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Recent Advances in

the Treatment of Shock

Jon Meliones MD, MS, FCCM

Professor of Pediatrics & Anesthesia

Duke University Medical Center

Definition

Shock

Diagnosis

Effects of Shock

Types of Shock

Treatment for Shock

Definition

Shock

Acute disruption of both the micro- and macro-circulation

Inadequate DO2 (Do2 = C.O. x Oxygen

content), VO2 and cellular oxygen deficiency

Limitation or maldistribution of blood

flow

Stages of Shock

Vital organ function maintained

BP remains normal

Microvascular perfusion becomes marginal

Organ and cellular function deteriorate

Hypotension develops

MOSF with end organ injury

Compensated

Uncompensated

Irreversible

Hypotension:

MAP < 5th percentile for age

lowest acceptable SBP = 70 + [2 x age (in yrs)]

Age of child

Lowest acceptable SBP

Term neonates Infants 1-12mo Children 1-10yr Children >10yr

Term neonates Infants 1-12mo Children 1-10yr Children >10yr
Term neonates Infants 1-12mo Children 1-10yr Children >10yr
Term neonates Infants 1-12mo Children 1-10yr Children >10yr

60

70

70 + [2 x age (in years)]

90

Shock Quick Look

The lowest acceptable SBP for a 6 year old child is

76

80

82

93

SBP for a 6 year old child is – 76 – 80 – 82 – 93

FORMULA = 70 + [2 x age (in years)]

70 + [2 x 6]

70 + 12

82

Early Reversal of Septic Shock

Early reversal of pediatric-neonatal septic shock by community

physicians is associated with improved outcome

(Han et al, Pediatrics 2003)

Controlling for

severity of illness, with each

hour of

persistent shock,

risk of mortality

doubled

al, Pediatrics 2003) Controlling for severity of illness, with each hour of persistent shock, risk of
LFTs, ileus MS ARDS SHOCK BP UO
LFTs, ileus MS ARDS SHOCK BP UO

LFTs,

ileus

LFTs, ileus MS ARDS SHOCK BP UO

MS

ARDS

SHOCK
SHOCK
LFTs, ileus MS ARDS SHOCK BP UO

BP

LFTs, ileus MS ARDS SHOCK BP UO

UO

How do we Treat Shock?

American College of Critical Care

Medicine

Guidelines for management of pediatric

septic shock

Guidelines are not hard

BUT: they’re demanding

Time-sensitive

Requires some hustle to get it right

Cannot be followed if you’re working alone

You will need help

Stepwise management of hemodynamic support with goals of normal perfusion and perfusion pressure (MAP-CVP) in infants and children with septic shock. Proceed to next step if shock persists.

0 min Recognize decreased mental status and perfusion. Maintain airway and establish access according to
0
min
Recognize decreased mental status and perfusion.
Maintain airway and establish access according to PALS
guidelines.
5
min
Push 20cc/kg isotonic saline or colloid boluses up to and over 60
cc/kg
Correct hypoglycemia and hypocalcemia
NO
Fluid refractory shock?
YES
15
min
Observe in hospital or
Establish central venous access, begin
PICU as appropriate
dopamine therapy and establish arterial
monitoring
NO
Fluid refractory-dopamine resistant
YES
shock?
Observe in PICU
Titrate epinephrine for cold shock, norepinephrine for
warm shock to normal MAP-CVP and SVC O2
saturation > 70%
60
min
At Risk of Adrenal
Catecholamine-resistant
Not at
Insufficiency?
shock?
Risk?
Give hydrocortisone
Do not give
hydrocortisone
Normal Blood Pressure
Cold Shock
SVC O 2 sat < 70%
Low Blood Pressure
Cold Shock
SVC O 2 sat < 70%
Low Blood
Pressure
Warm Shock
Titrate Volume and
Add vasodilator or Type III PDE
Titrate Volume and
Epinephrine with volume
Norepinephrine
inhibitor
(? vasopressin or angiotensin)
loading
Persistent catecholamine-resistant shock ?
Place pulmonary artery catheter and direct fluid, inotrope,vasopressor,vasodilator, and hormonal
therapies to attain normal MAP-CVP and CI > 3.3 and < 6.0 L/min/m 2 and consider ECMO

Stepwise management of hemodynamic support with goals of

normal perfusion and perfusion pressure (MAP-CVP) in infants and children with septic shock. Proceed to next step if shock persists.

Recognize decreased mental

status and perfusion.

Maintain airway and establish access according to

0 min

PALS guidelines.

5 min

Push 20cc/kg isotonic saline or colloid boluses up

to and over 60 cc/kg

Correct hypoglycemia and hypocalcemia

Recognize Shock

Cold “High SVR” Shock

Tachycardic

Maybe BP

Skin and

extremities:

cool

pale

mottled

cyanotic

poor cap refill

• Maybe  BP • Skin and extremities: – cool – pale – mottled – cyanotic

Recognize Shock

Warm “Low SVR” Shock

Tachycardic

Maybe BP

Diastolic

hypotension

Skin and

extremities:

warm

flushed

flash capillary refill

Maybe  BP – Diastolic hypotension • Skin and extremities: – warm – flushed – flash

Recognize Shock

Poor capillary refill

Anything longer than 2 seconds is delayed

If you get as far as 5

sec, you’d better be calling for help

refill • Anything longer than 2 seconds is delayed – If you get as far as

Recognize Shock

Neurological

Poor muscle tone

Uncooperative

Depressed or fluctuating mental

status are late

signs

Renal

Scant,

concentrated urine

– Uncooperative – Depressed or fluctuating mental status are late signs • Renal – Scant, concentrated

Shock: Diagnosis

Noninvasive

Impaired perfusion

Capillary refill

Peripheral Vs core temp

Vital signs

HR, B.P. nl- , RR

End organ function- UOP Mental

status changes

Shock: Diagnosis

Invasive

Laboratory evaluation

Metabolic acidosis

Lactic acidosis

pH < 7.2

Mixed venous saturations

Depressed = inadequate DO2

Elevated = maldistribution, impaired utilization

Monitoring C.O. in Shock

Optimize DO2 and Enhance VO2

Echocardiography - Differentiate Systolic/Diastolic Function

SvO2 to Monitor DO2

High SvO2

No benefit in driving delivery

Low SvO2

Enhance Delivery

Secondary Effects

Organ Dysfunction

Renal insufficiency

Respiratory insufficiency

Primary pump failure

Secondary to shock

Coagulation abnormalities

DIC

Secondary Effects

Organ Dysfunction

Hepatic dysfunction

Closely linked to outcome

GI

Related to ischemia

Endocrine disturbances

Ca++, hypoadrenalism

Neuro

Hypoperfusion syndromes

Shock

Hypovolemic Shock

Cardiogenic Shock

Septic Shock

Distributive

Endocrine

Hypovolemic Shock

Physiology

Diagnosis

Management

Hypovolemic Shock

# 1 Cause of Death World Wide

Hemorrhagic - Trauma, GI Bleeding

Gastroenteritis

Children: Frequently extreme

Late Dx - Previously Healthy

Inability to compensate for rapid changes

in volume

Physiology of Hypovolemic Shock

Intravascular volume-

Preload- stroke volume (SV) - C.O.- DO2. SvO2

Compensation- Endogenous catechol

HR- C.O- DO2 SVR- B.P.

Compensation for <15%

Hypovolemic Shock (Puppies)

140

120

100

% 80

Control

60

40

20

0

30%  in SVR 40%  in Blood Vol 50%  in C.O.
30%  in SVR 40%  in Blood Vol 50%  in C.O.
30%  in SVR 40%  in Blood Vol 50%  in C.O.

30% in SVR

40%  in Blood Vol 50%  in C.O.
40% 
in Blood Vol
50% 
in C.O.
30%  in SVR 40%  in Blood Vol 50%  in C.O.
30%  in SVR 40%  in Blood Vol 50%  in C.O. Vascular Resistance Blood
Vascular Resistance

Vascular Resistance

30%  in SVR 40%  in Blood Vol 50%  in C.O. Vascular Resistance Blood

Blood PressureCardiac Output

Blood Pressure Cardiac Output
Blood Pressure Cardiac Output

Cardiac OutputBlood Pressure

Blood Pressure Cardiac Output
Vascular Resistance Blood Pressure Cardiac Output 0 5 10 15 20 25 30 35 40 45
Vascular Resistance Blood Pressure Cardiac Output 0 5 10 15 20 25 30 35 40 45
Vascular Resistance Blood Pressure Cardiac Output 0 5 10 15 20 25 30 35 40 45

0 5

10 15 20 25 30 35 40 45 50 55 60 65 70 75

% Blood Volume Deficit

Delaying Resuscitation in Hypovolemic

Shock Effects Outcome

10 0 5 0 Late Resuscitation - Death 0 2 4 6 8 10 12
10
0
5
0
Late Resuscitation -
Death
0
2
4
6
8
10
12
BP
Blood
(% Control)
Loss

Time (hrs)

Diagnosis of Hypovolemic Shock

Early

HR, Perfusion (SVR)

Pulse width (low SV)

Late

 HR,  Perfusion,BP

End organ dysfunction

Treatment of Hypovolemic

Shock

Volume infusion

Goal = reverse signs of DO2

Replace what is lost

Crystalloid 20 ml/kg x 2

No response - invasive monitor

If CVP>10, & DO2, need re-eval

Hypovolemic Shock

Summary

Primary goal

Volume replacement

Secondary goal

Prevent ischemia

Minimize inflammatory mediator

release

Use of Albumin increases

mortality

Septic Shock

Definition

Molecular Basis

Diagnosis

Treatment

Terminology in Sepsis

Infection= response to micro-org

Bacteremia= bug in blood

Systemic Inflammatory

Response Syndrome (SIRS)

T>38, <36

HR

RR, PaCO2 <32 WBC>12,000, <4,000, >10% bands

Terminology in Sepsis

Sepsis = SIRS as response to a known infection

Severe Sepsis = Sepsis + organ dysfunction

Septic shock = Sepsis + inadequate tissue

DO2

Multiple Organ Dysfunction Syndrome

(MODS)

Organ dysfunction that requires intervention

Molecular Basis of Shock

NFkB - nuclear transcription factor

TNF TNF TNF R2 R1 Fas Acute Acute Apoptosis Inflammatory Inflammatory Response Response iNO Tissue
TNF
TNF
TNF
R2
R1
Fas
Acute
Acute
Apoptosis
Inflammatory
Inflammatory
Response
Response
iNO
Tissue Factor
NFkB
Complement
Cytokines
Endonuclease

Adhesion Molecules

Sepsis

bacteremia trauma fungemia Infection Sepsis SIRS viremia burns other other
bacteremia
trauma
fungemia
Infection
Sepsis
SIRS
viremia
burns
other
other
bacteremia trauma fungemia Infection Sepsis SIRS viremia burns other other pancreatitis Adapted from Bone, 1996

pancreatitis

Adapted from Bone, 1996

Host

Death

Cascade

Microbes

Multiorgan

dysfunction

Host Death Cascade Microbes Multiorgan dysfunction Endotoxin/ Exotoxin Host response Pathophysiologic Changes

Endotoxin/

Exotoxin

Host response

Host Death Cascade Microbes Multiorgan dysfunction Endotoxin/ Exotoxin Host response Pathophysiologic Changes

Pathophysiologic

Changes

Infection

Infection Microbial Products (endotoxin/Peptidoglycans) Cellular Responses Thromboanes Leukotrienes/PAF sPLA2 Oxidases

Microbial Products

(endotoxin/Peptidoglycans)

Infection Microbial Products (endotoxin/Peptidoglycans) Cellular Responses Thromboanes Leukotrienes/PAF sPLA2 Oxidases
Cellular Responses
Cellular Responses

Thromboanes

Leukotrienes/PAF sPLA2

Oxidases

Kinins

Complement TNF, IL1, IL6, IL8

Cytokines

Thromboanes Leukotrienes/PAF sPLA2 Oxidases Kinins Complement TNF, IL1, IL6, IL8 Cytokines Inflammation/Vascular Injury

Inflammation/Vascular Injury

Inflammation/Vascular Injury

Inflammation/Vascular Injury Mediators (e.g. TNF) Endothelial Injury Tissue Factors Coagulation Sys. Activation Consume
Inflammation/Vascular Injury Mediators (e.g. TNF) Endothelial Injury Tissue Factors Coagulation Sys. Activation Consume

Mediators (e.g. TNF) Endothelial Injury

Tissue Factors Coagulation Sys. Activation

Injury Tissue Factors Coagulation Sys. Activation Consume Protein C Apoptosis Uncontrolled Inflammation

Consume Protein C

Apoptosis Uncontrolled Inflammation

Impaired Fibrinolysis

Coagulation

/ DIC

MOSF Shock Death
MOSF
Shock
Death

Therapeutic Interventions

Antibiotics

Eliminate endotoxin

Therapeutic Interventions Antibiotics Eliminate endotoxin Host Microbes Antagonize mediators Anti-inflammatory

Host

Interventions Antibiotics Eliminate endotoxin Host Microbes Antagonize mediators Anti-inflammatory intervention

Microbes

Antagonize mediators Anti-inflammatory intervention

Reverse coagulopathy

Anti-inflammatory intervention Reverse coagulopathy Endotoxin/ Exotoxin Host response Death Multiorgan

Endotoxin/

Exotoxin

Host response

Death

Reverse coagulopathy Endotoxin/ Exotoxin Host response Death Multiorgan dysfunction Pathophysiologic Changes Supportive

Multiorgan

dysfunction

coagulopathy Endotoxin/ Exotoxin Host response Death Multiorgan dysfunction Pathophysiologic Changes Supportive Measures
coagulopathy Endotoxin/ Exotoxin Host response Death Multiorgan dysfunction Pathophysiologic Changes Supportive Measures

Pathophysiologic

Changes

Supportive Measures

Infection

Infection Microbial Products (Endotoxin/Peptidoglycans) Cellular Responses Mediators (e.g. TNF) Coagulation activation

Microbial Products (Endotoxin/Peptidoglycans)

Cellular Responses

Products (Endotoxin/Peptidoglycans) Cellular Responses Mediators (e.g. TNF) Coagulation activation Coagulopathy

Mediators (e.g. TNF)

Cellular Responses Mediators (e.g. TNF) Coagulation activation Coagulopathy Treatment Block

Coagulation activation

Responses Mediators (e.g. TNF) Coagulation activation Coagulopathy Treatment Block Endotoxin Block Mediators Block

Coagulopathy

Treatment

Block Endotoxin

Block Mediators

Block Coagulation

Cytoprotectives

Adverse Systemic Effects of

Cytokines and Endotoxin

Hypotension- Fluid refractory

Upregulation of Inducible NO (iNO)

NO + O2, superoxide - free radicals

Cardiac dysfunction -systolic & diastolic

TNFa (Hagmolen: Euro. J of Peds 2000)

Coagulopathy: Microvascular thrombosis and inflammation

Protein C pathway

TNFa

Diagnosis of Septic Shock

Establish presence of infection

HR, NL - BP, - Perfusion

Uncoupling of HR & BP (Toweill CCM 2000)

Metabolic acidosis / lactic acidosis

Elevated SVO2

Organ dysfunction

Renal

Respiratory

Early vs Late Septic Shock

Early hyperdynamic shock

Late septic shock

Intact O 2 utilization Capillary leak

Disrupted O 2 utilization Myocardial dysfunction

Poor prognostic indicators:

•decreased VO 2 decreased avDO 2 decreased O 2 extraction

Meta Analysis - Corticosteroids

Favors Steroids

Favors Control

1.07 * * 1.35 * 1.11 * 1.01 * * 0.30 0.97 * * *
1.07
*
*
1.35
*
1.11
*
1.01
*
*
0.30
0.97
*
*
*
*
0
0.5
1
1.5
2
2.5
3
3.5

Luce (1988)

VASSCg (1987)

Bone (1987)

Sprung(1984)

Thompson(1978)

Lucas(1984)

Schumer(1976)

Klastersky(1971)

(0.72-1.60)

0.95 (0.57-1.58)

(0.98-1.84)

(0.74-1.67)

(0.77-1.31)

1.09 (0.36-3.27)

(0.13-0.72)

(0.65-1.45)

CS Group

Common Relative Risk

(1963)

1.72 (1.23-2.41)

1.13 (0.99-1.29)

Cronin CCM 1995

Summary of Clinical Trials in Sepsis

# studies # pts

Mortality % con

exp

p value

High dose steroids

>9

1300

35

39

<.05

Anti-bradykinin

2

755

36

39

Anti-PAF

2

870

50

45

Anti-PG (ibuprofen)

3

508

40

38

IL-1Ra

3

1898

35

31

Anti-TNF mAb

8

4139

36

35

TNF soluble receptor

p75-SR

1

141

30

45

<.05

p75 SR phaseI/II

1

444

29

34

p75-SR phase III

1

1340

28

27

NO synthase inhibitor

2

1059

50

56

New Selective Therapy

Recombinant Human Activated Protein C

Protein C pathway

Antithrombotic/ profibrinolytic agent

Maintains vascular patency

Loss of protein C:

Loss of modulation

Vascular dysfunction

Selective replacement (Bernard: NEJM 2001)

1690 pts

Mortality: CTL = 31%: Tx = 25%

Serious bleeding = CTL = 2%: Tx = 3.5%

Controversy in Manipulating

Inflammatory Response

Target Therapy - No Benefit

Too Little? Too Late? Timing?

Early Global Therapy - No Benefit

Timing, Dose, Disease?

Poor Understanding of Pathophysiology?

Clinical Trials?

Cocktail Therapy -What, When, Dose?

Treatment in Septic Shock

Control Infection

Reverse cardiovascular dysfunction

Early aggressive restoration of preload

0.9% NS may base deficit (Skellett: Arch Dis Child 2000)

Inotropic agents in fluid refractory shock (Ceneviva: Ped

1998)

Prevent secondary end organ injury

Renal- Maintain BP

Respiratory- monitor

Steroids (steroid deficient shock) (Annane: CCM

2000)

injury – Renal- Maintain BP – Respiratory - monitor • Steroids (steroid deficient shock) ( Annane:

Distributive Shock

Anaphylaxis, spinal shock

Maldistribution of blood flow

NL or CO, Inadequate tissue DO2 Treatment

Fluid

Reversal of etiology

Differential Dx in Shock

State

CO

SVR

BP

CVP

PCWP

Hypovolemic

NL /



 

Cardiac Sys

 



NL /

Cardiac Dias

NL



NL





Sepsis Early



 

NL /

Sepsis Late

 

 

 





Differential Dx in Shock

State

CO

SVR

BP

CVP

PCWP

Hypovolemic

NL /



 

Cardiac Sys

 



NL /

Cardiac Dias

NL



NL





Sepsis Early

/

NL /

Sepsis Late

 

 

 





Conclusion

Hypovolemic Shock -

Early Intervention to Prevent Ischemia/Reperfusion

Cardiogenic Shock -

Targeted Treatment

Septic Shock - ???

Global or Selective Modification of

the Inflammatory Response

Steroids -

Anti TNFa

Adhesion Molecules

Selectin Inhibitors

Interleukin 1, 6

Complement

No Benefit, ? No Benefit

No Benefit

No Benefit Current Trials