Recent Advances in

the Treatment of

Shock

Jon Meliones MD, MS, FCCM

Professor of Pediatrics & Anesthesia

Duke University Medical Center

Shock

• Definition

–Diagnosis

–Effects of Shock

• Types of Shock

• Treatment for Shock

Shock• Definition

– 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

• Compensated

– Vital organ function maintained

– BP remains normal

• Uncompensated

– Microvascular perfusion becomes marginal

– Organ and cellular function deteriorate

– Hypotension develops

• Irreversible

– MOSF with end organ injury

Hypotension:

MAP < 5th percentile for age

lowest acceptable SBP =

70 + [2 x age (in yrs)]

Age of child Lowest acceptable SBP

Term neonates 60

Infants 1-12mo 70

Children 1-10yr 70 + [2 x age (in years)]

Children >10yr 90

Shock Quick Look

• The lowest acceptable 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

Controlling for severity of

illness, with each hour of

persistent shock, risk of mortality

doubled

• Early reversal of pediatric-neonatal septic shock by community

physicians is associated with improved outcome(Han et al, Pediatrics 2003)

SHOCK

ARDSMS

BP UO

LFTs,

ileus

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

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/m2 and consider ECMO

Titrate epinephrine for cold shock, norepinephrine for

warm shock to normal MAP-CVP and SVC O2

saturation > 70%

Fluid refractory-dopamine resistant

shock?Observe in PICU

Normal Blood Pressure

Cold Shock

SVC O2 sat < 70%

Add vasodilator or Type III PDE

inhibitor

Low Blood

Pressure

Warm Shock

Low Blood Pressure

Cold Shock

SVC O2 sat < 70%Titrate Volume and

Norepinephrine

(? vasopressin or angiotensin)Titrate Volume and

Epinephrine with volume

loading

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.

Push 20cc/kg isotonic saline or colloid boluses up to and over 60

cc/kg

Correct hypoglycemia and hypocalcemia

Recognize decreased mental status and perfusion.

Maintain airway and establish access according to PALS

guidelines.

0 min

Observe in hospital or

PICU as appropriate

Establish central venous access, begin

dopamine therapy and establish arterial

monitoring

Fluid refractory shock?

15 min

5 min

Give hydrocortisone

At Risk of Adrenal

Insufficiency?

60 min

Do not give

hydrocortisone

Catecholamine-resistant

shock?

Not at

Risk?

YESNO

NO YES

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.

Push 20cc/kg isotonic saline or colloid boluses up

to and over 60 cc/kg

Correct hypoglycemia and hypocalcemia

Recognize decreased mental status and perfusion.

Maintain airway and establish access according to

PALS guidelines.0 min

5 min

• Tachycardic

• Maybe BP

• Skin and

extremities:

– cool

– pale

– mottled

– cyanotic

– poor cap refill

Recognize Shock

Cold “High SVR” Shock

• Tachycardic

• Maybe BP– Diastolic

hypotension

• Skin and extremities: – warm

– flushed

– flash capillary refill

Recognize Shock

Warm “Low SVR” Shock

Recognize Shock

• Anything longer than 2 seconds is delayed– If you get as far as 5

sec, you’d better be calling for help

Poor capillary refill

• Neurological

– Poor muscle tone

– Uncooperative

– Depressed or

fluctuating mental

status are late

signs

• Renal

– Scant,

concentrated urine

Recognize Shock

Shock: Diagnosis

• Impaired perfusion

– Capillary refill

– Peripheral Vs core temp

• Vital signs– HR, B.P. nl- , RR

• End organ function- UOP – Mental status changes

Noninvasive

Shock: Diagnosis

• Laboratory evaluation

–Metabolic acidosis

• Lactic acidosis

• pH < 7.2

–Mixed venous saturations

• Depressed = inadequate DO2

• Elevated = maldistribution, impaired

utilization

Invasive

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

• Renal insufficiency

• Respiratory insufficiency

–Primary pump failure

–Secondary to shock

• Coagulation abnormalities

–DIC

Organ Dysfunction

Secondary Effects

• Hepatic dysfunction

– Closely linked to outcome

• GI

– Related to ischemia

• Endocrine disturbances

– Ca++, hypoadrenalism

• Neuro

– Hypoperfusion syndromes

Organ Dysfunction

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 catechols

– HR- C.O- DO2

– SVR- B.P.

• Compensation for <15%

Hypovolemic Shock (Puppies)

0

20

40

60

80

100

120

140

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Vascular Resistance

Blood Pressure

Cardiac Output

%Control

% Blood Volume Deficit

40% in Blood Vol

50% in C.O.

30% in SVR

Delaying Resuscitation in Hypovolemic

Shock Effects Outcome

0 2 4 6 8 10 12

BP

(% C

on

tro

l)

5

0

10

0

Blo

od

L

os

s

Late Resuscitation -

Death

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

TNF TNF TNF

R2 R1 Fas

AcuteInflammatory

Response

NFkB

AcuteInflammatory

ResponseApoptosis

Adhesion Molecules

CytokinesComplement

iNO Tissue Factor

Endonuclease

NFkB - nuclear transcription factor

Sepsis

SIRSSepsisInfection

Adapted from Bone, 1996

bacteremia

fungemia

viremia

other

trauma

burns

other

pancreatitis

Cascade

Host Microbes Endotoxin/

Exotoxin

Host response

Pathophysiologic

Changes

Multiorgan

dysfunction

Death

Infection

Microbial Products

(endotoxin/Peptidoglycans)

Cellular Responses

Thromboanes Oxidases Kinins CytokinesLeukotrienes/PAF sPLA2 Complement TNF, IL1, IL6, IL8

Inflammation/Vascular Injury

Inflammation/Vascular Injury

Mediators (e.g. TNF) Tissue Factors

Endothelial Injury Coagulation Sys. Activation

Consume Protein C

Apoptosis Impaired Fibrinolysis

Uncontrolled Inflammation Coagulation / DIC

MOSF Shock

Death

Therapeutic Interventions

Host Microbes Endotoxin/

Exotoxin

Host response

Pathophysiologic

Changes

Multiorgan

dysfunction

Death

Antibiotics Eliminate endotoxin

Antagonize mediators

Anti-inflammatory intervention

Reverse coagulopathy

Supportive Measures

Infection Treatment

Microbial Products Block Endotoxin

(Endotoxin/Peptidoglycans)

Cellular Responses

Mediators (e.g. TNF) Block Mediators

Coagulation activation Block Coagulation

Coagulopathy 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 O2 utilization

Capillary leak

Disrupted O2 utilization

Myocardial dysfunction

Poor prognostic indicators:

•decreased VO2

•decreased avDO2

•decreased O2 extraction

Meta Analysis - Corticosteroids

Luce (1988) 1.07 (0.72-1.60)

VASSCg (1987) 0.95 (0.57-1.58)

Bone (1987) 1.35 (0.98-1.84)

Sprung(1984) 1.11 (0.74-1.67)

Thompson(1978) 1.01 (0.77-1.31)

Lucas(1984) 1.09 (0.36-3.27)

Schumer(1976) 0.30 (0.13-0.72)

Klastersky(1971) 0.97 (0.65-1.45)

CS Group (1963) 1.72 (1.23-2.41)

Common Relative Risk 1.13 (0.99-1.29)

0 0.5 1 1.5 2 2.5 3 3.5

**

**

**

**

*

*

Cronin CCM 1995

Favors Steroids Favors Control

Summary of Clinical Trials in Sepsis

High dose steroids

Anti-bradykinin

Anti-PAF

Anti-PG (ibuprofen)

IL-1Ra

Anti-TNF mAb

TNF soluble receptor

p75-SR

p75 SR phaseI/II

p75-SR phase III

NO synthase inhibitor

>9

2

2

3

3

8

1

1

1

2

1300

755

870

508

1898

4139

141

444

1340

1059

35

36

50

40

35

36

30

29

28

50

39

39

45

38

31

35

45

34

27

56

<.05

<.05

# studies # pts con exp p valueMortality %

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: Ped1998)

• Prevent secondary end organ injury– Renal- Maintain BP

– Respiratory- monitor

• Steroids (steroid deficient shock) (Annane: CCM

2000)

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 - No Benefit, ?

• Anti TNFa No Benefit

• Adhesion Molecules

–Selectin Inhibitors No Benefit

• Interleukin 1, 6 No Benefit

• Complement Current Trials