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

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 Severe Pneumonia Severe Diarrhea Severe Malaria 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% 1968 Univ Minn 1985 NCMC 1999 U.S. 2000 St M UK 2001 Vietnam Mortality

SEPSIS Tachycardia + Tachypnea + Suspicion of infection

Tachycardia as a Predictor of Sepsis (Graves GR et al Ped Inf Dis 1984) 70 60 50 40 30 20 10 0 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) 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

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

Fluid Resuscitation HR/SBP 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% 50% 40% 30% 20% 10% 0% RL NS Colloid Surv NS

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 Stroke Volume More fluid Vasodilator Inotrope Volume bolus 70% SVCO 2 Left Ventricular End Diastolic Volume

CI > 3.3 Stroke Volume Vasodilator Normal SVCO 2 70% 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 O 2 sat > 70% 28 day Mortality 39.2% 20/51 P = 0.0027 28 day Mortality 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 * * * Proper Antibiotics /Source Control Hold Immunesupression Yes No

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)

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. 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

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%

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

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 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

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

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 study Vlasselaers et al LANCET Jan 27,2009

New Sepsis Therapies Brilliant! or Crazy! Questions or Comments