Issues in Pediatrics. Management of Newborn and Pediatric Septic Shock and Multiple Organ Failure Joseph A. Carcillo M.D.

Transcription

1 Issues in Pediatrics Management of Newborn and Pediatric Septic Shock and Multiple Organ Failure Joseph A. Carcillo M.D.

2 Role of Severe Sepsis as a World wide killer of Children WHO Leading Causes of Mortality Severe Pneumonia Severe Diarrhea Severe Malaria Severe Measles $1.7 billion nationally/yr. More deaths in children associated with sepsis than with cancer!!

3 Improving Outcomes in Septic Shock with Early Goal Directed Resuscitation 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1968 Univ Minn 1985 NCMC 1999 U.S St M UK 2001 Vietnam Mortality

4 SEPSIS Tachycardia + Tachypnea + Suspicion of infection

5 Tachycardia as a Predictor of Sepsis (Graves GR et al Ped Inf Dis 1984) 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

6 STEP 1 : GIVE ANTIBIOTICS STEP 2: GIVE FLUIDS STEP 3: GIVE INOTROPES

7 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 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

8 What Defines Septic Shock? Abnormal Perfusion Capillary Refill > 2 seconds Flash Capillary Refill OR Hypotension

9 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) Hour 2 Hours 3 hours

10 Beating Heart

11 Age-specific susceptibility to hypovolemic shock Age Baseline HR 2X Newborn year old Adult

12 Capillary refill slide

13 Fluid Resuscitation HR/SBP HR CR BP INTRAVASCULAR VOLUME LOSS (-)20cc/kg (-) 40cc/kg (-) 60cc/kg

14 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

15 STEP 2: GIVE FLUIDS STEP 3: GIVE INOTROPES

16 100% 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% 50% 40% 30% 20% 10% 0% RL NS Colloid Surv NS

17 Can I Give Too Much Fluid? (if so give furosemide) Check for Hepatomegaly Listen for Rales Evaluate MAP-CVP

18 STEP 2: GIVE FLUIDS STEP 3: GIVE INOTROPES

19 Early fluid and inotrope resuscitation 10 - fold reduction in mortality rate (Booy R et al, Arch Dis Child 2001; 85(5) ).

20 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

21 The Starling Curve CI > 3.3 Stroke Volume More fluid Vasodilator Inotrope Volume bolus 70% SVCO 2 Left Ventricular End Diastolic Volume

22 CI > 3.3 Stroke Volume Vasodilator Normal SVCO 2 70% Decreased Cardiac function Inotrope AORTIC Diastolic Pressure

23 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 O 2 sat > 70% 28 day Mortality 39.2% 20/51 P = day Mortality 11.8% 6/51

24 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 : )

25 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

26 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

27 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

28 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

29 ACCM Therapy, Source control, and Holding Immune Suppression Improves Survival 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ACCM Guidelines * * * Proper Antibiotics /Source Control Hold Immunesupression Yes No

30 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 O 2 sat > 70% in term newborns.. 0 min 5 min 15 min Push 10cc/kg isotonic crystalloid or colloid boluses to 60 cc/kg, correct hypoglycemia,and hypocalcemia. Begin prostaglandin infusion until echocardiogram shows no ductaldependent lesion. Fluid responsive Recognize decreased perfusion, cyanosis, RDS. Maintain airway and establish access according to NRP guidelines. Fluid-refractory shock Establish Central Venous and Arterial Access Titrate dopamine and dobutamine Observe in NICU Fluid refractory-dopamine resistant shock Titrate epinephrine. Systemic alkalinization if PPHN is present 60 min Cold shock Normal blood pressure Poor LV function, CVC O2 sat < 70% Catecholamine-resistant shock Direct therapies using echocardiogram and arterial and CVP monitoring Cold or Warm Shock Poor RV function PPHN, CVC O2 sat < 70% Warm shock Low blood pressure Titrate vasodilator Type III PDE inhibitor with volume loading Inhaled nitric oxide Refractory Shock ECMO Titrate volume and epinephrine (? Vasopressin or angiotensin)

31 ECMO baby

32 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. 0 min 5 min 15 min Fluid responsive Recognize decreased mental status and perfusion. Maintain airway and establish access according to PALS guidelines. Push 20cc/kg isotonic saline or colloid boluses up to and over 60 cc/kg Correct hypoglycemia and hypocalcemia Fluid refractory shock Establish central venous access, begin dopamine therapy and establish arterial monitoring. Observe in PICU Fluid refractory-dopamine resistant shock Titrate epinephrine for cold shock, norepinephrine for warm shock to normal MAP-CVP and SVC O2 saturation > 70% At Risk of Adrenal Insufficiency? Catecholamine -resistant shock Not at Risk? 60 min Give hydrocortisone Do not give hydrocortisone Normal Blood Pressure Low Blood Pressure Low Blood Pressure Cold Shock Cold Shock Warm Shock SVC O 2 sat < 70% SVC O 2 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 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/m 2 Refractory shock Consider ECMO

33 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%

34 1) Suspicion of infection tachycardia = sepsis abnormal capillary refill = shock TIME MATTERS! 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 % reduces sepsis mortality 5-fold Fluid / inotrope resuscitation 2 % reduces shock mortality 10-fold

35 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)

36 Aggressive Resuscitation and Glycerol for Meningitis

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38 Early use of PALS/APLS therapy reduced neurologic morbidity across non-trauma diagnostic categories (Carcillo et al Pediatric 2009) 12.00% 13/ % 8.00% 6.00% 4.00% 2.00% 0.00% 14/316 5/128 5/173 2/194 * 2/156 0/81 0/59 0/59 1/115 Resp Neuro Cardiac Sepsis Other No PALS/APLS PALS/APLS

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40 Surfactant for ARDS

41 Calfactant associated with improved survival with ARDS (Willson et al JAMA 2005)

42 Management of Multiple Organ Failure

43 Sequential Diuretics followed by CRRT for fluid overload > 10% and Multiple Organ Failure Maintain Intra-abdominal Pressure < 12 mc H2O

44 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

45 Fluid overload before continuous hemofiltration and survival in critically ill children a retrospective study Foland et al CCM (9)

46 Intensive Plasma Exchange Therapy for DIC / TAMOF

47 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

48 Prot C Prothrombin APC (+) Thrombomodulin Endothelium (-) THROMBOSIS Tissue Factor (-) (-) Antithrombin I I I Heparin (-) TFPI Thrombin Fibrinogen Aminocaproic Acid Tranexamine Aprotinin FIBRINOLYSIS Plasminogen PAI-1 (-) (+) Plasmin Fibrin TPA Streptokinase Urokinase

49 Intensive plasma exchange increases ADAMTS 13 activity and reverses organ dysfunction in children with TAMOF Nguyen et al CCM (10)

50 PLASMA EXCHANGE MAN

51 Intensive plasma exchange increases ADAMTS 13 activity and reverses organ dysfunction in children with TAMOF Nguyen et al CCM (10)

52 Plasmapheresis in severe sepsis and septic shock a prospective randomized controlled trial Busund et al Intens Care Med (10):1434-9

53 Time course of organ dysfunction in thrombotic microangiopathy patients receiving either plasma perfusion or plasma exchange Darmon et al CCM (8)

54 GM-CSF for Immunoparalysis

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57 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 T H 1 Low T H 2 0/19 0% High T H 1 High T H 2 9/11 15% Low T H 1 Low T H 2 1/8 15% Low T H 1 High T H 2 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

58 Host Response to Infection LYMPHOID DEPLETION and IMMUNEPARALYSIS APOPTOSIS APC Immune paralysis decreased TNF α response and HLA-DR expression Antigen presentation; costimulatory signals APOPTOSIS APOPTOSIS

59 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

60 GM-CSF Increases PMNs Monocytes CD4+ cells CD8+ cells Not B cells Or NK cells Meisel et al AJRCCM 2009

61 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

62 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 TNF alpha response pg/ml With GM-CSF treatment Without GM-CSF treatment Plasma IL-6 levels pg/ml With GM-CSF treatment Without GM-CSF treatment Days 1 and Days 1 and 7 No secondary Infections with GM-CSF 1 + per patient Without GM-CSF GM-CSF Standard Day 7 Day14 Day 21 Total

63 A randomized phase II trial of GM-CSF therapy in severe sepsis with respiratory dysfunction AJRCCM Presneill et al 2002;166(2);

64 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

65 Hepatic Apoptosis and FAS SuperAntigen Stimulates Lymphocyte Proliferation Cytotoxic T Lymphocyte Soluble FasR Perforin Granzymes TCR receptors DEATH Fas Fas Ligand Deactivated Lymphocyte Inhibits Apoptosis SFasL Induces Liver Apoptosis Necrosis

66 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

67 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)

68 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

69 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% 10% 0% * HLH protocol Other therapie s HLH SHLH EBV HLH

70 MOSES

71 Management of Multiple Organ Failure in this patient included 1) Hypothermia for cardiac arrest 2) Cooling and Epinephrine and Milrinone for ScvO 2 < 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

72 Management of Multiple Organ Failure

73 MOF Phenotype Directed Therapies Phenotype MOF TAMOF Plt Ct < 100K, Increased LDH Immunoparalysis Neutro / Lymphopenic Anergic Leukocytosis > 100K Cancer / Pertussis Related Sequential MOF Daily Plasma Exchange Until TAMOF resolves Hold Immunesuppression Give GM-CSF Leukopheresis PTLD Hold Immunesuppression Give Rituximab MOF - Two or more organ failures TAMOF Thrombocytopenia Associated MOF commonly found with hemophagocytosis Immunoparalysis Whole blood ex vivo LPS stimulated TNF response < 200 pg/ml, or 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 HLH Hemophagocytic Lympho Histiocytosis Syndrome. MAS/HLH diagnosis made when 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. MAS/ shlh Plasma exchange IVIG / Solumedrol Primary HLH HLH Protocol

74

75 Bundle A > 30/1, % mortality Bundle B < 30/1,000 22% mortality Developing Country 23 % mortality Developed Country 4 % mortality

76 Future therapies Hydrolase for Clysis when IO / IV not possible High flow nasal cannula O 2 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 or

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81 Whole body hypothermia for neonates with hypoxia-ischemic encephalopathy Shankaran et al NEJM (15)

82

83 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

84 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

85 Mild hypothermia to improve neurologic outcome after cardiac arrest(nejm 2002;346(8):549-56

86 Treatment of comatose survivors of out of hospital cardiac arrest with induced hypothermia ( Bernard et al NEJM (8):557-63)

87 Whole body hypothermia for neonates with hypoxia-ischemic encephalopathy Shankaran et al NEJM (15)

88 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

89 Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Rivers et al NEJM 545(19)

90 GM-CSF associated with antibiotic treatment in non traumatic abdominal sepsis: a randomized, double blinded, placebo controlled trial Orozco et al Arch Surg (2):150-3

91 Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Kumar et al CCM (6)

92 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.

93 Plasmapheresis in severe sepsis and septic shock a prospective randomized controlled trial Busund et al Intens Care Med (10):1434-9

94 Time course of organ dysfunction in thrombotic microangiopathy patients receiving either plasma perfusion or plasma exchange Darmon et al CCM (8)

95 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.

96 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.

97 Improved survival of critically ill trauma patients treated with recombinant human erythropoietin Napolitano et al J Trauma (2):285-97

98 Intensity of Acute Renal Failure Support Trial NEJM (1):7-20

99 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 :226-33

100 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 :226-33

101 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.

102 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.

103 Benefits and risks of tight glycemic control in critically ill adults Wiener et al (8);

104 Benefits and risks of tight glycemic control in critically ill adults Wiener et al (8);

105 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

106 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

107 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

108 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

109 Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Kumar et al CCM (6)

110 New Sepsis Therapies Brilliant! or Crazy! Questions or Comments

111 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)

112 MOSES

113 Management of Multiple Organ Failure in this patient included 1) Hypothermia for cardiac arrest 2) Cooling and Epinephrine and Milrinone for ScvO 2 < 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

114 A randomized phase II trial of GM-CSF therapy in severe sepsis with respiratory dysfunction AJRCCM Presneill et al 2002;166(2);

115

116 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

117 Whole body hypothermia for neonates with hypoxia-ischemic encephalopathy Shankaran et al NEJM (15)

118 Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Kumar et al CCM (6)

119 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

120 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

121 Mild hypothermia to improve neurologic outcome after cardiac arrest(nejm 2002;346(8):549-56

122 Fluid overload before continuous hemofiltration and survival in critically ill children a retrospective study Foland et al CCM (9)

123 Treatment of comatose survivors of out of hospital cardiac arrest with induced hypothermia ( Bernard et al NEJM (8):557-63)

124 Whole body hypothermia for neonates with hypoxia-ischemic encephalopathy Shankaran et al NEJM (15)

125 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

126 Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Rivers et al NEJM 545(19)

127 Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Kumar et al CCM (6)

128 GM-CSF associated with antibiotic treatment in non traumatic abdominal sepsis: a randomized, double blinded, placebo controlled trial Orozco et al Arch Surg (2):150-3

129 Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Kumar et al CCM (6)

130 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.

131 Intensity of Acute Renal Failure Support Trial NEJM (1):7-20

132 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.

133 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 :226-33

134 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 :226-33

135 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.

136 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.

137 Benefits and risks of tight glycemic control in critically ill adults Wiener et al (8);

138 Benefits and risks of tight glycemic control in critically ill adults Wiener et al (8);

139 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

140 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

141 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

142 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study Vlasselaers et al LANCET Jan 27,2009

143 New Sepsis Therapies Brilliant! or Crazy! Questions or Comments