1. Recent Advances in
the Treatment of
Shock
Jon Meliones MD, MS, FCCM
Professor of Pediatrics & Anesthesia
Duke University Medical Center

2. Shock
• Definition
–Diagnosis
–Effects of Shock
• Types of Shock
• Treatment for Shock

3. 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

4. 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

5. 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

6. 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

7. 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

8. LFTs,
ileus ARDS
MS
SHOCK
BP UO

9. 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

10. 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
Norepinephrine
Add vasodilator or Type III PDE Titrate Volume and
(? vasopressin or angiotensin)
inhibitor Epinephrine with volume
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

11. 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

12. Recognize Shock
Cold “High SVR” Shock
• Tachycardic
• Maybe  BP
• Skin and
extremities:
– cool
– pale
– mottled
– cyanotic
– poor cap refill

13. Recognize Shock
Warm “Low SVR” Shock
• Tachycardic
• Maybe  BP
– Diastolic
hypotension
• Skin and
extremities:
– warm
– flushed
– flash capillary
refill

14. 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

15. Recognize Shock
• Neurological
– Poor muscle tone
– Uncooperative
– Depressed or
fluctuating mental
status are late
signs
• Renal
– Scant,
concentrated urine

16. 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

17. Shock: Diagnosis
Invasive
• Laboratory evaluation
– Metabolic acidosis
• Lactic acidosis
• pH < 7.2
– Mixed venous saturations
• Depressed = inadequate DO2
• Elevated = maldistribution, impaired
utilization

18. 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

19. Secondary Effects
Organ Dysfunction
• Renal insufficiency
• Respiratory insufficiency
– Primary pump failure
– Secondary to shock
• Coagulation abnormalities
– DIC

20. Secondary Effects
Organ Dysfunction
• Hepatic dysfunction
– Closely linked to outcome
• GI
– Related to ischemia
• Endocrine disturbances
– Ca++, hypoadrenalism
• Neuro
– Hypoperfusion syndromes

21. Shock
• Hypovolemic Shock
• Cardiogenic Shock
• Septic Shock
• Distributive
• Endocrine

22. Hypovolemic Shock
Physiology
Diagnosis
Management

23. 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

24. 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%

25. Hypovolemic Shock (Puppies)
140
30%  in SVR
120
40% 
100
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

26. Delaying Resuscitation in Hypovolemic
Shock Effects Outcome
Loss (% Control)
10
0
BP
5
0
Blood
Late Resuscitation -
Death
0 2 4 6 8 10 12
Time (hrs)

27. Diagnosis of Hypovolemic Shock
• Early
–  HR,  Perfusion ( SVR)
–  Pulse width (low SV)
• Late
–  HR,  Perfusion, BP
– End organ dysfunction

28. 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

29. Hypovolemic Shock
Summary
• Primary goal
– Volume replacement
• Secondary goal
– Prevent ischemia
– Minimize inflammatory mediator
release
• Use of Albumin increases
mortality

30. Septic Shock
Definition
Molecular Basis
Diagnosis
Treatment

31. 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

32. 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

33. Molecular Basis of Shock
NFkB - nuclear transcription factor
TNF TNF TNF
R2 R1 Fas
Acute Acute
Apoptosis
Inflammatory Inflammatory
Response Response
iNO Tissue Factor
NFkB
Complement Cytokines Endonuclease
Adhesion Molecules

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

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

36. Infection
Microbial Products
(endotoxin/Peptidoglycans)
Cellular Responses
Thromboanes Oxidases Kinins Cytokines
Leukotrienes/PAF sPLA2 Complement TNF, IL1, IL6, IL8
Inflammation/Vascular Injury

37. 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

38. 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

39. Infection Treatment
Microbial Products Block Endotoxin
(Endotoxin/Peptidoglycans)
Cellular Responses
Mediators (e.g. TNF) Block Mediators
Coagulation activation Block Coagulation
Coagulopathy Cytoprotectives

40. 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

41. 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

42. 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

43. 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

44. Summary of Clinical Trials in Sepsis
Mortality %
# studies # pts con exp p value
High dose steroids 39 <.05
>9 1300 35
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 45 <.05
1 141 30
p75 SR phaseI/II 1 444 29 34
p75-SR phase III 1 1340 28 27
NO synthase inhibitor 2 1059 50 56

45. 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%

46. 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?

47. 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)

48. Distributive Shock
• Anaphylaxis, spinal shock
• Maldistribution of blood flow
• NL or  CO, Inadequate tissue DO2
• Treatment
– Fluid
– Reversal of etiology

49. Differential Dx in Shock
State CO SVR BP CVP PCWP

  NL /   
Hypovolemic
  NL /  
Cardiac Sys

  
Cardiac Dias NL NL
   NL /   
Sepsis Early
   
Sepsis Late


50. Differential Dx in Shock
State CO SVR BP CVP PCWP

  NL /   
Hypovolemic
  NL /  
Cardiac Sys

  
Cardiac Dias NL NL
 / NL /   
Sepsis Early
    
Sepsis Late

51. Conclusion
• Hypovolemic Shock -
– Early Intervention to Prevent
Ischemia/Reperfusion
• Cardiogenic Shock -
– Targeted Treatment
• Septic Shock - ???

52. 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