Transcript Septic Shock - Cleveland Clinic

SHOCK
September 6, 2005
Andrew Filiatraut
In General

Shock

Clinical syndrome defined as hypoperfusion

Hypotension and Cellular Hypoxia



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Elevated lactate
Oliguria
Hepatic/GI dysfunction
Mental status changes
In General

Four Classifications




Hypovolemic
Cardiogenic
Obstructive
Distributive

Septic, Addison’s, Anaphylactic, Neurogenic,
Thyrotoxicosis, Beriberi, Paget’s, Cirrhosis, Chroinc
Anemia, Osler-Weber-Rendu
Hemodynamic Profiles
TYPE
BP
C.O.
PCWP
SVR
↓ Vol.
↓
↓
↓
↑
Cardio
↓
↓
↑
↑
Tmpnad
↓ or N
↓ or N
↑ or N
↑
P. E.
↓
↓
↓ or N
↑
Distrib
↓
↑
↓
↓
Septic Shock
Epidemiology

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
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751,000 cases of severe sepsis /year
Up to half develop shock
Overall mortality rate of 45%
Cause



Gram+ 35-40%
Gram- 55-60%
Slightly higher incidence in men, older
adults (55-60 yrs)
Definitions

Infection


Inflammation against microorganism
Bacteremia

Viable bacteria in blood
Definitions
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SIRS
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Evidence of inflammation NOT necessarily
infection
2 or more of the following
Temp>38 or <36
 HR >90bpm
 RR >20 or PaCo2 <32
 WBC’s >12,000 or <4000 or >10% bandemia

Definitions

Sepsis


systemic inflammatory response as a result of
infection
Severe Sepsis

sepsis associated with organ dysfunction


Lactic acidosis, oliguria, mental status change
Septic shock

sepsis-induced hypotension with presence of
perfusion abnormalities
Definitions

Sepsis-induced hypotension


SBP<90 or reduction of 40mm Hg from
baseline without other cause
Multiple Organ Dysfunction Syndrome

Altered organ dysfunction in acutely ill patient
requiring intervention to maintain
homeostasis
Pathophysiology
Pathophysiology

Focus of infection

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Pneumonia, UTI, cellulitits, abscess, indwelling device
ICU: catheters, sinusitis, acalculus cholecystitis,
C. diff, resistant organism, fungal infection
Blood stream invasion or proliferation of
organism at site
Exogenous toxin release
Activation of endogenous mediators
Molecular Mediators in
Pathophysiology

Three phases
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
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Induction
Cytokine synthesis & secretion
Cascade
Molecular Mediators in
Pathophysiology

Induction

Interaction of microbial molecules with host
Mediators activated that amplify & transmit the
microbial signal to other cells
 Ex LPS binds to LPS binding protein which is
detected by CD14 releasing TNF-alpha
 Peptidoglycan & lipoteichoic acid of gram (+)
induce similarly

Molecular Mediators in Pathophys
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Cytokine cascade
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Activation & release of central mediators
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Release of secondary mediators
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TNF-alpha and IL-1
IL-6, IL-8, PAF, PG’s, leukotrienes
Activation of neutrophils, complement system,
vascular endothelial cells
Synthesis of acute phase reactants
Molecular Mediators in Pathophys

Parallel to SIRS is CARS

Compensatory Anti-inflammatory Response
System
Attempts to down regulate the SIRS response
 IL-4, IL-10, transforming growth factor beta, CSF,
soluble receptors to TNF, antagonists to TNF-alpha
and IL-1
 If CARS reaction is severe it will manifest as
anergy and infection susceptibility
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Vasoactive Mediators in Pathophys
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Nitric Oxide
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Produced by endothelium
Increased levels during shock
Actions at high levels
Mediator of vasodilation & hypotension
 Direct cellular toxicity
 Myocardial depression
 Increased permeability
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Clinical Features
Clinical Features
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Constitutional
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Hyper/hypothermia
Tachycardia
Tachypnea
Wide pulse pressure
Mental status change

Most likely obtunded
Clinical Features
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Cadiovascular
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Early, vasodilators predominate
Cardiac output is increased with tachycardia
CO=SV x HR
 i.e. Initially patients will have warm extremities
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If not treated aggressively decompensation
ensues
Typically hypotension is not reversible with
fluids alone
Clinical Features
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Pulmonary
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Sepsis is most common condition associated
with ARDS
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Lung edema from increased permeability
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Alveolar edema dyspnea, hypoxemia, opacities on CXR
B/L infiltrates, wedge pressure <18
Endotoxin, TNF-alpha, IL-1, IL-6, IL-8,
bactericidal/permeability-increasing (BPI) protein
Clinical Features
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Pulmonary
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ARDS
B/L pulmonary infiltrates
 PCWP <18 (non-cardiogenic pulm edema)
 PaO2/FiO2 <200
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If PaO2/FiO2 >200, but <300 then ALI
Clinical Features
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Renal
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Acute renal failure w/ azotemia, oliguria,
active urinary sediment
Hypotension/Dehydration, aminoglycosides,
pigmenturia (e.g. myoglobinuria)
 Immune complex deposition
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IgG, IgM,C3, bacterial antigens & antibodies
Tubulointersitial disease
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S. pneumoniae, S. pyogenes, Legionella, salmonellosis,
brucellosis, diptheria
Clinical Features
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Gastrointestinal
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Accelerated apoptosis of GI epithelial cells

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Can lead to blood loss anemia
Cholestatic jaundice (most frequent
abnormality)
Transaminase/Alkaline phosphatase 1-3x normal
 Bilirubin concentrations, usually not >10mg/dL

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Hemolysis of RBC’s, hepatocellular dysfunction due to
endotoxin
Clinical Features
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Hematologic
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Minor blood loss secondary to erosions in
mucosal layer of stomach/duodenum
Accelerated apoptosis of lymphocytes
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Possibly due to elevated glucocorticoids
Most frequent changes are neutrophilia or
neutropenia, thrombocytopenia, DIC
Clinical Features

Hematologic
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Neutrophilia
Most common
 Left shift


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Demargination & release of less mature granulocytes
from BM
 C3a causes release of neutrophil releasing substance
Sustained neutrophilia is secondary to CSFs
Clinical Features
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Hematologic continued
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Neutropenia
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Morphological changes of WBC’s in sepsis
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Increases mortality
Increased peripheral use of cells, damage to cells by
bacterial byproducts, depression of marrow by inflammatory
mediators
Toxic granulations, Dohle bodies, vacuolization
Functional changes of WBC’s
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Increased phagocytic/cytotoxic activities
Clinical Features
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Hematologic continued
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RBC production & survival are decreased
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Usually does not cause anemia unless infection is
prolonged
Low serum Fe concentrations
Decrease by 50%
 Influx into liver & other reticuloendothelial cells
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Clinical Features
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Hematologic continued
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Thrombocytopenia
Usual a consequence of DIC
 May be early sign of bacteremia

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Inhibition of thrombopoiesis, increased platelet turnover,
increased endothelial adherence, increased destruction
Clinical Features
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DIC
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Clotting & fibrinolytic systems activated
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Consumption of coagulation factors & platelets
Clotting system activated through the extrinisic clotting
system by bacteria, viruses, fungi, endo/exotoxins
Gram(-) precipitate DIC more readily than gram (+)
Fibrinolytic system is activated by tissue type plasminogen
activator

As sepsis progresses, increase release of plasminogen activator
inhibitor type 1
Clinical Features

DIC continued
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Two forms
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Compensated
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“slower” generalized activation
Bleeding prevented by increasing coagulation factor production
in liver, release of platelets from reserve, synthesis of inhibitors
at accelerated rate
Decompensated
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Clinical bleeding and/or thrombosis
Thrombocytopenia, prolonged PT/PTT, decreased fibrinogen &
antithrombin III, increased fibrin monomer/fibrin split
products/D-dimer
Clinical Features
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Endocrine
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Hyperglycemia
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Increased catecholamines, cortisol, glucagon, peripheral
insulin resistance, impaired glucose use, decreased insulin
secretion
Significant risk for adverse outcome

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Must maintain tight control w/insulin infusion to keep b/w 80100 mg/dl (NEJM Nov 8, 2001; vol 345, #19)
Hypoglycemia

Assoc. w/S. pneumoniae, S. aureus, S. pyogenes, Listeria,
Neisseria meningitidis, H. flu, Enterobacteriaceae
Clinical Features
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Acid/Base



Early in sepsis  resp alkalosis
Metabolic acidosis suggests inadequate
perfusion, impaired hepatic clearance of
lactate/pyruvate, increased glycolysis
Hypoxemia often present due to
vent/perfusion mismatch
Clinical Features
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Cutaneous
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Direct bacterial involvement
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Lesions as a consequence of
sepsis/hypotension/DIC
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Cellulitis, erysipelas, fasciitis
Acrocyanosis & necrosis of peripheral tissue
Lesions secondary to intravascular infection
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Microemboli &/or immune complex vasculitis
Diagnosis
Diagnosis
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Pt presents with
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Hypotension not responsive to fluid bolus
Inadequate perfusion
Complaints attributable to a serious infection
Hot flushed skin
Mental obtundation or agitation
Widened pulse pressure
Hyperventilation
Dysthermia
**beware of the old, young, immunocompromised
Diagnosis
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Differential Diagnosis
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Other causes of shock
Cardiogenic
 Neurogenic
 Hypovolemic
 Anaphylactic
 Obstructive (PE, tamponade)
 Endocrine (adrenal insufficiency, thyroid storm)
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Diagnosis
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
H&P
Basic lab and x-rays are usually successful
in identification of source
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CNS
Meningitis (nuchal rigidity, MS change, petechiae)
 Brain abscess, sub/epi dural empyemas
 Viral CNS infections
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Diagnosis
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Pulmonary
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Intra-abdominal processes
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Acute bacterial pneumonia
Most common source of infection leading to sepsis
Acute pancreatits
Cholangitis
Septic abortion/endometritis/myometritis
Pyelonephritis
Occult Abscess
Skin
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Cellulitis (S.aureus, S.pyogenes)
Decubitus ulcer(s)
Diagnosis
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No obvious source
Endocarditis
 Primary bacteremia
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S.aureus, S.pneumoniae, N.meningitidis
Asplenia
 Salmonella, H flu, S pneumo, N. meningitidis
IVD users, Pseudomonas & gram(-) bacteria
 Skin abscess from “popping”
Diagnosis
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Ancillary Studies
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CBC
DIC panel (PT,PTT,fibrinogen,D-dimer, ATIII)
CMP (include Mag, Ca, Phosphate)
Lactate level
ABG
UA
CXR
Cultures (blood, urine)
If H&P suggest
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LP, CT (abd . . .)
Consider
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CRP, pro-calcitonin, IL-6 level
Standard Treatment
Standard Treatment
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ABC’s!
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Maintain O2 sat’s above 90%
Hemodynamic Stabilization
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Rapid fluid administration
Rate of 0.5L of NS every 5-10min
 May require 2-6L in initial stabilization phase
 Be careful with heart failure patients
 Monitor response with BP, HR, RR, mental status,
urine output (1cc/kg/hr), CVP, skin perfusion

Standard Treatment
▪ Inotropic support
If no response to fluids or signs of fluid overload
present
 Goal is to keep MAP above 65 mm Hg
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Dopamine 5-20 micrograms/kg/min
 Beta-1, dopaminergic and alpha adrenergic activity
Norepinephrine
 Beta-1 and alpha adrenergic stimulation
Short term vasopressin infusion (0.04 units/min for 416h)
 Vasodilatory septic shock
Standard Treatment
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End points
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Early goal directed therapy provides
significant benefit & improves outcome

Rivers et al. NEJM vol. 345:1368, 2001
Maintain CVP b/w 8-12
 Hct 30%
 SVO2 >70%
 Reduction in mortality from 44% in control group
to 29% in intervention group
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Standard Treatment
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Empiric Antimicrobial Therapy
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Start ASAP
Try to get culture samples before
Select based on adequate coverage of
potential pathogens
Should cover gram +/Give maximum dose allowed
Give IV
Empiric Antibiotics in Sepsis
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Table 32-3
Standard Treatment
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Removal of Source of Infection
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Indwelling catheters  send tip for culture
Replace Foley catheters
Intra-abdominal or soft tissue sites of pus
require urgent drainage
Standard Treatment

Initial Baseline Assessment & Continued
Monitoring (again goal directed)
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Some use serum lactate to monitor response
ABG’s to monitor ventilation & perfusion
2 large bore IV’s
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Consider central line early
If requiring vasoactive drugs consider pulm artery
thermal-dilution catheter
Other monitoring gadgets
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Sublingual capnography, gastric pH tonometry, muscle
oximetry, bioimpedance determination of CO
New Innovative Therapies
Innovative Therapy

Based in premise that neutralizing
bacterial toxins, cytokines, & other
mediators could stop or slow the
syndrome
Innovative Therapies

Corticosteroids
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Meta-analysis has shown physiologic doses of
hydrocortisone improves outcomes
(200-300mg/d) for 5-7 days
 Then tapered for 5-7 days



Early studies (proir to 1989) used high doses and had
increased mortality
Those published after 1997 (5)used lower doses and
reported improved survival similar to that of Activated
Protein C
 Annal of Internal Med 2004;141:47-56
Innovative Therapy

Activated Protein C (Xigris)
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Inactivates Factors Va and VIIIa
Inhibits thrombin (decreases inflammation)
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Inhibits platelet activation, neutrophil recruitment,
and mast cell degranulation
Blocks cytokine production
Inhibits cell adhesion
Anti-apoptotic actions
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Apoptosis (i.e. GI epithelial cell) induces anergy
Innovative Therapy
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Summary

To date the only treatments shown to produce
benefit
Early goal directed hemodynamic stabilization
 Tight control of blood glucose with insulin
 Activated protein C


“Efficacy and Safety of Recombinant Human
Activated Protein C for Severe Sepsis” NEJM 2001,
vol. 344; 699-709
Cardiogenic Shock
Cardiogenic Shock

A state of decreased cardiac output(CO)
producing inadequate tissue perfusion
despite adequate or excessive circulating
volume
Cardiogenic shock

Etiology

AMI
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Depression of contractility
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Sepsis, myocarditis, contusion
Mechanical obstruction


Pump failure (40% of LV involved)
Mechanical complications (MR,VSD,free wall rupture)
RV infarction
AS, hypertrophic CM, MS, LA myxoma
Regurgitation of LV output

AI, chordal rupture
Pathophysiology


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AMI
cell death
loss of contractile
function
Decreased CO/SV
tachycardia/hypotension
decreased coronary perfusion/diastolic filling
time
Further ischemia
SNS/Renin-Angiotension
System activation
Increased SVR and myocardial O2 consumption
Cardiogenic Shock

Clinical Features

PE

Hypoperfusion
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+/-hypotension (SBP<90)

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Skin mottling, obtunded
May be compensated (pulse pressure <20, ST) or pre-existing
hypertension
Tachypnea, rales (clear if RV), JVD
Murmur


MR (chordae tendinea rupture): holosystolic at apex going to
axilla
VSD: holosystolic at L parasternal
Cardiogenic Shock

Ancillary Studies



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
ECG: ischemia/infarction,electrolyte abnormality,drug
toxicity
CXR: helps r/o other causes (pneumonia, aortic
dissection, pericardial effusion)
Labs: BNP, cardiac enzymes, ABG, lactate,
electrolytes, serum drug levels
Echo: ventricular/valve dysfunction
HD monitoring (table 33-3): invasive vs bioimpedance
Cardiogenic Shock

Differential Diagnosis
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AMI
PE
COPD
Pneumonia
Aortic dissection
Tamponade
Acute valvular insufficiency
Hemorrhage
Sepsis
Drug OD of negative inotropic/chronotropic agent
Cardiogenic Shock

Treatment
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


ABC’s first
IV access/cardiac monitor/art line/foley
Correct hypoxia/hypovolemia/rhythm
disturbance/electrolyte abnormalities/acid-base
alterations
Hypotension




Dopamine,dobutamine
Fluid bolus if RV involved
Acute MR consider dobutamine and nitroprusside
IABP
Cardiogenic Shock

Treatment continued

Thrombolytic therapy

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Intraaortic balloon conterpulsion


Better outcomes if followed by revascularization
Decreases afterload, increases diastolic BP
Early revascularization

Most important life saving intervention
Cardiogenic Shock

Treatment continued

Inotropic agents
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Dopamine
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Dobutamine
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Use for signs of poor perfusion when SBP>90
2-20micrograms/kg/min
Norepinephrine
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First line agent
2.5-5 micrograms/kg/min beta-1
5-10 alpha & beta-1
10-20 alpha
Use only when inadequate response to other pressors
2 micrograms/min and titrate to response
Milrinone

50 microgram/kg bolus followed by 0.5microgram/kg/min infusion—watch BP!
Anaphylactic Shock
Anaphylactic Shock


Severe systemic hypersensitivity with
multisystem involvement
Life-threatening release of mediators by
mast cells and basophils
Anaphylactic Shock

Pathophysiology

4 classic mechanisms
1. cross-linking of 2 IgE molecules on a mast cell
or basophil by a multivalent antigen
 2. reaction of IgM & IgG to cell surface antigens
 3. soluble antigen-antibody complexes activating
complement
 4. activation of T lymphocytes

Anaphylactic Shock

Pathophysiology

Classic anaphylaxis

2 separate exposures




First the antigen or hapten-protein complex is processed
by macrophage & dendritic cells
Presented externally with MHC-2
T helper cells recognize and stimulate plasma cells to
produce IgE
Second exposure recognized by these IgE antibodies
triggers degranulation of mast cells and basophils
Anaphylactic Shock

Pathophysiology

Complement mediated reaction

Occur after administration of blood products
secondary to immune complexes


C3a & C5a cause degranulation
Non-immunologic anaphylaxis (anaphylactoid)

Exogenous substances directly degranulate mast
cells

Radiocontrast dye, opiates, depolarinzing drugs, dextrans
Anaphylactic Shock

Pathophysiology

ASA/NSAIDS
Non-mast cell process
 Modulate cyclooxygenase-arachidonic acid
metabolism


Idiopathic anaphylaxis

Diagnosis of exclusion
Anaphylactic Shock

Clinical Features




Diffuse urticaria & angioedema
+/- abd pain or cramping, N/V, diarrhea,
bronchospasm, rhinorrhea, conjunctivitis,
dysrhythmias, hypotension
c/o “lump” in the throat heralds life-threatening
laryngeal edema
Usually begin w/in 60 minutes of exposure


Faster the onset the more severe the reaction
Biphasic phenomenon

Second release of mediators clinically evident 3-4h after the
initial manifestations clear
Anaphylactic Shock

Diagnosis

History and physical
2 or more body systems involved
 Differential


Vasovagal reaction, status asthmaticus, seizure,
epiglottitis, hereditary angioedema, FB airway
obstruction, carcinoid, mastocytosis, non-IgE drug
reactions, AMI, dysrhythmias
Anaphylactic Shock

Treatment

First Line
ABC’s
 Epinephrine, oxygen, fluids (NS 1-2L)




Epi 0.1mg in 10cc NS over 5-10minutes IV if signs of CV
collapse
 If refractive start infusion: 1mg in 500ccD5W at 1-4
micrograms/min
Less severe, give 0.3-0.5 mg IM in the thigh
decontamination
Anaphylactic Shock

Treatment

Second Line

Corticosteroids



Methylprednisolone 125mg IV
2mg/kg in children
Antihistamines


Diphenhydramine (H1) 25-50mg IV
Ranitidine or cimetidine(H2)
 Avoid cimetidine in elderly, renal/hepatic failure, or if
patient is on beta blocker
Anaphylactic Shock

Treatment

Second Line

Agents for bronchospasm




Albuterol
Ipratropium bromide
Magnesium 2g IV over 20-30minutes
 25-50mg/kg in children
Glucagon

1 mg IV q 5min until response followed by infusion 5-15
micrograms/min if patient on beta blockers with
refractive hypotension
Anaphylactic Shock

Disposition


Unstable patients admit to ICU
If patient received epi-observe for 4h
Consider distance from care, someone to go home
with, comorbidities, age
 Good discharge instructions is a must
 Send with epipen, short course of antihistamines
and steroids

Neurogenic Shock
Neurogenic Shock




Acute spinal cord injury
Disruption of sympathetic outflow
Hypotension & bradycardia
Majority caused by blunt trauma



MVA, falls, sports
Cervical region most commonly injured
Penetrating injury (10-15% of cases)

GSW’s and stab wounds
Neurogenic Shock

Pathophysiology

33 bony vertebrae



Anterior body, posterior arch, sup/inf articular processes,
pedicles, laminae
Spinal cord is cylindrical arising from base of brain &
covered by 3 layers of meninges & CSF
31 pairs of spinal nerves exit the canal via
intervertebral foramen

Spinal nerves are formed by ant/post nerve roots
Neurogenic Shock

Pathophysiology

Spinal cord contains white & gray matter



White: nerve fibers running up & down in cord tracts
Gray: nerve cells
Autonomic Nervous System

Sympathetic



Outflow tracts in lateral gray horns of 1st thoracic to 2nd lumbar
Controlled by hypothalamus
Lateral hornanterior nerve rootganglia of paraspinal
sympathetic trunktravel throughout the body
Neurogenic Shock

Pathophysiology

Autonomic Nervous System

Parasympathetic

Cranial Nerves & 2-4th sacral segments (splanchnic
nerves)
Neurogenic Shock
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Clinical features
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Hypotensive with warm,dry skin
Bradycardic ususally
Hypothermic
These symptoms last 1-3 weeks
Neurogenic Shock
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Treatment
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ABCDE’s
Investigate all other possible sources of hypotension &
bradycardia
Infuse crystalloids rapidly
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Attempt to keep MAP 85-90mm Hg for the first 7 days to minimize
secondary cord injury
Dopamine & dobutamine may be helpful
Severe bradycardia can be treated with atropine or pacing
Steroids are not indicated in the treatment of neurogenic shock
per se
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Indicated in blunt injury with neuro deficits if started within 8h
(30mg/kg bolus then 45 mins later infuse at 5.4mg/kg/h for 23h)
Questions
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1. In cardiogenic shock the PCWP is
A. Decreased
 B. Increased
 C. Normal
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Questions
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2. SIRS is defined as inflammation
secondary to infection
A. True
 B. False
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3. Which is not a parameter used to
define ARDS
A. Bilateral infiltrates on CXR
 B. PCWP>18
 C. PaO2/FIO2 <200
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4. What is considered the first line
inotrope in cardiogenic shock
A. Dopamine
 B. Dobutamine
 C. Milrinone
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5.
Which is not considered a first line agent
in treatment of anaphylaxis
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A. Epi
B. Oxygen
C. albuterol
Answers
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1.
2.
3.
4.
5.
B
B
B
A
C