Sepsis and Septic Shock

Question 1

Epidemiology

Answer 1

• ~ 2% of hospitalizations in developed countries
• 6-30% of intensive care unit patients
• Severe sepsis reported in 50-100 per 100,000 persons
• May account for > 34% of in-hospital deaths in United States

Question 2

Pathophysiology

Answer 2

• Host immune system recognizes and responds to
presence of microorganisms in the body
• Host cells bind to Toll-like receptors and others on
microorganisms
• Triggers increased transcription of
• pro-inflammatory mediators (TNF-α, IL-1β),and
• anti-inflammatory cytokines (IL-10)
• These immunomodulatory cytokines activate neutrophils
which attack the offending microorganism
• Result: “overly exuberant inflammation”

• Activated neutrophils also injure endothelium
• Leads to release of mediators that ↑ vascular permeability
• Increased permeability leads to fluid loss to ‘third space’ (hypotension and edema)
• Activated endothelial cells release nitric oxide which causes profound vasodilation
• Vasodilation and intravascular fluid loss result in
***profound hypotension

Question 3

Pathophysiology
what cascade is activated?

_________ lodge in small vessels and contribute to hypoperfusion and damage to tissues and organs

Answer 3

• Activated endothelium produces tissue factors and activation
of the clotting cascade
• Factor VIIIa → thrombin → fibrinogen to fibrin → binding of platelets = microvascular thrombi and disseminated intravascular coagulation (DIC)
• Microvascular thrombi lodge in small vessels and contribute to hypoperfusion and damage to tissues and organs

Question 4

see slide 9

Answer 4

during a protective immune response which is depicted on the left hand side of this chart a balanced response entails a variety of pro-inflammatory reactions followed by a return to homeostasis by a set of compensatory mechanisms aimed at tempering the initial inflammation and tissue repair but if the pathogen succeeds in multiplying the immune response becomes unbalanced and harmful to the host (right hand side of chart), so host repsonse during sepsis characterized by concurrent hyperinflation (top of chart) and immunosuppressin (bottom)

Question 5

pathophys

Vasodilation and increased vascular permeability and
fluid loss can lead to profound hypotension
• Profound hypotension and intravascular coagulation
contribute to:

Hypotension and intravascular fluid loss
• result in: reduced ______ and __________ lead to _______

Answer 5

hypoperfusion and damage to vital
organs
• Kidneys
• Brain
• Heart
• Lungs
• Liver

Hypotension and intravascular fluid loss
• result in reduced preload and
• along with tissue damage to the heart
• lead to reduced cardiac output

Myocardial depressants (nitric oxide and others)
• result in reduced myocardial contractility and
• reduced cardiacoutput

Question 6

pathophys

summary

______ + ______ = hypotension
______ + ______ = reduced Cardiac Output and profound hypotension

increased clotting leads to formation of _______

Answer 6

• Increased Permeability + Reduced intravascular volume
= Hypotension
• Myocardial Depressants Produced (Nitric Oxide etc)
• Hypotension + Myocardial Depression = reduced Cardiac Output and profound hypotension
• Increased clotting leads to formation of Microthrombi

• Hypotension + Reduced Cardiac Output + Microthrombi = Profound Hypotension and Reduced Tissue Perfusion and End Organ Damage

Question 7

Pathophysiology

what does poor tissue perfusion lead to?

Answer 7

• Poor tissue perfusion and reduced oxygenation
results in lactic acid production and acidosis
• Poor perfusion and intravascular coagulation result in
renal dysfunction and reduced urine output
• Poor perfusion, increased permeability, and intravascular coagulation result in acute pulmonary injury, pulmonaryn edema, and acute respiratory distress syndrome (ARDS), which also results in poor oxygenation and increasing acidosis
• Poor perfusion, increased permeability, and intravascularcoagulation result in reduced perfusion of the brain, confusion, delerium, loss of consciousness

Question 8

Pathogenesis of Cardiovascular Deficiency

signs of hypoperfusion

Answer 8

serum lactate, bicarb

markers like C-reactive protein, BNP, interleukin B, endog protein C, endotoxin

Question 9

Systemic Inflammatory Response Syndrome (SIRS)

• Old term for systemic response to a wide range of stresses

Answer 9

• Criteria included two or more of the following:
▫ Temperature > 38ºC or < 36ºC
▫ Heart rate > 90 bpm
▫ Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHG
▫ WBC > 12 (or < 4) x 109
/L or > 10% immature (band) forms

Question 10

Sepsis
old vs new definition

dont need to use SOFA score - predict morbidity rather than mortality

Answer 10

• The systemic response to infection
• Old definition: SIRS + proven or clinically suspected infection
▫ With exceptions of leukopenia and hypothermia, these changes are among the body’s normal systemic responses to infection and do not necessarily
imply a poor prognosis

• New definition more closely matches old definition of “severe sepsis”:
▫ Life-threatening organ dysfunction caused by a dysregulated host responseto infection. Organ dysfunction – acute change in total Sequential Organ
Failure Assessment (SOFA) score ≥ 2 points

Question 11

Quick SOFA (qSOFA) Criteria
KNOW THIS

Answer 11

• May be used at bedside to identify patients likely to have prolonged ICU
stay or to die in hospital
• At least 2 of the following:
▫ Respiratory rate ≥ 22/min
▫ Altered mentation
▫ SBP ≤ 100 mmHg

if pt doesn’t have score of 2, can’t rule out sepsis

Question 12

Severe Sepsis

• Old definition

Answer 12

• Sepsis associated with dysfunction of organ(s) distant from the site of
infection, hypoperfusion, or hypotension
• May include:
▫ Lactic acidosis
▫ Oliguria
▫ Acutely altered mental status
▫ Acute lung injury

similar to new def

Question 13

Septic Shock

Answer 13

• Sepsis with hypotension that does not respond to adequate fluidresuscitation and requires vasopressor therapy
• Sepsis with circulatory, cellular, and metabolic dysfunction associated with higher risk of mortality than sepsis alone
• Patients require vasopressors to maintain mean arterial pressure (MAP)
≥ 65 mmHG and have serum lactate > 2 mmol/L (in the absence of hypovolemia)

Question 14

Surviving Sepsis Campaign

Answer 14

Collaboration between
• European Society of Critical Care Medicine
• International SepsisForum
• Society of Critical Care Medicine
With the overall goal of more timely management of patients with sepsis or at risk of developing sepsis

Question 15

Most Common Sources of Sepsis

Answer 15

• Pneumonia
(most common cause, half of cases)
• Intra-abdominal Infections
• Urinary Tract Infections
(increased risk with catheterization)
• Blood stream infections
(associated with IV catheters)
• Osteomyelitis
• CNS (meningitis, encephalitis)
• In ~ 20-30% the source can not be found

Question 16

Targets for Treatment

The Three Heads of Sepsis
Hypotension, Hypoperfusion, Organ Dysfunction

Answer 16

Infection
Hypotension
Due to
• Vasodilation and increased vascular permeability
• Volume depletion

Reduced Cardiac Output
Due to
• reduced preload and / or reduced contractility
Intravascular coagulation
Hormonal Alterations

need to treat infectious insult

Question 17

Antibacterial Therapy

timing

Answer 17

• Effective antibacterials delivered within 1 hour
of diagnosis resulted in 79% survival
• For every additional hour antibacterials
are withheld there is 7.6% drop in survival
• Antibacterials withheld 9 -12h: survival ↓ to 25%

• Cultures should be taken before antimicrobial therapy
• IV antimicrobials should be given as soon as possible
and within 1 hour for both sepsis and septic shock
• Empiric broad spectrum antimicrobials to cover all
likely pathogens (bacterial and potentially fungal) based on risk factors
• Dosing based on PK/PD principles
• Consider source control and removal of infected
intravascular access devices

avoid recent use of ABX in last 3 months

Question 18

Antibacterial Therapy
daily assessment for?
______to support discontinuation of antibacterials if optimal duration of therapy is unclear

Answer 18

• Empiric therapy narrowed once pathogen identified
• Shorter durations of therapy preferred over longer durations
o Optimal duration depends on many factors, including host, microbe, drug, and anatomical site
• Daily assessment for de-escalation of antimicrobial therapy
• Procalcitonin levels (in conjunction with clinical evaluation) to support discontinuation of antibacterials if optimal duration of therapy is unclear (not widely avail in AB)

Question 19

Antibacterial Choice\

which are common organisms?

Blood cultures typically
• positive in only 1/3cases
• in up to 1/3 of cases cultures from all sites are negative

Patients with severe sepsis and positive cultures
• 62% Gram negative organisms
• 47% Gram positive
• 19% fungi

Answer 19

Most common Gram positive organisms
• Staphylococcusaureus
• Streptococcuspneumoniae
• Enterococcus spp

Most common Gram negative organisms
• Escherichia coli
• Klebsiella pneumoniae
• Pseudomonasaeruginosa
Antibacterial therapy is directed at the suspected source

if it’s sepsis of unknown source and
they have septic shock then a

carbopenum annd vanco typically be recommended
source control such as surgical drainage of abscess, debridement of necrotic aterial

Question 20

Fluid Resuscitation

for hypovalemia

Answer 20

• Sepsis and septic shock are medical emergencies,
resuscitation should begin immediately
• At least 30 mL/kg (IBW) of IV crystalloid be given within first 3 hours followed by re-assessment
• Monitor - HR, BP, arterial oxygen saturation, RR, urine
output, temperature
• Initial target of MAP ≥ 65 mmHg (drives pressure of tissue perfusion)
• Goal to normalize lactate (≤ 2mmol/L)

after additional fluids are guided by reassess of hemodynamic status

Question 21

vasodilation

if sepsis is still not responding, vasopressor indicated
Vasopressor Therapy

Answer 21

• Norepinephrine (Levophed®) first choice as vasopressor
• May add vasopressin or epinephrine to meet target
• Use dopamine as alternative to norepinephrine in selectedpatients (e.g., if low risk tachyarrhythmias or absolute orrelative bradycardia)
- dopamine for compromised systolic fxn but causes more tachycardia (more erythrogenic than NE)
• If norepinephrine not available, epinephrine or dopamine can be used as alternatives (watch for arrythmias) –> more AE with E than NE
low doses of vasopressin may raise BP

Target
Mean Arterial Pressure ≥ 65 mm Hg
Normalized serum lactate < 2mmol/L

Question 22

AE of NE

Answer 22

peripheral Ischemia Due to Norepinephrine

Norepinephrine is a profound vasoconstrictor
primarily an α-agonist with some β-agonist properties
high alpha vasoconsticting fx
dark limbs due to vasoconstiction

Question 23

target myocardial depression

Inotropes

Answer 23

• Suggest dobutamine in patients with hypoperfusion
despite adequate fluid and vasopressor
• Dobutamine recommended if low cardiac output
• Primarily a β-stimulant
• Increases contractility and HR
• Few α-adrenergic effects
• Can either add dobutamine to norepinephrine or
use epinephrine (also an inotrope) alone

Question 24

endocrine system

Corticosteroids

Answer 24

• Not necessary if adequate fluid resuscitation and
vasopressor therapy able to restore BP
• If refractory septic shock, suggest IV corticosteroids
• typically hydrocortisone 200 mg /day

Question 25

Glycemic Control

Answer 25

• Septic patients often hyperglycemic → impaired neutrophilfunction, impaired wound healing, pro-coagulant effects, etc.
• Initial studies showed benefit of tight glycemic control of serum glucose (4 - 6 mmol/L)
• Largest study to date – NICE-SUGAR:
• tight glycemic control lead to increased rates of harm from hypoglycemia
• 2016 Blood Glucose Target ~10 mmol/L
(2021: 8-10 mmol/L) tight glycemic control led to increased rates of harm from hypoglycemia so now guidelines want 10mmol

Question 26

Other Treatment

read

Answer 26

• Sedation and Analgesia
• Mechanical ventilation to improve oxygenation and
respiratory acidosis in acute respiratory distress syndrome
(ARDS) associated with sepsis
• Renal replancement therapy (dialysis) if required
• Bicarbonate therapy in patients with severe metabolic
acidemia with pH ≤ 7.2 and acute kidney injury
• Venous thromboembolism prophylaxis with low molecular
weight heparin or unfractionated heparin
• Stress ulcer prophylaxis if risk factors for GI bleeding
(proton pump inhibitor or H2-receptor blocker)