Issues in Pediatrics Management of Newborn and Pediatric ... · Tachycardia as a Predictor of...

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


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


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

http://www.pediatricsepsis.org/

http://www.wfpiccs.org/

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

http://www.wfpiccs.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)

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

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

Intensive insulin therapy for patients in paediatric intensive

care: a prospective, randomised controlled studyVlasselaers et al LANCET Jan 27,2009


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)