Shock: Pathology & Pathophysiology

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

Hypovolemic
Hemorrhage Dehydration

Cardiogenic
Myocardial disease Valvular disease Arrythmia

Obstructive
Pulmonary embolus Aortic aneurysm Tamponade

Distributive
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 inhibito rs) 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)

Trichrome accentuates contraction bands

EM: sarcomeres hypertrophied, aligned

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), hyaline membrane (arrow)

Proliferating type II pneumocytes (arrowhead); cell debris (arrow)

Diffuse hyaline membranes

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

Flattening of cells dilated lumen

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

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 Heart Lungs Kidneys Brain GI tract Liver Other organs Path manifestations Contraction bands Subendocardial hemorrhages DAD (diffuse alveolar damage) ARDS (adult respiratory distress syndrome) Ischemic acute tubular necrosis Oliguric acute renal failure

Watershed infarcts Laminar necrosis Ischemic bowel disease Gastrointestinal hemorrhage Superficial necrosis Centrilobular necrosis Disseminated intravascular coagulation Adrenal cortical hemorrhages & lipid depletion Acute pancreatitis