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 • $1.7 billion nationally/yr. • More deaths in children associated with sepsis than with cancer !! Improving Outcomes in Septic Shock with Early Goal Directed Resuscitation 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Mortality 1968 Univ Minn 1985 1999 NCMC U.S. 2001 2000 St M Vietnam UK SEPSIS • Tachycardia + Tachypnea • + Suspicion of infection Tachycardia as a Predictor of Sepsis (Graves GR et al Ped Inf Dis 1984) 70 60 50 40 Tachycardia 30 Eucardia 20 10 0 Sepsis • Only 21 out of 4350 newborns had tachycardia (4.6/1000) • 82 newborns underwent a sepsis evaluation and 13 had sepsis. • 12/13 had tachycardia vs 6/69 without sepsis STEP 1 : GIVE ANTIBIOTICS STEP 2: GIVE FLUIDS STEP 3: GIVE INOTROPES Home-based neonatal care and Sepsis management Reduces Neonatal Mortality (Bang et al 1999, The Lancet) 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% Pre Pre Post • Oral co-trimoxazole and IM gentamycin given to neonates with apnea, tachypnea, poor Post feeding temperature instability, or diarrhea • Cost 5$/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 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 Intensive plasma exchange increases ADAMTS 13 activity and reverses organ dysfunction in children with TAMOF Nguyen et al CCM 2009 26(10) 2878-2886 Intensive plasma exchange increases ADAMTS 13 activity and reverses organ dysfunction in children with TAMOF Nguyen et al CCM 2009 26(10) 2878-2886 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 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 Improved survival of critically ill trauma patients treated with recombinant human erythropoietin Napolitano et al J Trauma 2008 65(2):285-97 PLASMA EXCHANGE MAN 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