VP
administration
• As for VP, it can be used concomitantly with
NE. Due to its important β-adrenergic effect,
the use of epinephrine is indicated to a
greater extent in cases of cardiac dysfunction
53. • Furthermore, its administration may lead to
more side effects than those induced by NE
(e.g., tachycardia, tachyarrhythmia, and
increased blood lactate concentrations
54. Emergency Physician’s Point of View
• Vasopressors should be administered in cases of
an MAP < 65 mmHg despite fluid replacement.
• NE (at a dose of 0.1–1.2 μg/kg/min) is the drug of
choice for septic patients, and its early
administration could prevent fluid overload, thus
reducing mortality.
• VP (at a dose of 0.25–0.5 μg/kg/min) might be
associated with NE when target MAP is not
achieved.
55. Ventilation
• low-tidal-volume ventilation (LTVV), proposing
a reduction in tidal volume from 10 to 6 mL/kg
for septic patients at the ED
• The use of LTVV is associated with improved
clinical outcomes for mechanically ventilated
ED patients.
56. Oxygenation and Ventilation Support
• In clinical practice, oxygen is overused, often
leading to hypoxemia, which may negatively
impact patients’ survival.
• Oxygen therapy or targets (generally defined
as PaO2 55 to 70 mmHg; SpO2 88 to 92%) for
adults(risk of hypercarbia)
• Very low evidence regarding an optimal
oxygenation strategy for acutely ill adults
57. High-Flow Nasal Cannula
• HFNC provides heated and humidified oxygen
at high flow rates, generating low levels of
positive pressure in the upper airways.
• HFNC induces multiple effects, including
increased oxygenation, lower respiratory
rates, and reduced inspiratory effort, thus
improving survival rates for patients with
acute hypoxic respiratory failure
58. Emergency Physician’s Point of View
• Oxygen therapy should be started at 15 L/min
via a reservoir mask and titrated to aim
toward SpO2 94–98% or SpO2 88–92% if the
patient is at risk of hypercapnic respiratory
failure
• For patients on NIV/MV, we suggest a low tidal
volume (6 mL/kg).
• An HFNC may be successfully used in septic
patients with hypoxic respiratory failure.
59. Other Treatments
• Heparin
• VTE prophylaxis should be administered to
sepsis/septic shock patients, preferably using
LMWH (rather than UFH)
• Mechanical prophylaxis may be advised for
the treatment of patients with absolute
contraindications to heparin treatment.
60. Insulin
• glycemic control (with a glucose target
between 144 to 180 mg/dL), preferably via
insulin administration, is highly recommended
for septic patients
61. Proton Pump Inhibitors
• The current evidence does not provide any
further information about PPI assessment for
stress ulcer prophylaxis in patients with
sepsis/septic shock
62. Renal Replacement Therapy
• AKI is a common complication in septic
patients, sepsis alone is not an indication for
RRT. Thus, we suggest referring to specific AKI
guidelines for this highly debated issue
63. Steroids
• The routine table use of glucocorticoids (alone
or in combination with fludrocortisone) in
septic shock management is not adequately
supported by the current evidence.
• The use of hydrocortisone may be considered
for patients with a vasopressor-resistant,
inadequate MAP.
64. Sodium Bicarbonate
• Despite controversial evidence, sodium
bicarbonate is a reasonable treatment for
septic patients with severe metabolic/lactic
acidosis (bicarbonate levels <5 mEq/L and/or
pH < 7.1) or an AKI stage 2 or 3.
• Therefore, this therapy should be indicated as
a bridge to be crossed before the main pillars
of treatment begin to be effective.
66. Antibiotics
• Parenteral antibiotics should be given as soon as
possible after specimens of blood, body fluids, and
wound sites have been taken for Gram stain and
culture.
• Prompt empiric therapy, started immediately after
suspecting sepsis, is essential and may be lifesaving.
• Antibiotic selection requires an educated guess based
on the suspected source (eg, pneumonia, urinary tract
infection), clinical setting, knowledge or suspicion of
causative organisms and of sensitivity patterns
common to that specific inpatient unit or institution,
and previous culture results.
67. • Typically, broad-spectrum gram-positive and
gram-negative bacterial coverage is used
initially; immunocompromised patients should
also receive an empiric antifungal medication.
• There are many possible starting regimens;
when available, institutional trends for
infecting organisms and their antibiotic
susceptibility patterns (antibiograms) should
be used to select empiric treatment.
68. • In general, common antibiotics for empiric gram-
positive coverage
include vancomycin and linezolid.
• Empiric gram-negative coverage has more
options and includes broad-spectrum penicillins
(eg, piperacillin/tazobactam), 3rd- or 4th-
generation cephalosporins, imipenems, and
aminoglycosides.
• Initial broad-spectrum coverage is narrowed
based on culture and sensitivity data.
69. Source control
• The source of infection should be controlled as early as
possible.
• IV and urinary catheters and endotracheal tubes should be
removed if possible or changed.
• Abscesses must be drained, and necrotic and devitalized
tissues (eg, gangrenous gallbladder, necrotizing soft-tissue
infection) must be surgically excised.
• If excision is not possible (eg, because of comorbidities or
hemodynamic instability), surgical drainage may help.
• If the source is not controlled, the patient’s condition will
continue to deteriorate despite antibiotic therapy.
70. Other supportive measures
• Normalization of blood glucose improves
outcome in critically ill patients, even those not
known to be diabetic, because hyperglycemia
impairs the immune response to infection.
• A continuous IV insulin infusion (starting dose 1
to 4 units/hour) is titrated to maintain glucose
between 110 and 180 mg/dL (7.7 to 9.9 mmol/L).
This approach necessitates frequent (eg, every 1
to 4 hours) glucose measurement.
71. • Corticosteroid therapy (eg, hydrocortisone < 400 mg IV
per day in divided doses) is indicated for patients with
adrenal insufficiency documented by cortisol testing.
• However, in refractory septic shock (systolic blood
pressure < 90 mm Hg for more than 1 hour following
both adequate fluid resuscitation and vasopressor
administration, attainment of source control, and
antibiotics), no cortisol testing is required before
starting corticosteroid therapy
• Continued treatment is based on patient response.
72. Prognosis for Sepsis and Septic shock
• Overall mortality in patients with septic shock
is decreasing and now averages 30 to 40%
(range 10 to 90%, depending on patient
characteristics).
• Poor outcomes often follow failure to institute
early aggressive therapy
73. • Once severe lactic acidosis with
decompensated metabolic acidosis becomes
established, especially in conjunction with
multiorgan failure, septic shock is likely to be
irreversible and fatal.
• Mortality can be estimated with different scores
• Mortality in emergency department sepsis
(MEDS) score.
• The multiple organ dysfunction score (MODS)
measures dysfunction of 6 organ systems and
correlates strongly with risk of mortality
74. Home messages
• The management of sepsis/septic shock is challenging
and involves different pathophysiological aspects
• empirical antimicrobial treatment (which is promptly
administered after microbial tests)
• fluid (crystalloids) replacement (to be established
according to fluid tolerance and fluid responsiveness)
• vasoactive agents (e.g., norepinephrine (NE)), which
are employed to maintain mean arterial pressure
above 65 mmHg and reduce the risk of fluid overload.
75. • In cases of refractory shock, vasopressin (rather
than epinephrine) should be combined with NE
to reach an acceptable level of pressure control.
• If mechanical ventilation is indicated, the tidal
volume should be reduced from 10 to 6 mL/kg.
• Heparin is administered to prevent venous
thromboembolism and glycemic control is
recommended
76. • The efficacy of other treatments (e.g., proton-
pump inhibitors, sodium bicarbonate, etc.) is
largely debated, and such treatments might
be used on a case-to-case basis.
