Post on 08-Jul-2020
Issues in Pediatrics
Management of Newborn and Pediatric Septic Shock and
Multiple Organ FailureJoseph A. Carcillo M.D.
Role of Severe Sepsis as a World wide killer of Children
WHO Leading Causes of MortalitySevere PneumoniaSevere DiarrheaSevere MalariaSevere Measles
• $1.7 billion nationally/yr.• More deaths in children associated with
sepsis than with cancer !!
Improving Outcomes in Septic Shock with Early Goal Directed Resuscitation
0%10%20%30%40%50%60%70%80%90%
100%
1968UnivMinn
1999U.S.
2001Vietnam
Mortality
1985NCMC
2000St MUK
SEPSIS
• Tachycardia + Tachypnea
• + Suspicion of infection
Tachycardia as a Predictor of Sepsis (Graves GR et al Ped Inf Dis 1984)
0
10
20
30
40
50
60
70
Sepsis
Tachycardia
Eucardia
• Only 21 out of 4350 newborns had tachycardia (4.6/1000)
• 82 newborns underwent a sepsis evaluation and 13 had sepsis.
• 12/13 had tachycardia vs 6/69 without sepsis
STEP 1 : GIVE ANTIBIOTICS
STEP 2: GIVE FLUIDS
STEP 3: GIVE INOTROPES
Home-based neonatal care and Sepsis management Reduces Neonatal Mortality
(Bang et al 1999, The Lancet)
0.00%2.00%4.00%6.00%8.00%
10.00%12.00%14.00%16.00%18.00%
Pre Post
Pre Post
• Oral co-trimoxazole and IM gentamycin given to neonates with apnea, tachypnea, poor feeding temperature instability, or diarrhea
• Cost 5$/baby• 5-fold reduction in
mortality rate
What Defines Septic Shock?
Abnormal Perfusion
Capillary Refill > 2 secondsFlash Capillary Refill
OR
Hypotension
Survival after Adjustment for Patient Survival after Adjustment for Patient Severity:Severity:Every hour without appropriate Every hour without appropriate resuscitation and restoration of resuscitation and restoration of capillary refill < 2 s and normal blood capillary refill < 2 s and normal blood pressure increases mortality risk by pressure increases mortality risk by 40%! 40%! (Han et al Pediatrics 2003)(Han et al Pediatrics 2003)
1 Hour 2 Hours 3 hours
10987654321
Beating Heart
Age-specific susceptibility to hypovolemic shock
NewbornNewborn 140 280140 280
AgeAge BaselineBaseline 2X2XHRHR
1 year old 100 2001 year old 100 200
Adult 70 Adult 70 140140
• Capillary refill slide
HR/SBP
INTRAVASCULAR VOLUME LOSS
(-) 60cc/kg
CR
BP
(-) 40cc/kg
Fluid Resuscitation
HR
(-)20cc/kg
• SCCM, AHA, PALS have developed a set a guidelines for the management of septic shock
• Early goals areNormal heart rateCapillary refill < 2 secondsNormal 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)
0%10%20%30%40%50%60%70%80%90%
100%
RL NS Colloid
SurvNS
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 resuscitation10 - fold reduction in mortality rate(Booy R et al, Arch Dis Child 2001; 85(5) 386-90).
Patient I
The PICU fellow was called for respiratory distress in this 5 mos old with RSV bronchiolitis.
What she found was a baby in SHOCK!!!
The Starling Curve
Left Ventricular End Diastolic Volume
Stroke Volume
70%
SVCO2
Volume bolus
Inotrope
Vasodilator
More fluidCI > 3.3
Normal
DecreasedCardiac function Inotrope
Vasodilator
CI > 3.3
SVCO2
70%StrokeVolume
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 ShockPatients
28 day Mortality
39.2%
20/51
P = 0.0027
28 day Mortality
11.8%
6/51
Goal normal perfusion Goal O2 sat > 70%
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)
Patient B
• 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
Clindamycin and IVIGfor 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
Patient G
• 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
ACCM Therapy, Source control, and Holding Immune Suppression Improves Survival
0%10%20%30%40%50%60%70%80%90%
100%
ACCM Guidelines HoldImmunesupression
YesNo
ProperAntibiotics/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..
0 min5 min
Fluid responsive
15 min
Fluid refractory-dopamine resistant shock
Establish Central Venous and Arterial AccessTitrate dopamine and dobutamine
Establish Central Venous and Arterial AccessTitrate dopamine and dobutamine
Fluid-refractory shock
Push 10cc/kg isotonic crystalloid or colloid boluses to 60 cc/kg, correct hypoglycemia,and hypocalcemia. Begin prostaglandin infusion until echocardiogram shows no ductal-
dependent lesion.
Push 10cc/kg isotonic crystalloid or colloid boluses to 60 cc/kg, correct hypoglycemia,and hypocalcemia. Begin prostaglandin infusion until echocardiogram shows no ductal-
dependent lesion.
Recognize decreased perfusion, cyanosis, RDS.Maintain airway and establish access according to NRP guidelines.
Recognize decreased perfusion, cyanosis, RDS.Maintain airway and establish access according to NRP guidelines.
Observein NICU
Observein NICU
Titrate epinephrine. Systemic alkalinization if PPHN is present
Inhaled nitric oxide Inhaled nitric oxide
Refractory Shock
Cold or Warm Shock Poor RV function PPHN, CVC
O2 sat < 70%
Titrate vasodilator Type III PDE
inhibitor with volume loading
Titrate vasodilator Type III PDE
inhibitor with volume loading
Cold shockNormal blood pressure Poor LV
function, CVC O2 sat < 70%
60 min
ECMOECMO
Warm shockLow blood pressure
Titrate volume and epinephrine(? Vasopressin or angiotensin)
Catecholamine-resistant shock
Direct therapies using echocardiogram and arterial and CVP monitoring
• 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.
Fluid responsive
Titrate epinephrine for cold shock, norepinephrine for warm shock to normal MAP-CVP and SVC O2 saturation > 70%
Titrate epinephrine for cold shock, norepinephrine for warm shock to normal MAP-CVP and SVC O2 saturation > 70%
Fluid refractory-dopamine resistant shock
Establish central venous access, begin dopamine therapy and establish arterial monitoring .
Establish central venous access, begin dopamine therapy and establish arterial monitoring .
Fluid refractory shock
Push 20cc/kg isotonic saline or colloid boluses up to and over 60 cc/kgCorrect hypoglycemia and hypocalcemia
Push 20cc/kg isotonic saline or colloid boluses up to and over 60 cc/kgCorrect hypoglycemia and hypocalcemia
Recognize decreased mental status and perfusion.Maintain airway and establish access according to PALS guidelines.
Recognize decreased mental status and perfusion.Maintain airway and establish access according to PALS guidelines.
Observe in PICUObserve in PICU
0 min5 min
15 min
At Risk of Adrenal Insufficiency? Catecholamine -resistant shock Not at Risk?
60 minGive hydrocortisoneGive hydrocortisone Do not give hydrocortisoneDo not give hydrocortisone
Normal Blood Pressure Low Blood Pressure Low Blood PressureCold Shock Cold Shock Warm Shock
SVC O2 sat < 70% SVC O2 sat < 70%
Refractory shockPlace 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
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 Consider ECMOConsider ECMO
Persistent Catecholamine-resistant shock
Add vasodilator or Type III PDE inhibitor Volume and Epinephrine Volume and Norepinephrinewith volume loading (?vasopressin or angiotensin)
Epi 0.1 µg/kg/minMilrinone 1 µ/kg/minKetamineHC80 mL/Kg albuminCI 3.86PCWP 15SVRI 1100mVO2 75%
VasopressinNE 1 µg/kg/minKetamineHCEpi 0.5 µg/kg/minCI 1.85PCWP 27SVRI 1996mVO2 37%
TIME MATTERS!1) Suspicion of infection
tachycardia = sepsisabnormal 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 outcome100 %23 %
Fluid / inotrope resuscitation reduces shock mortality 10-fold2 %Antibiotic / source control reduces sepsis mortality 5-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)
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
Resp Neuro Cardiac Sepsis Other
No PALS/APLSPALS/APLS
14/316
13/108
5/173
0/59
5/128
0/59
*2/194
0/81
2/156
1/115
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 FailureMaintain Intra-abdominal Pressure
< 12 mc H2O
Sequential Diuretics
After volume resuscitation the OUT mustbe equal or greater than the IN
If not then fluid overload will lead to MultipleOrgan Failure
Furosemide infusion 1-4 mg/kg/dHydrochorthiazide 5-10 mg/kg q 12 hAminophylline 1 mg / kg q 6hrFenoldopam, 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 ofThree organ failure, renal dysfunction andElevated Lactate De Hydorgenase (LDH)
Spectrum
DIC - Thrombotic Micro Angiopathy - TTP
Prot C Prot C
ThrombomodulinThrombomodulin
APC
ProthrombinProthrombin ThrombinThrombin
HeparinHeparinAntithrombin I I IAntithrombin I I I
Tissue FactorTissue Factor
TFPITFPI
EndotheliumEndothelium
THROMBOSISTHROMBOSIS
PAIPAI--11 (-)
Plasminogen
PlasminPlasmin
FIBRINOLYSISFIBRINOLYSIS
(+)
(-)
FibrinogenFibrinogen FibrinFibrin
(-)
(-)
(-)(+)
TPATPAStreptokinaseStreptokinaseUrokinaseUrokinaseAminocaproic AcidAminocaproic Acid
TranexamineTranexamineAprotininAprotinin
Intensive plasma exchange increases ADAMTS 13 activity
and reverses organ dysfunction in children with TAMOFNguyen et al CCM 2009 26(10) 2878-2886
PLASMAEXCHANGE
MAN
Intensive plasma exchange increases ADAMTS 13 activity
and reverses organ dysfunction in children with TAMOFNguyen 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 exchangeDarmon 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 TH1High TH29/1115%
High TH1Low TH20/190%
Low TH1Low TH21/815%
Low TH1High TH25/1567%
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
APC
Antigenpresentation;costimulatorysignals
Immune paralysisdecreasedTNF α responseand HLA-DR expression
APOPTOSIS
APOPTOSIS
APOPTOSIS
LYMPHOID DEPLETIONand
IMMUNEPARALYSIS
ImmunoparalysisGM-CSF therapy
Subcutaneous 5 mcg/kg or 125 mcg/m2 dailyX 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 IncreasesPMNsMonocytesCD4+ cellsCD8+ cells
NotB cells OrNK cells
Meisel et alAJRCCM2009
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
Days 1 and 7
0 1 2 3
TNF
alph
a re
spon
se p
g/m
L
0
200
400
600
800
With GM-CSF treatment Without GM-CSF treatment
Systemic IL-6 response with and without GM-CSF treatment
Days 1 and 7
0 1 2 3
Pla
sma
IL-6
leve
ls p
g/m
L
-100
0
100
200
300
400
500
With GM-CSF treatment Without GM-CSF treatment
0
1
2
3
4
5
6
7
8
Day 7 Day14 Day 21 Total
GM-CSFStandardNo secondary
Infections with GM-CSF1 + per patientWithout GM-CSF
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
SuperAntigenStimulates Lymphocyte Proliferation
TCRreceptors
Fas
Fas Ligand
DEATH
SolubleFasRCytotoxic T Lymphocyte
Deactivated Lymphocyte
Inhibits Apoptosis
Induces LiverApoptosisNecrosis
SFasL
PerforinGranzymes
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 MOFHLH / 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 %
0%10%
20%30%
40%50%
60%70%80%
HLHprotocol
Othertherapies
*
HLH SHLH EBV HLH
• MOSES
Management of Multiple Organ Failure in this patient included
1) Hypothermia for cardiac arrest2) Cooling and Epinephrine and Milrinone for
ScvO2 < 35%3) Meropenem for ESBL4) Intensive Plasma Exchange for
Thrombocytopenia Associated MOF5) GM-CSF for Immune Paralysis6) Erythropoietin for Anemia7) Insulin and D10 for hyperglycemia
Management of Multiple Organ Failure
MOF Phenotype Directed Therapies
Phenotype MOF
TAMOFPlt Ct < 100K , Increased LDH
ImmunoparalysisNeutro / Lymphopenic
AnergicSequential MOF
Daily Plasma ExchangeUntil TAMOF resolves
Hold ImmunesuppressionGive GM-CSF
PTLDHold Immunesuppression
Give Rituximab
MAS/ sHLHPlasma exchangeIVIG / Solumedrol
Leukocytosis > 100KCancer / Pertussis
Related
Leukopheresis
Primary HLHHLH Protocol
MOF - Two or more organ failuresTAMOF –Thrombocytopenia Associated MOF commonly found with hemophagocytosisImmunoparalysis – Whole blood ex vivo LPS stimulated TNF response < 200 pg/mL, ormonocyte HLA-DR < 8,000 for > 3 days.
Sequential MOF – Respiratory distress followed several days later by hepatorenal dysfunctionPTLD – Post transplant Lympho Proliferative Disease – EBV related B cell proliferationMAS- Macrophage activation syndrome associated with rheumatologic diseaseHLH – Hemophagocytic Lympho Histiocytosis Syndrome. MAS/HLH diagnosis made when5/ 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 inlymphoproliferation.
www.pediatricsepsis.orgwww.wfpiccs.org
Bundle A> 30/1,000 48 % mortality
Bundle B< 30/1,000 22% mortality
DevelopingCountry 23 % mortality
4 % mortalityDeveloped Country
Future therapies (carcilloja@ccm.upmc.edu)• 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
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 trialOrozco 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 exchangeDarmon 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 TrialNEJM 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 studyVlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled studyVlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled studyVlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled studyVlasselaers 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 arrest2) Cooling and Epinephrine and Milrinone for
ScvO2 < 35%3) Meropenem for ESBL4) Intensive Plasma Exchange for
Thrombocytopenia Associated MOF5) GM-CSF for Immune Paralysis6) Erythropoietin for Anemia7) 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 trialOrozco 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 TrialNEJM 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 studyVlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled studyVlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled studyVlasselaers et al LANCET Jan 27,2009
Intensive insulin therapy for patients in paediatric intensive
care: a prospective, randomised controlled studyVlasselaers et al LANCET Jan 27,2009
New Sepsis Therapies
Brilliant! or Crazy!
Questions or Comments