1. health and fitness
2. disease

Issues in Pediatrics
Management of Newborn and
Pediatric Septic Shock and
Multiple Organ Failure
Joseph A. Carcillo M.D.
Role of Severe Sepsis as a
World wide killer of Children
WHO Leading Causes of Mortality
¾ Severe Pneumonia
¾ Severe Diarrhea
¾ Severe Malaria
¾ Severe Measles
• $1.7 billion nationally/yr.
• More deaths in children associated with
sepsis than with cancer !!
Improving Outcomes in Septic Shock
with Early Goal Directed Resuscitation
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Mortality
1968 1985 1999
Univ NCMC U.S.
Minn
2001
2000
Vietnam
St M
UK
SEPSIS
• Tachycardia + Tachypnea
• + Suspicion of infection
Tachycardia as a Predictor of Sepsis
(Graves GR et al Ped Inf Dis 1984)
70
60
50
40
Tachycardia
30
Eucardia
20
10
0
Sepsis
• Only 21 out of 4350
newborns had
tachycardia
(4.6/1000)
• 82 newborns
underwent a sepsis
evaluation and 13
had sepsis.
• 12/13 had tachycardia
vs 6/69 without sepsis
STEP 1 : GIVE ANTIBIOTICS
STEP 2: GIVE FLUIDS
STEP 3: GIVE INOTROPES
Home-based neonatal care and Sepsis
management Reduces Neonatal Mortality
(Bang et al 1999, The Lancet)
18.00%
16.00%
14.00%
12.00%
10.00%
8.00%
6.00%
4.00%
2.00%
0.00%
Pre
Pre
Post
• Oral co-trimoxazole
and IM gentamycin
given to neonates
with apnea,
tachypnea, poor
Post
feeding temperature
instability, or diarrhea
• Cost 5$/baby
• 5-fold reduction in
mortality rate
What Defines Septic Shock?
Abnormal Perfusion
Capillary Refill > 2 seconds
Flash Capillary Refill
OR
Hypotension
Survival after Adjustment for Patient
Severity:
Every hour without appropriate
resuscitation and restoration of
capillary refill < 2 s and normal blood
pressure increases mortality risk by
40%!
(Han et al Pediatrics 2003)
10
9
8
7
6
5
4
3
2
1
1 Hour
2 Hours 3 hours
Beating Heart
Age-specific susceptibility to
hypovolemic shock
Age
Baseline
HR
2X
Newborn
140
280
1 year old
100
200
Adult
70
140
• Capillary refill slide
HR/SBP
Fluid Resuscitation
HR
CR
BP
INTRAVASCULAR VOLUME LOSS
(-)20cc/kg
(-)
40cc/kg
(-) 60cc/kg
• SCCM, AHA, PALS have developed a
set a guidelines for the management of
septic shock
• Early goals are
Normal heart rate
Capillary refill < 2 seconds
Normal blood pressure
Accomplished in a time-sensitive manner
STEP 2: GIVE FLUIDS
STEP 3: GIVE
INOTROPES
100% survival attained in Dengue Shock when
fluid resuscitation given before hypotension
(Ngo et al Clin Inf Dis 2001, Wills et al NEJM 2006)
100%
90%
80%
70%
60%
Surv
NS
50%
40%
30%
20%
10%
0%
RL
NS
Colloid
Can I Give Too Much Fluid?
(if so give furosemide)
• Check for Hepatomegaly
• Listen for Rales
• Evaluate MAP-CVP
STEP 2: GIVE FLUIDS
STEP 3: GIVE INOTROPES
Early fluid and inotrope resuscitation
10 - fold reduction in mortality rate
(Booy R et al, Arch Dis Child 2001; 85(5) 386-90).
The PICU fellow was called for respiratory distress in this 5
mos old with RSV bronchiolitis.
What she found was a baby in SHOCK!!!
Patient I
The Starling Curve
CI > 3.3
More fluid
Vasodilator
Inotrope
Stroke
Volume
70%
SVCO2
Volume bolus
Left Ventricular End Diastolic Volume
CI > 3.3
SVCO2
Vasodilator
Stroke
Volume
70%
Normal
Decreased
Cardiac function
Inotrope
AORTIC Diastolic Pressure
Reduced Mortality with ACCM-PALS Guidelines
compared to Standard Care for Pediatric Septic Shock
- A Randomized Control Trial (C Oliveira et al 2006)
102 Septic Shock
Patients
Goal normal perfusion
Goal O2 sat > 70%
28 day Mortality
28 day Mortality
39.2%
20/51
P = 0.0027
11.8%
6/51
ACCM/PALS haemodynamic support guidelines for pediatric septic
shock: an outcomes comparison with and without monitoring central
venous oxygen saturation (de Oliveira et al Intens Care Med 2008 34:1065-1075)
•
•
•
•
•
5 African American male who had been admitted 3 days ago with fever, tachycardia to 160’s
He has had no urine output in 12 hours
A Condition C was called for increasing respiratory distress
Patient was breathing in the 50’s, tachycardic to the 160’s, febrile and with a red rash seen all over his body.
80cc/kg of fluid was pushed and he was transferred to the PICU
Patient B
Clindamycin and IVIG
for Gram + Toxin Mediated Septic Shock
(Frank et al Pediatr Inf Dis J 2002)
Use clindamycin and IVIG reduce for
exotoxin produced by organisms
including Group A streptococcus and
MRSA
Patient F
•
•
•
•
12 year old developed fever and leg pain and went to
bed.
Awoke the next morning with purpura
Brought to community ER by mother
Did not improve with fluid resuscitation alone
•
•
•
•
10 y.o. male s/p Small Bowel Transplant on FK 506 who
develops hypotension on the floor
40 cc/kg fluid was pushed
FK506 was stopped
Brought to PICU
Patient G
ACCM Therapy, Source control, and Holding
Immune Suppression Improves Survival
*
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ACCM Guidelines
*
*
Yes
No
Hold
Proper
Immunesupression
Antibiotics
/Source Control
Figure 5
Stepwise management of hemodynamic support with goals of normal perfusion and perfusion pressure (MAP
- CVP)
and pre and post- ductal oxygen saturation difference <5%, and central venous O2 sat > 70% in term newborns..
Recognize
Recognize decreased
decreased perfusion,
perfusion, cyanosis,
cyanosis, RDS.
RDS.
Maintain
Maintain airway
airway and
and establish
establish access
access according
according to
to NRP
NRP guidelines.
guidelines.
0 min
5 min
Push
Push 10cc/kg
10cc/kg isotonic
isotonic crystalloid
crystalloid or
or colloid
colloid boluses
boluses to
to 60
60 cc/kg,
cc/kg, correct
correct hypoglycemia,and
hypoglycemia,and
hypocalcemia.
hypocalcemia. Begin
Begin prostaglandin
prostaglandin infusion
infusion until
until echocardiogram
echocardiogram shows
shows no
no ductalductaldependent
lesion.
dependent lesion.
Fluid-refractory shock
15 min
Fluid
responsive
Establish
Establish Central
Central Venous
Venous and
and Arterial
Arterial Access
Access
Titrate
Titrate dopamine
dopamine and
and dobutamine
dobutamine
Observe
Observe
in
in NICU
NICU
Fluid refractory-dopamine resistant shock
Titrate epinephrine. Systemic alkalinization if PPHN is present
Catecholamine-resistant shock
60 min
Direct therapies using echocardiogram and arterial and CVP monitoring
Cold shock
Normal blood pressure Poor LV
function, CVC O2 sat < 70%
Titrate
Titrate vasodilator
vasodilator Type
Type III
III
PDE
PDE
inhibitor
inhibitor with
with volume
volume loading
loading
Cold or Warm Shock Poor
RV function PPHN, CVC
O2 sat < 70%
Inhaled
Inhaled nitric
nitric oxide
oxide
Refractory Shock
ECMO
ECMO
Warm shock
Low blood pressure
Titrate volume and
epinephrine
(? Vasopressin or
angiotensin)
• ECMO baby
Figure 4
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
Recognize decreased
decreased mental
mental status
status and
and perfusion.
perfusion.
Maintain
Maintain airway
airway and
and establish
establish access
access according
according to
to PALS
PALS guidelines.
guidelines.
0 min
5 min
Push
Push 20cc/kg
20cc/kg isotonic
isotonic saline
saline or
or colloid
colloid boluses
boluses up
up to
to and
and over
over 60
60 cc/kg
cc/kg
Correct
Correct hypoglycemia
hypoglycemia and
and hypocalcemia
hypocalcemia
15 min
Fluid refractory shock
Fluid responsive
Establish
Establish central
central venous
venous access,
access, begin
begin
dopamine
dopamine therapy
therapy and
and establish
establish arterial
arterial monitoring
monitoring ..
Fluid refractory-dopamine resistant shock
Observe
Observe in
in PICU
PICU
Titrate
Titrate epinephrine
epinephrine for
for cold
cold shock,
shock, norepinephrine
norepinephrine for
for warm
warm shock
shock to
to
normal
normal MAP-CVP
MAP-CVP and
and SVC
SVC O2
O2 saturation
saturation >> 70%
70%
At Risk of Adrenal Insufficiency?
60 min
Give
Give hydrocortisone
hydrocortisone
Catecholamine -resistant shock
Not at Risk?
Do
Do not
not give
give hydrocortisone
hydrocortisone
Normal Blood Pressure
Low Blood Pressure
Low Blood Pressure
Cold Shock
Cold Shock
Warm Shock
SVC O2 sat < 70%
SVC O2 sat < 70%
Add vasodilator or Type III PDE inhibitor
Volume and Epinephrine
Volume and Norepinephrine
with volume loading
(?vasopressin or angiotensin)
Persistent Catecholamine-resistant shock
Place
Place pulmonary
pulmonary artery
artery catheter
catheter and
and direct
direct fluid,
fluid,
inotrope,vasopressor,vasodilator,
inotrope,vasopressor,vasodilator, and
and hormonal
hormonal therapies
therapies to
to attain
attain normal
normal
2
2
MAP-CVP
and
CI
>
3.3
and
<
6.0
L/min/m
MAP-CVP and CI > 3.3 and < 6.0 L/min/m
Refractory shock
Consider
Consider ECMO
ECMO
Vasopressin
NE 1 µg/kg/min
Ketamine
HC
Epi 0.5 µg/kg/min
CI 1.85
PCWP 27
SVRI 1996
mVO2 37%
Epi 0.1 µg/kg/min
Milrinone 1 µ/kg/min
Ketamine
HC
80 mL/Kg albumin
CI 3.86
PCWP 15
SVRI 1100
mVO2 75%
TIME MATTERS!
1) Suspicion of infection
tachycardia = sepsis
abnormal capillary refill = shock
2) Sepsis and septic shock respond to antibiotics, fluid resuscitation
and inotropes in a time-sensitive manner
(mortality doubles every hour without therapy)
3) Adherence to ACCM/AHA/PALS hemodynamic support guidelines,
Implementation of appropriate antibiotic therapy/source control,
Withdrawal of immune suppression
Improve outcome
100 %
Antibiotic / source control
23 %
Fluid / inotrope resuscitation
2%
reduces sepsis mortality 5-fold
reduces shock mortality 10-fold
Management of other organ failures
Meningitis – Oral glycerol x 48 h reduces mortality and
morbidity 2 – fold (Peltola et al, Clin Inf Dis 2007)
ARDS/pneumonia – Calfactant reduces mortality 2 - fold
(Willson et al JAMA, 2005)
Endocarditis, necrotizing pneumonia, necrotizing fasciitis
- require surgical control
Coagulopathy - TTP plasma exchange protocol reduces
TAMOF mortality 4 fold (Nguyen et al CCM, 2008)
CRRT most effective when used before > 10 % fluid
overload occurs (Foland et al CCM 2005)
Immunoparalysis – GM-CSF reverses immunoparalysis
(Meisel et al AJRCCM 2009)
Aggressive Resuscitation and
Glycerol for Meningitis
Early use of PALS/APLS therapy reduced neurologic
morbidity across non-trauma diagnostic categories
(Carcillo et al Pediatric 2009)
13/108
12.00%
10.00%
8.00%
6.00%
14/316
5/173
4.00%
2/194
No PALS/APLS
PALS/APLS
5/128
*
2/156
2.00%
0/81
0/59
0/59
1/115
0.00%
Resp
Neuro
Cardiac
Sepsis
Other
Surfactant for ARDS
Calfactant associated with improved survival
with ARDS
(Willson et al JAMA 2005)
Management of
Multiple Organ Failure
Sequential Diuretics followed by
CRRT for fluid overload > 10%
and Multiple Organ Failure
Maintain Intra-abdominal Pressure
< 12 mc H2O
Sequential Diuretics
After volume resuscitation the OUT must
be equal or greater than the IN
If not then fluid overload will lead to Multiple
Organ Failure
Furosemide infusion 1-4 mg/kg/d
Hydrochorthiazide 5-10 mg/kg q 12 h
Aminophylline 1 mg / kg q 6hr
Fenoldopam, dopexamine, low dose dopamine
Fluid overload before continuous hemofiltration and
survival in critically ill children a retrospective study
Foland et al CCM 2004 32(9) 1771-6
Intensive Plasma Exchange
Therapy for DIC / TAMOF
Thrombocytopenia Associated
Multiple Organ Failure
Defined by new onset thrombocytopenia
( < 100,000 platelets) in the presence of
Three organ failure, renal dysfunction and
Elevated Lactate De Hydorgenase (LDH)
Spectrum
DIC - Thrombotic Micro Angiopathy - TTP
THROMBOSIS
Tissue Factor
(-)
Prothrombin
APC
Prot C (+)
(-)
Thrombomodulin
Endothelium
(-)
TFPI
Thrombin
Antithrombin I I I
Heparin
(-)
Fibrinogen
Fibrin
FIBRINOLYSIS
Plasminogen
TPA
PAI-1 (-) (+) Streptokinase
Aminocaproic Acid
Plasmin Urokinase
Tranexamine
Aprotinin
Intensive plasma exchange increases ADAMTS 13 activity
and reverses organ dysfunction in children with TAMOF
Nguyen et al CCM 2009 26(10) 2878-2886
PLASMA
EXCHANGE
MAN
Intensive plasma exchange increases ADAMTS 13 activity
and reverses organ dysfunction in children with TAMOF
Nguyen et al CCM 2009 26(10) 2878-2886
Plasmapheresis in severe sepsis and septic shock
a prospective randomized controlled trial
Busund et al Intens Care Med 2002 28(10):1434-9
Time course of organ dysfunction in thrombotic microangiopathy
patients receiving either plasma perfusion or plasma exchange
Darmon et al CCM 2006 34(8) 2127-2133
GM-CSF for Immunoparalysis
23. Westendorp RG. Langermans JA. Huizinga TW. Elouali AH. Verweij CL. Boomsma DI. Vandenbroucke JP.
Vandenbrouke JP. Genetic influence on cytokine production and fatal meningococcal disease.[comment][erratum appears in
Lancet 1997 Mar 1;349(9052):656 Note: Vandenbrouke JP[corrected to Vandenbroucke JP]]. [Journal Article] Lancet.
349(9046):170-3, 1997 Jan 18.
High TH1
Low TH2
0/19
0%
High TH1
High TH2
9/11
15%
Low TH1
Low TH2
1/8
15%
Low TH1
High TH2
5/15
67%
Fig. 2. Production of TNF and IL-10 in whole blood samples incubated with 1000 ng/mL endotoxin Symbols represent the
family means of TNF production and IL-10 production. Open circles represent cytokine production in 42 families of patients
who survived (121 first-degree relatives), and closed circles represent production of cytokines in 13 families of dead patients
(43 first-degree relatives). Dotted lines indicate medians of the family estimates for both cytokines
Host Response to Infection
APOPTOSIS
LYMPHOID DEPLETION
and
IMMUNEPARALYSIS
APC
Immune paralysis
decreased
TNF α response
and HLA-DR
expression
Antigen
presentation;
costimulatory
signals
APOPTOSIS
APOPTOSIS
Immunoparalysis
GM-CSF therapy
Subcutaneous 5 mcg/kg or 125 mcg/m2 daily
X 3-7 days
Biomarkers > 3 days
Monocyte HLA-DR expression
< 30% or 12,000 molecules per cell
Whole blood ex vivo TVF alph repsone to LPS
< 200 pg/mL
GM-CSF
Increases
PMNs
Monocytes
CD4+ cells
CD8+ cells
Not
B cells
Or
NK cells
Meisel et al
AJRCCM
2009
The effect of GM-CSF therapy on leukocyte function and
clearance of serious infection in non neutropenic patients
Rosenbloom et al CHEST 2005;127(6):1882-5
GM-CSF treatment reactivated the deactivated monocyte.
(n = 7 per group, RM ANOVA p <0.001 for TNF response)
Monocyte TNF alpha response with and without GM-CSF treatment
Systemic IL-6 response with and without GM-CSF treatment
800
500
With GM-CSF treatment
Without GM-CSF treatment
600
Plasma IL-6 levels pg/mL
TNF alpha response pg/mL
400
With GM-CSF treatment
Without GM-CSF treatment
400
200
300
200
100
0
0
-100
0
1
2
3
0
1
Days 1 and 7
No secondary
Infections with
GM-CSF
1 + per patient
Without GM-CSF
2
Days 1 and 7
8
GM-CSF
Standard
7
6
5
4
3
2
1
0
Day 7
Day14
Day 21
Total
3
A randomized phase II trial of GM-CSF therapy in severe
sepsis with respiratory dysfunction
AJRCCM Presneill et al 2002;166(2);129-130
Viral / lympho proliferative disease
associated Sequential MOF
• Respiratory failure / ARDS followed by
hepato-renal failure associated with viral
lympho-proliferative disease
• Increased ALT
• Increased Creatinine
• Increased sFas and sFasL, sFasL level >
500 ng/mL
Hepatic Apoptosis and FAS
SuperAntigen
Stimulates
Lymphocyte
Proliferation
Perforin
Granzymes
Cytotoxic T Lymphocyte
Fas
TCR
receptors
Soluble
FasR
Inhibits
Apoptosis
Fas Ligand
SFasL
DEATH
Deactivated Lymphocyte
Induces Liver
Apoptosis
Necrosis
Patinet with Sequential MOF had higher sFasL levels. A
sFasL level > 500 pg/mL was associated with liver
destruction Doughty et al Ped Res 2006
Biomarkers of MOF
HLH / MAS syndromes
• 5 of 8 criteria; Ferritin > 500, sCD25 > 2500,
decreased NK cell activity, Hemophagocytosis,
Increased Triglycerides, Decreased Fibrinogen,
Hepato or Splenomegaly, Cytopenia of two or more
cell lines. sCD 163 > 10 is the most specific marker
• Macrophage Activation Syndrome – Rheumatological
disease, rash, joint involvement , High C-reactive
protein
• Hemophagocytic Lympho Histiocytosis Syndrome –
Familial history, Low or mildly elevated C- reactive
protein in the absence of sepsis, low or mildly elevated
IL-1 (personal communication Dr. Schneider, Ulm)
Considerable overlap between diagnostic criteria for HLH
and what has been reported in Sepsis / SIRS / MODS and
in Systemic Juvenile Idiopathic Arthritis associated MAS
Castillo and Carcillo PCCM 2009
Survival according to treatment protocols in
literature Halstead et al CCM 2010
• Literature review 203
patients from 17 studies
• 40% EBV, 21% positive
family history (FHLH), 9%
Leishmaniasis
• Survival advantage with
HLH chemotherapy BMT
protocol compared to
other therapies, for FHLH
(69 % vs 17 %), but not
for SHLH (55 % vs 58 %)
nor for EBV associated
(48 % vs 71 %
80%
70%
60%
50%
40%
30%
20%
*
HLH
protocol
Other
therapie
s
10%
0%
HLH SHLH EBV HLH
• MOSES
Management of Multiple Organ Failure in this
patient included
1) Hypothermia for cardiac arrest
2) Cooling and Epinephrine and Milrinone for
ScvO2 < 35%
3) Meropenem for ESBL
4) Intensive Plasma Exchange for
Thrombocytopenia Associated MOF
5) GM-CSF for Immune Paralysis
6) Erythropoietin for Anemia
7) Insulin and D10 for hyperglycemia
Management of Multiple Organ
Failure
MOF Phenotype Directed Therapies
Phenotype MOF
TAMOF
Plt Ct < 100K ,
Increased LDH
Immunoparalysis
Neutro / Lymphopenic
Anergic
Leukocytosis > 100K
Cancer / Pertussis
Related
Daily Plasma Exchange
Until TAMOF resolves
Hold Immunesuppression
Give GM-CSF
Leukopheresis
Sequential MOF
PTLD
Hold Immunesuppression
Give Rituximab
MOF - Two or more organ failures
MAS/ sHLH
TAMOF –Thrombocytopenia Associated MOF commonly found with hemophagocytosis
Plasma exchange
Immunoparalysis – Whole blood ex vivo LPS stimulated TNF response < 200 pg/mL, or
IVIG / Solumedrol
monocyte HLA-DR < 8,000 for > 3 days.
Sequential MOF – Respiratory distress followed several days later by hepatorenal dysfunction
PTLD – Post transplant Lympho Proliferative Disease – EBV related B cell proliferation
MAS- Macrophage activation syndrome associated with rheumatologic disease
Primary HLH
HLH – Hemophagocytic Lympho Histiocytosis Syndrome. MAS/HLH diagnosis made when
HLH Protocol
5/ 8 criteria met including fever, two line cytopenia, hypertrygyceridemia, hypofibrinogenemia,
hepatosplenomegaly, hyperferritinemia > 500, hemophagocytosis, decreased NK cell activity.
Secondary HLH – Infection associated with decreased NK cell function - responds to removing infection.
Primary HLH – Consanguinous parenst or family history, genetic mutations, absent NK cell function results in
lymphoproliferation.
www.pediatricsepsis.org
www.wfpiccs.org
Bundle A
> 30/1,000
Bundle B
< 30/1,000
48 % mortality
22% mortality
Developing
Country
23 % mortality
Developed
Country
4 % mortality
Future therapies ([email protected])
•
•
•
•
•
•
•
•
•
•
Hydrolase for Clysis when IO / IV not possible
High flow nasal cannula O2
Levosimendan / enoximone for refractory cardiac failure
Statins to reduce inflammation and increase CYP450 1A
activity
Nosocomial sepsis prophylaxis with immune modulators – zinc
,selenium, glutamine, metoclopramide, melatonin, Indole 3
carbinol, levamisole,
Interferon alpha + IVIG for infection associated
Hemophagocytic Lympho Histiocytosis
Leukopheresis for Pertussis Leukocytosis ARDS
Bone marrow derived Mesenchymal Stem Cells for sepsis
Autologous cord blood stem cells for immune depletion /
paralysis immune system reconstitution
Global sepsis initiative www.wfpiccs.org
or
www.pediatricsepsis.org
www.pediatricsepsis.org
www.pediatricsepsis.org
www.pediatricsepsis.org
www.pediatricsepsis.org
Whole –body hypothermia for neonates with
hypoxia-ischemic encephalopathy
Shankaran et al NEJM 2005 353(15)1574-84
Meropenem for ESBL
• Brilliant! Early use of proper antibiotic reduces
mortality by 7% per hour!
• Crazy! We cannot be held to that standard. We
can’t get antibiotics into our patients within the
first hour. And we cant use broad spectrum
coverage because that would induce resistance.
These patients don’t die form infection anyway!
They die form the host response
Hypothermia for Cardiac Arrest
• Brilliant! – reduces metabolism and
ischemia reperfusion injury with minimal
risk and preservation of brain function
• Crazy! – It does not work. At best it
provides the world with vegetative state
patients. At worse patients die because
hypothermia reduces the ability to get rid
of infection
Mild hypothermia to improve neurologic
outcome after cardiac arrest(NEJM 2002;346(8):549-56
Treatment of comatose survivors of out of hospital
cardiac arrest with induced hypothermia
( Bernard et al NEJM 2002 346(8):557-63)
Whole –body hypothermia for neonates with
hypoxia-ischemic encephalopathy
Shankaran et al NEJM 2005 353(15)1574-84
Cooling, Epinephrine and Milrinone
to restore ScvO2 to 70%
• Brilliant! – By delivering oxygen according
to the needs of the patient one can
prevent new cellular injury
• Crazy! – That doesn’t work because
patients have cellular dysoxia no matter
what you do with oxygen delivery.
Besides we use femoral catheters not
SVC catheters
Early Goal Directed Therapy in the Treatment of
Severe Sepsis and Septic Shock
Rivers et al NEJM 545(19) 1368-1377
GM-CSF associated with antibiotic treatment in non
traumatic abdominal sepsis: a randomized , double blinded,
placebo controlled trial
Orozco et al Arch Surg 2006 141(2):150-3
Duration of hypotension before initiation of effective antimicrobial
therapy is the critical determinant of survival in human septic shock
Kumar et al CCM 2006 34(6) 1589-1595
Intensive Plasma Exchange for
Thrombocytopenia Associated MOF
• Brilliant – Patients with new onset
thrombocytopenia, increased LDH, and MOF
have complex thrombotic microangiopathy which
respond to intensive plasma exchange in the
same manner as TTP with resolution of organ
failure .
• Crazy – This is a huge waste of resources with
no proven benefit and a risk of blood borne
pathogens. Besides I cannot get my
plasmapheresis people to do it.
Plasmapheresis in severe sepsis and septic shock
a prospective randomized controlled trial
Busund et al Intens Care Med 2002 28(10):1434-9
Time course of organ dysfunction in thrombotic microangiopathy
patients receiving either plasma perfusion or plasma exchange
Darmon et al CCM 2006 34(8) 2127-2133
CRRT to ARF
• Brilliant – This technique allows
continuous control of fluid balance. It helps
resolve ARDS. I like it a lot. It is great for
the purpose of keeping fluid overload per
cent < 10%
• Crazy – This technique is no better than
intermittent dialysis.
GM-CSF for Immune paralysis
• Brilliant! - Patients with Sepsis and MOF
commonly develop immune paralysis 3
days after presentation. GM-CSF
reverses immune paralysis and reduces
the incidence of secondary infection
• Crazy – It doesn’t work in randomized
trials in premature infants.
Improved survival of critically ill trauma patients
treated with recombinant human erythropoietin
Napolitano et al J Trauma 2008 65(2):285-97
Intensity of Acute Renal Failure Support Trial
NEJM 2008 359(1):7-20
GM-CSF administered as prophylaxis for reduction of sepsis in
extremely preterm SGA neonates :a single blind multi center
randomized controlled trial Carr et al LANCET 2009 373:226-33
GM-CSF administered as prophylaxis for reduction of sepsis in
extremely preterm SGA neonates :a single blind multi center
randomized controlled trial Carr et al LANCET 2009 373:226-33
Erythropoietin for Anemia
• Brilliant! – Erythropoietin reduces transfusion
increase hemoglobin without blood transfusion.
Improves survival in Trauma patients in the ICU.
Improves neurological function in ischemia
models
• Crazy! – Erythropoietin tends towards increased
mortality when used long term in chronic renal
failure patients requiring dialysis.
D10% containing solution at maintenance and
Insulin for Hyperglycemia
• Brilliant! The glucose requirements are met by
giving D10% at maintenance fluid rate. Insulin
for hyperglycemia reverses catabolism,
decreases inflammation and improves outcome
• Crazy! Hypoglycemia occurs to frequently the
risks outweigh the benefits. Glucose is bad for
you. Insulin is dangerous for you. Our staff is
not very good at monitoring glucose in patients
on insulin infusions.
Benefits and risks of tight glycemic control in
critically ill adults
Wiener et al 2008 300(8);933-941
Benefits and risks of tight glycemic control in
critically ill adults
Wiener et al 2008 300(8);933-941
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Duration of hypotension before initiation of effective antimicrobial
therapy is the critical determinant of survival in human septic shock
Kumar et al CCM 2006 34(6) 1589-1595
New Sepsis Therapies
Brilliant! or Crazy!
Questions or Comments
How to manage other organ
failures in children besides shock
Meningitis – Oral glycerol x 48 h reduces mortality
and morbidity 2 – fold (Clin Inf Dis 2007)
ARDS/pneumonia – Calfactant reduces mortality 2
- fold (Willson et al JAMA, 2005)
Endocarditis, necrotizing pneumonia, necrotizing
fasciitis - require surgical control
Coagulopathy - TTP plasma exchange protocol
reduces TAMOF mortality 4 fold (Nguyen et al CCM,
2008)
CRRT most effective when used before > 10 %
fluid overload occurs (Foland et al CCM 2005)
• MOSES
Management of Multiple Organ Failure in this
patient included
1) Hypothermia for cardiac arrest
2) Cooling and Epinephrine and Milrinone for
ScvO2 < 35%
3) Meropenem for ESBL
4) Intensive Plasma Exchange for
Thrombocytopenia Associated MOF
5) GM-CSF for Immune Paralysis
6) Erythropoietin for Anemia
7) Insulin and D10 for hyperglycemia
A randomized phase II trial of GM-CSF therapy in severe
sepsis with respiratory dysfunction
AJRCCM Presneill et al 2002;166(2);129-130
The effect of GM-CSF therapy on leukocyte function and
clearance of serious infection in non neutropenic patients
Rosenbloom et al CHEST 2005;127(6):1882-5
Whole –body hypothermia for neonates with
hypoxia-ischemic encephalopathy
Shankaran et al NEJM 2005 353(15)1574-84
Duration of hypotension before initiation of effective antimicrobial
therapy is the critical determinant of survival in human septic shock
Kumar et al CCM 2006 34(6) 1589-1595
Meropenem for ESBL
• Brilliant! Early use of proper antibiotic reduces
mortality by 7% per hour!
• Crazy! We cannot be held to that standard. We
can’t get antibiotics into our patients within the
first hour. And we cant use broad spectrum
coverage because that would induce resistance.
These patients don’t die form infection anyway!
They die form the host response
Hypothermia for Cardiac Arrest
• Brilliant! – reduces metabolism and
ischemia reperfusion injury with minimal
risk and preservation of brain function
• Crazy! – It does not work. At best it
provides the world with vegetative state
patients. At worse patients die because
hypothermia reduces the ability to get rid
of infection
Mild hypothermia to improve neurologic
outcome after cardiac arrest(NEJM 2002;346(8):549-56
Fluid overload before continuous hemofiltration and
survival in critically ill children a retrospective study
Foland et al CCM 2004 32(9) 1771-6
Treatment of comatose survivors of out of hospital
cardiac arrest with induced hypothermia
( Bernard et al NEJM 2002 346(8):557-63)
Whole –body hypothermia for neonates with
hypoxia-ischemic encephalopathy
Shankaran et al NEJM 2005 353(15)1574-84
Cooling, Epinephrine and Milrinone
to restore ScvO2 to 70%
• Brilliant! – By delivering oxygen according
to the needs of the patient one can
prevent new cellular injury
• Crazy! – That doesn’t work because
patients have cellular dysoxia no matter
what you do with oxygen delivery.
Besides we use femoral catheters not
SVC catheters
Early Goal Directed Therapy in the Treatment of
Severe Sepsis and Septic Shock
Rivers et al NEJM 545(19) 1368-1377
Duration of hypotension before initiation of effective antimicrobial
therapy is the critical determinant of survival in human septic shock
Kumar et al CCM 2006 34(6) 1589-1595
GM-CSF associated with antibiotic treatment in non
traumatic abdominal sepsis: a randomized , double blinded,
placebo controlled trial
Orozco et al Arch Surg 2006 141(2):150-3
Duration of hypotension before initiation of effective antimicrobial
therapy is the critical determinant of survival in human septic shock
Kumar et al CCM 2006 34(6) 1589-1595
CRRT to ARF
• Brilliant – This technique allows
continuous control of fluid balance. It helps
resolve ARDS. I like it a lot. It is great for
the purpose of keeping fluid overload per
cent < 10%
• Crazy – This technique is no better than
intermittent dialysis.
Intensity of Acute Renal Failure Support Trial
NEJM 2008 359(1):7-20
GM-CSF for Immune paralysis
• Brilliant! - Patients with Sepsis and MOF
commonly develop immune paralysis 3
days after presentation. GM-CSF
reverses immune paralysis and reduces
the incidence of secondary infection
• Crazy – It doesn’t work in randomized
trials in premature infants.
GM-CSF administered as prophylaxis for reduction of sepsis in
extremely preterm SGA neonates :a single blind multi center
randomized controlled trial Carr et al LANCET 2009 373:226-33
GM-CSF administered as prophylaxis for reduction of sepsis in
extremely preterm SGA neonates :a single blind multi center
randomized controlled trial Carr et al LANCET 2009 373:226-33
Erythropoietin for Anemia
• Brilliant! – Erythropoietin reduces transfusion
increase hemoglobin without blood transfusion.
Improves survival in Trauma patients in the ICU.
Improves neurological function in ischemia
models
• Crazy! – Erythropoietin tends towards increased
mortality when used long term in chronic renal
failure patients requiring dialysis.
D10% containing solution at maintenance and
Insulin for Hyperglycemia
• Brilliant! The glucose requirements are met by
giving D10% at maintenance fluid rate. Insulin
for hyperglycemia reverses catabolism,
decreases inflammation and improves outcome
• Crazy! Hypoglycemia occurs to frequently the
risks outweigh the benefits. Glucose is bad for
you. Insulin is dangerous for you. Our staff is
not very good at monitoring glucose in patients
on insulin infusions.
Benefits and risks of tight glycemic control in
critically ill adults
Wiener et al 2008 300(8);933-941
Benefits and risks of tight glycemic control in
critically ill adults
Wiener et al 2008 300(8);933-941
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled study
Vlasselaers et al LANCET Jan 27,2009
New Sepsis Therapies
Brilliant! or Crazy!
Questions or Comments