Shock: Pathology & Pathophysiology

Definitions
Shock

Critical decrease in global tissue perfusion resulting in diffuse cellular hypoxia & organ dysfunction

Hypovolemic

Cardiogenic

Obstructive

Distributive

Hemorrhage
Dehydration

Myocardial disease
Valvular disease
Arrythmia

Pulmonary embolus
Aortic aneurysm
Tamponade

Sepsis
Anaphylaxis

Sepsis
SIRS (Systemic inflammatory response syndrome):
2+ of : abnormal temp, tachycardia, tachypnea, altered WBC ct
Sepsis: SIRS 2 to infection
Severe sepsis: associated organ dysfunction
Septic shock: severe sepsis with hypotension despite fluid resuscitation
Epidemiology of sepsis: 750k cases annually, 210k deaths, incidence increasing:

immunosuppressives (tumors, transplants, inflammatory diseases),

age with comorbidities, use of invasive devices

Pathogenesis of septic shock: Noninfectious or infectious trigger causes release of mediators, which causes shock!
Tons of mediators (TNF / ILs / IFN / etc, etc, etc.) no single answer (reductionist approach is limited)
Proinflammatory or anti-inflammatory balance is key
TNF
NO
Ceramide

Inducible product of variety of cell types

TNF infusion sepsis-like syndrome ( humans); TNF blockers attenuates sepsis in animals
Generated in various different ways (neuronal / endothelial / inducible), effects on cGMP, Hb, proteins, etc.
In shock: NO; vasoplegia 2 to NO from smooth muscle ( vessel response to norepi, restored with NOS inhibitors)
A phospholipid, TNF / sphingomyelin ceramide pathway linked, produced in response of LPS

Hyperinflammation & sepsis?

Former idea: just lots of inflammation in sepsis pathogenesis but probably not that simple
Cytokines: doses in animal studies excessive
Cant usually detect TNF, IL-1 levels in humans?

Defective immune function seen in septic patients

o
o
o

monocyte cytokine production

B-cells / CD4 cells in spleen with long sepsis
IL-10 (anti-inflammatory) in sepsis; levels predict mortality (even
though its anti-inflammatory)

The pro-inflammatory / anti-inflammatory balance may be key

PRRs / innate immune probably kicking it all off, triggering cytokine production
And then the pro-inflammatory / anti-inflammatory balance comes into play
The balance can be perturbed in lots of ways
Lots of details known, but no real good way to actually translate it into patient care!
1

Pathology of Sepsis
Shock: severe hemodynamic / metabolic disturbance resulting from inadequate blood flow to vital organs
Organ changes due primarily to anoxic / hypoxic cell injury
Individual organ changes arent specific for shock, but constellation of changes in multiple organs is
Organs / organ systems affected in shock (in most common organ of failure)
Lungs > Kidneys > liver / intestines > heart / brain / adrenals / pancreas / hematologic)
But this can change with comorbid disease states

Shock & the Cardiovascular System

Trigger mediators cardiovascular shock
In septic shock, primary defects are vascular (tone, permeability, volume)
SVR: gets at vascular tone (peripheral resistance), TPR is similar

MARKED REDUCTION IN SVR IS THE HALLMARK OF SEPTIC SHOCK

Oxygen delivery

Normally, VO2 is independent of O2 delivery down to really low levels of delivery

o O2 extraction varies to maintain VO2 in a supply dependent phase
o Keep tissues oxygenated!

Pathologic supply dependency in sepsis?

o Altered microvascular vasomotor regulation &
vascular plugging might be playing a role
o
o

O2 consumption elevated at baseline

smaller decrease in O2 transport leads to
coupling of supply & consumption!

survival with lactate

Cardiac manifestations
Remember: HR x SV = CO (SV determined by preload, contractility, & afterload)
Cardiac index:
In isolation (e.g. animal models), if you look at a muscle strip, contractility with exposure to mediators
But for patients: cardiac index with sepsis, and CI BAD PROGNOSIS
o contractility, but afterload (from SVR!)

Pathology: Contraction Bands & Subendocardial Hemorrhages

Contraction band necrosis:
bright, eosinophilic bands crossing fibers
o accentuated with trichrome stain
From calcium release hypercontraction
EM: sarcomeres aligned & hypertrophied

Subendocardial hemorrhages

Normal (left) vs contraction band necrosis

(right, lots of contraction bands)

EM: sarcomeres hypertrophied, aligned

Trichrome accentuates
contraction bands

Residual scarring after recovery

Hemodynamics
Cardiogenic
Hypovolemic
Obstructive
Distributive**

PCWP*

/
/nl

CO

SVR

*reflects loading of LV
**note that in septic / distributive shock, SVR is hallmark and CO as a result

The Lung in Septic Shock

metabolic demand ( O2 consumption / CO2 production) VE (minute ventilation)

permeability of circulation interstitial edema compliance (disrupt surfactant)

Both of these processes contribute to WORK OF BREATHING

If you cant keep up with the work of breathing, you need a ventilator!
o

Diaphragm affected too (septic shock)

Redistributed blood flow with work of breathing need to get more blood to respiratory muscles
o This exacerbates the lack of blood going to other tissues!

Hypoxemia results (from altered V/Q matching & shunt)

Pulmonary hypertension in animal models
Treg cells may be involved in recovery?
Adult respiratory distress syndrome (ARDS)
1. Acute onset
2. Diffuse infiltrates
3. Hypoxemia
4. Noncardiogenic pulmonary edema
Sepsis is #1 cause of ARDS, and ARDS occurs in 20-40% of septic shock cases

Pathology: DAD / ARDS

DAD is pathology, ARDS is clinical finding (difficulties in gas exchange!)
Pathogenesis
1. Endothelial cell injury
2. Leakage of protein-rich fluid (exudates) & inflammatory cells
(mostly PMNs) into interstitium
3. Injury to alveolar lining cells (type I pneumocytes)
leakage of fluid, some inflammatory cells into alveoli
4. Sloughing of type I pneumocytes into alveoli,
proliferation of type II pneumocytes to replace them
5. Hyaline membranes: come from
a. Deposition of protein (exudates)
b. Deposition of fibrin
c. Cellular debris (sloughed type I pneumocytes, inflammatory cells on top of type II pneumocytes)

ARDS: wet, heavy lungs

Normal lung (L) vs ARDS: widened septae,

RBC / debris / fibrin in alveoli, thrombi if DIC

Proliferating type II pneumocytes

(arrowhead); cell debris (arrow)

Diffuse hyaline membranes

Proliferating type II pneumocytes

(arrowhead), hyaline membrane (arrow)

Hyaline membranes (close-up)

The Kidney in Septic Shock

Oliguria, azotemia are common findings

Contributors are prerenal / renal / postrenal (prerenal most important early in sepsis)

Remember the glomerulus: interplay between afferent / efferent arteriolar tone regulates pressure gradient
many of the mediators in shock affect afferent / efferent arterioles
Prerenal ARF is frequent early in sepsis
MAP < 80 mm Hg start to lose the ability to autoregulate
Impaired autoregulation in sepsis from mediators
Vasoconstriction (endogenous / exogenous endotoxin, COXi, radiocontrast can play a role)
4

Renal ARF: from acute tubular necrosis (tubular / obstructive)

Caused by ischemia, sepsis / cytokines, oxidants, nephrotoxins
Cellular events: disordered transport (from ATP, loss of epithelial polarity)
Obstruction tubular pressure GFR
Acidosis can be exacerbated
if low pH, pressors are less effective & SMC contractility decreases

Pathology: ischemic acute tubular necrosis + oliguric renal failure

PCT, medullary thick ascending limb (same zone) are particularly susceptible to ischemia

Histology:
Flattening of proximal tubular epithelium apparent dilatation of tubular lumens
Necrosis, sloughing of individual proximal tubular epithelial cells
o

Widespread tubule cell necrosis is more typical of toxic ATN

Granular casts in distal / collecting tubules, sometimes with brownish pigmentation

Regenerative changes of tubular epithelium
Interstitial edema often present, but without prominent interstitial inflammation
Nucleated cells (WBCs) in vasa recta on biopsy (nonspecific on autopsy)
Glomeruli unremarkable (unless underlying renal disease)

Gross: congested

Normal tubules (L) vs necrosis (R):

single cell necrosis, flattened / reactive cells,
epithelial-mesynchemal transition, loss of
polarity / transport functions

EM: Normal (L): mitochondria stacked up

along brush border (Na/K ATPase needs
ATP). Shock (R): less infoldings, loss of
brush border ( reabsorptive capacity)

Congestion if more advanced:

endothelial injury; sludging of RBC (+
thrombi if DIC) into lumen

Flattening of cells dilated lumen

Proliferative changes if even

more advanced big nuclei,
reactive cells, trying to restore

The Brain in Septic Shock

Altered mental status is early, frequent

CNS disturbances is multifactorial (hypoperfusion, metabolic abnormalities, etc)
May contribute independently to respiratory alkalosis?

Some study results: both in the hospital and long term

Delirium means you spend longer in the hospital & have lower survival
For those who survive ARDS, many have psych sequelae (survival of pathophysiologic storm
muscle strength in general (still 50% at 1 yr!)

Pathology: watershed infarcts & laminar necrosis

Ischemic injury to the brain from hypoperfusion in vulnerable areas
Relative circulation
sensitivity of cells

Watershed infarcts (e.g. ACA/MCA watershed)

Laminar necrosis: deep gray matter (supplied by small penetrating arteries)
Purkinje cells of cerebellum, particular area of hippocampus cells are particularly sensitive

Vulnerable areas:
Watershed, laminar necrosis
Purkinje cells, part of hippocampus

ACA/MCA watershed infarct

Laminar necrosis (note thin line in deep

gray matter). Histology on right

The GI Tract in Septic Shock

Limited ability to augment O2 extraction

Mucosal barrier compromise can sustain trigger / mediator response MOF
Ileus (obstruction) can complicate fluid balance
Exacerbation of acidosis can result

Liver

Intrahepatic cholestasis common

o ( BILIRUBIN, alk-phos, transaminases a bit too)
reticularendothelial clearance
Cytokine / acute phase reactant expression altered
synthesis of coagulation pathway factors

Pathology: centrilobular necrosis

Area around central vein especially sensitive to hypoxic injury

Centrilobular necrosis (around CV)

Normal (L) vs centrilobular necrosis (R)

Degenerative & some

reactive changes

Hematology in Septic Shock

Leukocytosis or leukopenia
Thrombocytopenia common
Altered balance of clotting / fibrinolysis

fibrin generation of fibrinogen / split products (e.g. D-dimers)

Series of effect: pro-clot formation ( TNF, etc)

DIC (disseminated intravascular coagulation)

Widespread deposition of fibrin; microvascular thrombosis

Consuming feedback inhibitors more clotting
Consumption of clotting factors eventually leads to bleeding!

BIG PROBLEM: patients transition from clotting bleeding!

Pathology: DIC

Can see in glomerular capillary bed (really fine capillary)

Adrenal cortical hemorrhage & lipid depletion too
o Waterhouse Friderichsen syndrome (adrenal hemorrhage classically a/w meningococcus)
o ACUTE ADRENAL FAILURE (not cool)

Clotting in glomerular capillaries

Normal adrenal (L) vs W-F hemorrhage (R)

Lipid depletion

Summary of Septic Shock

mortality with # of organ failures (Intuitive, but important when considering what to do with a patient)

Septic shock

Can be seen as response to all categories of infection; similar with non-infectious stimuli
Critical decrease in tissue perfusion, cellular oxygenation
Reduction in SVR is hallmark, likely NO-mediated
Multiple organs are affected, and in turn affect other organs

Pathology
Organ system

Path manifestations

Heart

Contraction bands
Subendocardial hemorrhages

Lungs
Kidneys

DAD (diffuse alveolar damage)

ARDS (adult respiratory distress syndrome)
Ischemic acute tubular necrosis
Oliguric acute renal failure

Brain

Watershed infarcts
Laminar necrosis

GI tract

Ischemic bowel disease

Gastrointestinal hemorrhage
Superficial necrosis

Liver

Centrilobular necrosis

Other organs

Disseminated intravascular coagulation

Adrenal cortical hemorrhages & lipid depletion
Acute pancreatitis