Management of SepsisKarl Bolser DVM

SIRS Systemic Inflammatory Response Syndrome

MODS Multiple Organ Dysfunction Syndrome

Inflammatory MediatorsLipopolysaccharide Lipoteichoic acid Peptidoglycan Flagellin Mannan TNF⍺ IL-1 IL-6 Prekallikiein Bradykinin Cysteine-X-cysteine ligand 9 (CXCL-8;formerly IL-8)

SIRS

• Immunoparalysis

Compensatory Anti-inflammatory Response Syndrome

CARS

Definitions Prior to 2016Sepsis • 2 or more SIRS criteria with

suspected/known infection

Severe Sepsis • SIRS to infection • Organ dysfunction • hypoperfusion and/or

hypotension

Septic Shock • SIRS to infection • Hypotension refractory to

volume resuscitation

Definitions Prior to 2016Sepsis • 2 or more SIRS criteria with

suspected/known infection

Severe Sepsis • SIRS to infection • Organ dysfunction • hypoperfusion and/or

hypotension

Septic Shock • SIRS to infection • Hypotension refractory to

volume resuscitation

Sepsis after 2016

• Life-threatening organ dysfunction caused by a dysregulated host response to infection

DefinitionsSepsis • 2 or more SIRS criteria with

suspected/known infection

Severe Septis • SIRS to infection • Organ dysfunction • hypoperfusion and/or

hypotension

Septic Shock • SIRS to infection • Hypotension refractory to

volume resuscitation

Sepsis after 2016 • Life-threatening organ

dysfunction caused by a dysregulated host response to infection

c Shock

Severe

Proposed SIRS CriteriaDog Cat

Temperature (°F) ≥ 104 or ≤ 99 ≥ 104 or ≤ 100

Heart Rate (bpm) ≥ 140 ≥ 225 or ≤ 140

Respiratory Rate (bpm) > 20 ≥ 40

White Blood Cells(cells/µL)

≤ 5,000 or ≥ 16,000

≤ 5,000 or ≥ 19,000

+/- Bands (%) ≥ 3 ≥ 5

It takes 2 (or 3)

Potential Causes of Sepsis

• Gastroenteritis • Bite wounds • Pneumonia • Prostatitis/prostatic abscess • Peritonitis • Pyometra • Pyelonephritis • Pyothorax

https://www.cliniciansbrief.com/article/bite-wounds

Other Potential Signs of Sepsis

• Altered mentation • Hyperemic mucous membranes – or the opposite • Shortened or delayed CRT • Hyper or hypodynamic pulses • Petechia • Ecchymosis

”Normal” Inflammation – 1st reaction

Local arterioles • Rapid, inconsistent, transient vasoconstriction

https://www.google.com/imgres?imgurl=https%3A%2F%2Fpedsinreview.aappublications.org%2Fcontent%2Fpedsinreview%2F38%2F11%2F511%2FF4.large.jpg&imgrefurl=https%3A%2F%2Fpedsinreview.aappublications.org%2Fcontent%2F38%2F11%2F511&docid=mV6Q3PCQrqFWsM&tbnid=q2xxif0qw7PlfM%3A&vet=1&w=1280&h=960&client=firefox-b-1-d&bih=636&biw=1254&ved=0ahUKEwihvYGHg-ngAhVOKKwKHfVjBDIQ__EBCAM&iact=c&ictx=1

Rubor, Tumor, Calor, Dolor Redness, Swelling, Heat, Pain Celsus 25 BC – 50 AD

Cardinal Signs of Inflammation

Functio Laesa Loss of Function

Virchow 1821 - 1902

Vasodilation & Edema•Dilation of arterioles and capillaries • Increase blood flow

•Endothelial cell contraction (↑ cell gaps) • Increased permeability • Leakage of fluid and protein

• Increased viscosity of blood

•Aggregation of platelets • Increased adhesion of leukocytes

https://www.sdix.com/portfolio/red-blood-cells-abo/

• Dilute and Degrade • Toxins, foreign material

• Kill or Sequester • microbes, foreign material, necrotic tissue,

neoplastic cells

• Provide wound healing factors • Increase temperature

• Vasodilation • Inhibit replication of some microbes

• Restrict movement of appendages and joints to allow time for healing and repair

Benefits of Inflammation

Neutrophils• Kill or neutralize

• Microbes • Tumor cells • Foreign material

• Phagocytosis & fusion with lysosomes • Secretion of granules into exudate • Produce inflammatory mediators • Undergo apoptosis • NETs (Neutrophil Extracellular

Traps)

Neutrophils• Kill or neutralize

• Microbes • Tumor cells • Foreign material

• Phagocytosis & fusion with lysosomes • Secretion of granules into exudate • Produce inflammatory mediators • Undergo apoptosis • NETs (Neutrophil Extracellular

Traps)

Nitric Oxide

Production • Endothelium • Leukocytes - macrophages • Neurons

Ingested nitrate

•Vasodilation

•Decreased heart rate & contractility

•Decreases leukocyte adhesion

Hypotension

• Nitric Oxide • Increased/induced synthesis • Vasodilation

• Change in RMP • Lactic acidosis • K-ATP channels activated – more negative RMP • Voltage-gated calcium channels inactivated – decreased vascular

tone

• Pro-inflammatory cytokines • Breakdown tight junctions – fluid shifts between spaces

Increased Vascular Permeability Damaged Endothelial Glycocalyx

• Shields vascular walls from shear/stress of direct exposure to blood flow • Reduces nitric oxide production

• Retains protective enzymes and coagulation inhibition factors • Superoxide dismutase • Antithrombin • Protein C system

• Prevents leukocyte adhesion

Treatment• Fluids • Antibiotics • Glucose control • Nutrition • Eliminate the source

IV Fluids

Saline

Hyperchloridemia and Acidosis

• Increased cytokine production • Induced hypotension • Increased risk of AKI • Increased mortality

Fluid Boluses

• 10 ml/kg in 3 minutes – Dogs • 10ml/kg in 6 minutes – Cats and

puppies

11 pound cat = 500 ml/hr for 6 minutes = 50 ml

A More “Conservative” Approach - canine

Weight in Pounds X

10 .

ml to give over 20 minutes

66 pound dog • 660 ml = 1980ml/hr (20

min)

vs

• 300ml = 6000ml/hr (3 min)

…..and even more FLUIDS!!!

•Wait 5 minutes and reassess • If 2 -3 boluses • Colloid • 5 ml/kg over 5 minutes dog

• 2 ml/kg over 5 minutes cat

• Hypertonic saline

• If still hypotensive • vasopressors and/or inotropes

HypotensiveMAP < 60 – 65 mmHg Systolic < 90 mmHg

Poor Man’s DinaMap

Femoral pulse • BP ≥ 60 mmHg

Dorsal Pedal/Dorsal Metatarsal • BP ≥ 90 mmHg

Urine Output

• > 0.5 ml/kg/hr • Preferably > 1 ml/kg/hr

Lactate>4 mmol/L – give bolus of IVF

Dopamine CRIVasopressor with positive inotropic effect

1– 4 mcg/kg/min (dopaminergic) • enhance renal and mesenteric perfusion

5 – 10 mcg/kg/min (β-1 adrenergic) • increased myocardial contractility

10 – 15 mcg/kg/min (mixed α & β) >15 mcg/kg/min (α-1 adrenergic) • constriction of the renal arteries, thereby

potentially reducing renal perfusion and causing irreversible renal damage.

• Start at 5 mcg/kg/min • Maximum of 20 mcg/kg/min

 http://vetmed.illinois.edu/CRIcalculator 

http://www.vasg.org/blood_pressure_management.htm#

Others• Dobutamine • Ephedrine • Epinephrine • Norepinephrine • Etc.

Antibiotics

• Increase inflammation • Worsen AKI • Endotoxin release • Faster resolution of

inflammation and AKI • Usage correlated best with

survival

•Expect initial worsening of renal values

Antibiotics: When and Which Ones?• Mortality significantly increases for every hour of

delay 6 hours after diagnosis of septic shock • For every 1 hour delay of antimicrobials • Mortality increases 7.6%.

• Dickinson et al • 52.6% received appropriate therapy based on C&S

• 58.5% survived • 52.6% survival in those that received “inappropriate”

therapy

Antibiotics We Use• Unasyn (ampicillin sulbactam) • Enrofloxacin • E coli is frequently resistant

• Metronidazole

BUT

• Use something injectable (i.e. IV) – even aminoglycosides

Alterations in GlucoseHyperglycemia

• Increased cortisol (stress hyperglycemia) • Increased release of epinephrine,

norepinephrine, glucagon…. • Inhibition of insulin release due to pro-

inflammatory cytokines et al • Insulin resistance

Glucose

Increased production

Decreased cellular intake

Alterations in Glucose

Effects of Hyperglycemia

• Pro-inflammatory • Pro-thrombotic

Effects of Insulin

• Anti-inflammatory effects • Anti-thrombotic effects

Alterations in Glucose

Hypoglycemia

• Increased use • Both bacteria and leukocytes

• Depletion of glycogen • Decreased production

Other Causes

• Addison’s • Xylitol

Nutrition• NG and E Tubes • Intervene early

Septic Abdomen Treatment• Resect what you need to • Lavage • Lavage • Lavage • +/-drain

Abdominal Fluid Analysis Minimum

• PCV/TP • Need to be ≥ 5% before

considered hemorrhagic

• Cell Count • Hemocytometer is best *Machines may not be verified

• Cytology

www.badtaxidermy.com

What is it???

Classifying the Fluid• Transudate - clear • Protein (g/dl) <2.5 • Cell Count (cell/mcl) <1,500

• Modified Transudate – hazy to turbid • Protein (g/dl) 2.5 – 7.5 • Cell Count (cell/mcl) 1,000 – 7,000

• Exudate – opaque to turbid • Protein (g/dl) >3.0 • Cell Count (cell/mcl) >7,000

• Transudate Low Protein • Transudate High Protein • Exudate Nonseptic • Exudate Septic • Hemorrhagic • Lymphatic Loss

Classifying the Fluid• Transudate - clear • Protein (g/dl) <2.5 • Cell Count (cell/mcl) <1,500

• Modified Transudate – hazy to turbid • Protein (g/dl) 2.5 – 7.5 • Cell Count (cell/mcl) 1,000 – 7,000

• Exudate – opaque to turbid • Protein (g/dl) >3.0 • Cell Count (cell/mcl) >7,000

• Transudate Low Protein • Transudate High Protein • Exudate Nonseptic • Exudate Septic • Hemorrhagic • Lymphatic Loss

Pathologic Basis of Veterinary 6th Edition, Figure 3-3

Other Things to Think AboutUroabdomen? • Creatinine • Potassium

Bile Peritonitis? • Bilirubin

*Machines may not be verified

> 2 times peripheral blood

Suggestions of Sepsis

Glucose > 20 mg/dl difference

Lactate > 1.5 mmol/dl difference

*Polycythemia can cause a falsely low reading on some glucometers