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 FORMULA = 70 + [2 x age (in years)]
– 82 70 + [2 x 6]
– 93
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
 LFTs,
MS ileus ARDS

SHOCK

BP 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 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 Low Blood Pressure Low Blood

Cold Shock Cold Shock Pressure
SVC O2 sat < 70% SVC O2 sat < 70% Warm Shock
Titrate Volume and
Add vasodilator or Type III PDE Titrate Volume and Norepinephrine
inhibitor Epinephrine with volume (? 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/m2 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.

Push 20cc/kg isotonic saline or colloid boluses up

5 min 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
 Recognize Shock
Warm “Low SVR” Shock
• Tachycardic
• Maybe  BP
– Diastolic
hypotension
• Skin and
extremities:
– warm
– flushed
– flash capillary
refill
 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
 Recognize Shock
• Neurological
– Poor muscle tone
– Uncooperative
– Depressed or
fluctuating mental
status are late
signs
• Renal
– Scant,
concentrated urine
 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
30%  in SVR
120
100 40% 
in Blood Vol
% 80
50% 
Control 60 in C.O.
40 Vascular Resistance
Blood Pressure
20
Cardiac Output
0
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
(% Control)

10
0
BP

5
0
Bloo
Los
d
s

Late Resuscitation -
Death
0 2 4 6 8 10 12
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
NFB - nuclear transcription factor
TNF TNF TNF

R2 R1 Fas

Acute Acute
Inflammatory Inflammatory Apoptosis
Response Response

iNO Tissue Factor

Complement NFB Cytokines Endonuclease
Adhesion Molecules
 Sepsis

bacteremia trauma
fungemia pancreatitis
Infection Sepsis SIRS
viremia burns
other other

Adapted from Bone, 1996

 Cascade

Host Microbes Endotoxin/

Exotoxin

Host response

Death Multiorgan Pathophysiologic

dysfunction Changes
 Infection
Microbial Products
(endotoxin/Peptidoglycans)

Cellular Responses

Thromboanes Oxidases Kinins Cytokines

Leukotrienes/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
Antibiotics Eliminate endotoxin
Host Microbes Endotoxin/
Exotoxin
Antagonize mediators
Anti-inflammatory intervention Host response
Reverse coagulopathy
Death Multiorgan Pathophysiologic
dysfunction Changes

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
– TNF Hagmolen: Euro. J of Peds 2000)
• Coagulopathy: Microvascular thrombosis
and inflammation
– Protein C pathway
– TNF
 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 Disrupted O2 utilization

Capillary leak Myocardial dysfunction
Poor prognostic indicators:
•decreased VO2
•decreased avDO2
•decreased O2 extraction
 Meta Analysis - Corticosteroids
Favors Steroids Favors Control
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)
*
*

Cronin CCM 1995 0 0.5 1 1.5 2 2.5 3 3.5

Summary of Clinical Trials in Sepsis
Mortality %
# studies # pts 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)
 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 TNF No Benefit
• Adhesion Molecules
– Selectin Inhibitors No Benefit
• Interleukin 1, 6 No Benefit
• Complement Current Trials