What common features are shared among various forms of

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What common features are shared
among various forms of shock?
Anthony F. Suffredini M.D.
Critical Care Medicine Department
National Institutes of Health
Bethesda, MD, USA
Common Shock Syndromes
Septic Shock
Severe infection
with systemic
inflammation
Hypovolemic
Shock
Severe hemorrhage
Extensive trauma
Burns
Gastrointestinal loss
Cardiogenic
Shock
Myocardial
infarction
Mechanical
complications
Extrinsic
compression
Outflow
obstruction
Reduced Tissue Perfusion
Acute Mortality of Shock Syndromes
Within
2 - 3 hrs
(%)
Septic Shock
Hospital
death
(%)
31 - 63
Cardiogenic
Shock
Hemorrhagic
Shock
(trauma)
28 - 30
days
(%)
44
25 - 35
48
30 - 54
N Eng J Med 2001; 344:699
JAMA 2005; 294:448
N Engl J Med 1994; 331:1105
JAMA 2002; 288: 862
Circulation 2005; 112: 1992
J Trauma 1998; 45:545
Common Features of
Shock Syndromes
Clinical signs
 Histopathology
 Mechanisms of cell injury
 Systemic inflammation
 Immunosuppression

Common Nonspecific
Clinical Signs of Shock Syndromes
Hypotension
 Rapid, weak pulse
 Decreased skin perfusion
– Pallor, cold, cyanosis, mottling

•
Early sepsis warm, flushed
•
Late sepsis cool extremities
Altered sensorium
 Urine output low or absent

Hemodynamic Profiles
Hypovolemic
Cardiogenic
Septic
Low resistance
High resistance
Shock and Myocardial Depression
EF
(%)
CI
(L/min/m2)
PCW
(mmHg)
Cardiogenic
shock (SD)
31 ± 10
LV
1.8 ± 0.7
24 ± 8
Septic Shock
(SEM)
32 ± 4
LV
4.9 ± 0.5
17 ± 2
Hemorrhagic
shock (SD)
34 ± 6
RV
3.6 ± 0.9
16 ± 7
Ann Intern Med 1984; 100:483
Circulation 2005; 112:1992
J Trauma 1998; 45: 470
Are there
common histopathologic patterns
associated with
tissue hypoperfusion and shock?
Histopathology of Tissue Hypoperfusion
Associated with Shock
Myocardium
Lung
Coagulative necrosis
Diffuse alveolar damage
Contraction bands
Exudate, atelectasis
Edema
Edema
Neutrophil infiltrate
Hyaline membrane
Robbins & Cotran Pathologic Basis of Disease: 2005
Histopathology of Tissue Hypoperfusion
Associated with Shock
Small Intestine
Liver
Mucosal infarction
Centrilobular
hemorrhagic necrosis
Hemorrhagic mucosa
Epithelium absent
Nutmeg appearance
Robbins & Cotran Pathologic Basis of Disease: 2005
Histopathology of Tissue Hypoperfusion
Associated with Shock
Brain
Bland infarct
Punctate hemorrhages
Brain
Eosinophilia and
shrinkage of neurons
Neutrophil infiltration
Robbins & Cotran Pathologic Basis of Disease: 2005
Histopathology of Tissue Hypoperfusion
Associated with Shock
Kidney
Pancreas
Tubular cells, necrotic
Fat necrosis
Detached from
basement membrane
Parenchymal necrosis
Swollen, vacuolated
Robbins & Cotran Pathologic Basis of Disease: 2005
Incidence of Ischemic Histopathology
in Patients Dying with Shock
Hypovolemic
Septic
Cardiogenic
n = 102 (%)
n = 93 (%)
n = 197 (%)
Heart
37
17
100
Lung
55
65
10
Kidney
25
18
11
Liver
46
30
56
Intestine
9
26
16
Pancreas
7
6
3
Brain
6
3
4
McGovern VJ, Pathol Annu 1984;19:15
Tissue and Cell Hypoperfusion
What are the mechanisms
that contribute to cell injury?
Mechanisms Underlying
Cell Injury from Ischemia
Mitochondrial
dysfunction
Loss of selective
membrane permeability
Functional and Morphologic Consequences of
Decreased ATP During Cell Injury
Ischemia
Oxidative Phosphorylation
ATP
Anaerobic
glycolysis
Detachment
of ribosomes
Influx of Ca2+
H20, and Na+
Efflux of K+
Glycogen
pH
Protein synthesis
ER swelling
Cell swelling
Blebs
Clumping
chromatin
Lipid deposition
Na pump
Mitochondrial Dysfunction in Cell Injury
Increased cytosolic Ca2+,
oxidative stress, lipid peroxidation
Mitochondrial
PermeabilityTransition
Robbins & Cotran
Pathologic Basis of Disease: 2005
Cytochrome c and other
pro-apoptotic proteins
Apoptosis
Role of Increased
Cytosolic Calcium in Cell injury
Extracellular Ca2+
Mitochondrial Ca2+
Cytosolic Ca2+
ATPase
ATP
Phospholipase
Phospholipids
Endoplasmic
Reticulum Ca2+
Protease
Endonuclease
Disruption of
membrane and
cytoskeleton
proteins
Chromatin
damage
Membrane Damage
Hypoperfusion and Oxidative Stress
Triggers
Inflammatory cytokines
Endogenous Sources
Mitochondria
Peroxisomes
Lipoxygenases
NADPH oxidase
Cytochrome p450
Cell damage
Reactive
Oxygen
Species
Redox-sensitive
signaling
pathways
Defective
host defenses
Antioxidant Defenses
Enzymatic systems
Catalase, SOD
Glutathione peroxidase
Non-enzymatic systems
Glutathione
Vitamins (A, C, E)
Cell death
Summary of Mechanisms of
Cell Injury and Hypoperfusion
Cell and tissue damage depend in part on
the
– duration and severity of injury
– pre-existing state of cell
• ability to adapt to injurious stimuli
 Hypoperfusion compromises
– Aerobic respiration and energy production
– Cell membrane integrity
– Protein synthesis
– Genetic integrity

Does systemic inflammation
occur in all shock syndromes?
IL-6 (pg/mL)
IL-6 (pg/mL)
TNF (pg/mL)
TNF and IL-6: Septic vs Cardiogenic Shock
N = 29
deWerra I, Crit Care Med 1997; 25:607
Geppert A, Crit Care Med 2002; 30:1987
TNF and IL-6: Septic vs Hemorrhagic Shock
Septic Shock Hemorrhagic
Shock
N = 25
N=8
TNF (day 1)
30 ± 4
16 ± 3
1856 ± 621
244 ± 121
(pg/mL)
IL-6 (day 1)
(pg/mL)
Martin C, Crit Care Med 1997; 25:1813
sTNFR2 (ng/ml) sTNFR1 (ng/ml) TNF (pg/ml)
TNF, sTNFR1 and sTNFR2
after Trauma
N = 47
ISS median 32.5 (17-61)
Spielmann S, Acta Anaesthesiol Scand 2001: 45:364
Summary of Systemic Inflammation
Associated with Shock Syndromes



Systemic inflammation is present in varying
degrees in all shock syndromes
– Increased leuckocytes, CRP, cytokines, other
biomarkers
Septic shock has higher levels of cytokines and
inflammatory biomarkers than either hemorrhagic
or cardiogenic shock
Magnitude of biomarker elevation may be
associated with new infection or severity of organ
failure
Are all shock syndromes
associated with
immunosuppression?
Suppressed Whole Blood TNF Production
in Septic and Cardiogenic Shock
8
7
2.5
E. Coli stimulation
of whole blood
N = 10 / group
2
5
4
3
TNF (ng/ml)
TNF (ng/ml)
6
1.5
1
2
0.5
1
0
De Were I, Swiss Med Wkly 2001; 131:35
0
S. aureus stimulation
of whole blood
N = 10 / group
TNF (U/ml)
Suppressed Whole Blood TNF Production
after Severe Blunt Trauma
Healthy controls n = 10
LPS stimulated whole blood
Trauma patients n = 18
Days After Injury
ISS 24 (17 - 45)
Majetschak M, J Trauma 1997; 43:880
Summary of Immunosuppression
Associated with Shock Syndromes
Circulating leukocytes from patients with
septic, cardiogenic or traumatic shock have
impaired cytokine responses to microbial
products
 Mechanisms associated with depressed host
responses include:
– Circulating molecules
• anti-inflammatory cytokines, hormones,
catecholamines, ubiquitin
– Altered cell phenotypes

Summary of Common Features
Among Shock Syndromes
Fundamentally different etiologies underlie
shock associated with severe infections,
myocardial infarction or hypovolemia
 Common elements that link the morbid
events of these syndromes are hypotension
and decreased tissue perfusion

Summary of Common Features
Among Shock Syndromes
Hypoperfusion leads to cell injury and organ
dysfunction due to alterations in cell
permeability and mitochondrial energy
production
 Systemic inflammation and impaired host
immune responses occur in all three shock
syndromes
 While shock resuscitation is directed at
improving tissue hypoperfusion, definitive
therapy requires syndrome-specific
interventions

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