Issues in Pediatrics Management of Newborn and … › ... › 2011 › emergencias ›...

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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%

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)

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

• Oral co-trimoxazoleand IM gentamycingiven 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

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

(-) 40cc/kg

Fluid Resuscitation

(-)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%

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

Volume bolus

Inotrope

Vasodilator

More fluidCI > 3.3

Normal

DecreasedCardiac function Inotrope

Vasodilator

CI > 3.3

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

P = 0.0027

28 day Mortality

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%

ACCM Guidelines HoldImmunesupression

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

Fluid-refractory shock

Push 10cc/kg isotonic crystalloid or colloid boluses to 60 cc/kg, correct hypoglycemia,andhypocalcemia. Begin prostaglandin infusion until echocardiogram shows no ductal-

dependent lesion.

Push 10cc/kg isotonic crystalloid or colloid boluses to 60 cc/kg, correct hypoglycemia,andhypocalcemia. Begin prostaglandin infusion until echocardiogram shows no ductal-

dependent lesion.

Recognize decreased perfusion, cyanosis, RDS.Maintain airway and establish access according to NRP guidelines.

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%

Fluid refractory-dopamine resistant shock

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

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

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

Intensive plasma exchange increases ADAMTS 13 activity

and reverses organ dysfunction in children with TAMOFNguyen et al CCM 2009 26(10) 2878-2886

Intensive plasma exchange increases ADAMTS 13 activity

and reverses organ dysfunction in children with TAMOFNguyen 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 neurologicoutcome 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 Milrinoneto 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

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

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

Improved survival of critically ill trauma patients treated with recombinant human erythropoietin

Napolitano et al J Trauma 2008 65(2):285-97

PLASMAEXCHANGE

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

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

New Sepsis Therapies

Brilliant! or Crazy!

Questions or Comments

Issues in Pediatrics Management of Newborn and … › ... › 2011 › emergencias ›...

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