Pediatric Sepsis

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Pediatric Sepsis
Graham Thompson MD FRCPC FAAP CAEP Annual
Conference June 7th 2009
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Objectives

• Review the Definitions of the Pediatric Sepsis
  Continuum
• Review Epidemiology of Pediatric Sepsis
• Review Evidence for Therapies in Pediatric Sepsis
• Introduce CAEP 2010 Pediatric Sepsis Guidelines
  Project

This presentation will not include information on
Neonatal Sepsis and Neonatal Rule Out Sepsis
Protocols
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Disclosure

• I do not have an affiliation (financial or
  otherwise) with any commercial organization that
  may have a direct or indirect connection to the
  content of my presentation.

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The Sepsis Continuum a Winding Road

• Systemic Inflammatory Response Syndrome
• Sepsis
• Severe Sepsis
• Septic Shock

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Systemic Inflammatory Response Syndrome

• At least 2/4 (one must be temperature or WBC
  count)
• Core temperature gt 38.5 or lt 36.0
• HR gt 2SD for age OR lt10th ile if lt1yo
• RR gt 2SD from norm for age
• WBC depressed or increased or gt10 immature cells

Goldstein et al PCCM 2005 6(1)2
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Sepsis

• SIRS in the presence of or as a result of
  suspected or proven infection

Goldstein et al PCCM 2005 6(1)2
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Severe Sepsis

• Sepsis plus one of
• Cardiovascular (CVS) dysfunction
• Acute Respiratory Distress Syndrome (ARDS)
• Dysfunction of 2 other organ systems

Goldstein et al PCCM 2005 6(1)2
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Septic Shock

• Sepsis plus CVS dysfunction despite 40cc/kg
  fluids
• Hypotension lt 2 SD or lt 5ile for age
• Need for vasoactive drug to maintain BP
• Any 2 of
• Unexplained metabolic acidosis
• Oliguria lt 0.5cc/kg/hr
• Lactate gt 2x normal
• Prolonged cap refill gt 5 sec
• Core/peripheral temp difference gt 3C

Goldstein et al PCCM 2005 6(1)2
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Brierley et al CCM 2009 37(1)1
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Pediatric Severe Sepsis Statistics

• USA 2000 - 47 700 cases of severe sepsis
• Estimated annual cost in 2000 - 1.97 billion
• Average LOS 30 days (19 days for age 1-19)
• Reduction of mortality from 97 in 1963 to 9
• Recent US study of KID centres - mortality 4.2
• Mortality rate much better than adults (currently
  20-30)

PCCM 2005 6(3s)s3, CCM 2002 30(6)1365
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PCCM 2005 6(3s)s3, CCM 2002 30(6)1365
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What about in Canada?

• Alberta Childrens Hospital
• May 1st 2007 - April 30th 2008
• Age 1-17 years
• 25 sepsis admitted to PICU
• 7 Toxic Shock
• Note does not include post-operative/NICU

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What Patient Factors Affect Mortality?

• Age lt 1yr
• Premorbid condition (i.e. Bone Marrow Transplant)
• Multi-Organ Dysfunction Syndrome (MODS)
• Genetics

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Why is this Topic Important?

• United Kingdom Experience
• 20 did not receive gt60 cc/kg fluids
• 15 did not receive inotropes
• 23 did not receive catecholamines
• Only 8 of children in shock followed 2002 ACCM
  guidelines
• Odds Ratio of death with persistent shock 3.8
  (1.4-10.2)

Inwald Arch Dis Child 2009 94348
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What Interventions Influence Outcome?

• Early recognition
• Early vascular access
• Early aggressive fluid resuscitation
• Early broad spectrum antibiotics
• End organ monitoring
• Vasoactive meds
• Steroids?

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Early Recognition - Challenges

• Difficulties with age adjusted Vital Signs
• Fever altering HR/RR
• Frequent mimickers
• ED Wait times
• Pediatric compensation

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• Severe Sepsis can be recognized by a clinical
  triad that includes
• Hypo/hyperthermia
• Altered mental status
• Peripheral perfusion changes

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Can Labs Help Me?

• In adults
• Lactate gt 4 shown to be predictive of mortality
  (OR 6.1 95 CI 3.7-10.5)
• Serial lactates may predict Multi-Organ
  Dysfunction Syndrome (MODS)
• Lactate clearance in lt 6 hrs improves mortality
• ACCM - focus on clinical exam, lactate
  questionable in pediatrics

Trzeciak Inten Care Med 2007 33970, Bakker Am J
Surg. 1996171221-226.
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Trzeciak et al Inten Care Med 2007 33970
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What about Procalcitonin?

• May be good indicator for sepsis
• May be better marker for mortality
• Problem most Canadian EDs cant run it.

Viallon Euro J EM 2008 15 (1) 26, Rey Inten Care
Med 2007 33 (3) 477
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Vascular Access

• Simultaneous PIV and IO starts

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Fluids
How much, how fast, which ones?
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How Much Fluid Should I Give?

• lt 20 cc/kg vs 20-40 cc/kg vs gt 40 cc/kg in 1st hr
• Survival in gt 40 cc/kg group significantly better
  (8/9 vs 6/14 vs 4/11)
• No increase in pulmonary edema or ARDS

Frequently up to 60 cc/kg, reports up to 150-200
cc/kg
JAMA 1991, 2661242
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What Fluids Should I Use?

• Saline vs polymer product 20cc/kg boluses until
  BP, CVP and refill normal
• No difference in end plasma volume, inotrope
  requirements, organ dysfunction or case mortality
• Mean infused volume NaCl 50/kg (20-108) vs 30/kg
  (20-70)

Ind Ped 2005 42223
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What Fluids Should I Use?

• Colloids vs Saline vs Ringers in Dengue fever
• All survived
• Longest time to recovery - RL
• Quickest time to restored pulse pressure -
  colloids

Clin Inf Dis 2001, 32204
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How Do I Give Fluids?

• Gravity vs pressure bag vs push/pull over 5
  minutes
• No child gt 40 kg got 20/kg in 5 min.
• Pump 999 cc/hr so 20/kg in 5 min max wt of 4.16
  kg
• Rapid Infuser 1 L in 3 minutes

Ann EM 2007 50(5)601
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What Are My Therapeutic Endpoints?

• Capillary refill lt 2 sec
• Normal pulses and pulse pressure
• Warm extremities
• Urine output gt 1 ml/kg/hr
• Normal mental status
• Decreased lactate
• Central venous O2 saturation gt 70

Blood pressure by itself is not a reliable
endpoint for resuscitation
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Fluids - Summary

• Aggressive fluid resuscitation
• Boluses of 20 cc/kg over 5-10 min each
• Often requires 40-60 cc/kg
• May need 150-200 cc/kg
• Crystalloid or colloid
• Use Push/Pull or Pressure Bag or Rapid Infuser

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When Do I Start Vasoactive Meds?

• Increased mortality with every hour delay in
  initiation
• Start after fluid refractory (gt 60 cc/kg)
• New ACCM recommendation
• Dont need Central Venous Line
• Start Dopamine at 5-10 mcg

Brierley et al CCM 2009 37(1)1
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What Vasoactive Drugs do I Use?

• Dopamine initial drug of choice for hypotension
• infants lt6 mo may be dopamine refractory
• Epinephrine (cold) or norepinephrine (warm) for
  dopamine-refractory shock
• Dobutamine for low cardiac output state

Brierley et al CCM 2009 37(1)1
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Early Goal Directed Therapy (EGDT)
Rivers NEJM 2001 345(19)1368
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Early Goal Directed Therapy
Rivers NEJM 2001 345(19)1368
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Early Goal Directed Therapy
Rivers et al Curr Opin Anesthesiol 2008 21128
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Does EGDT Work in Pediatrics?

• Retrospective review
• ACCM guidelines for 1st hour
• 92 vs 62 survival
• Note used cap refill gt 2 sec vs SCVO2

Han et al Pediatrics 2003 112793
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Han et al Pediatrics 2003 112793
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EGDT in Pediatrics

• Effect of using SCVO2 on EGDT
• 102 children with fluid resistant shock
  (gt40cc/kg)
• 28 day mortality - 39.2 vs 11.8 (p0.002)
• 60 day mortality - 41.2 vs 15.7 (p0.002)

de Oliveira et al Int Care Med 2008 341065
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ACCM Guidelines - the Goals

• First hour goals
• Restore and maintain HR thresholds, capillary
  refill lt2 sec, and normal BP in the 1st hour in
  the ED
• Support oxygenation and ventilation as
  appropriate
• Normalize perfusion pressure (mean arterial
  pressure-central venous pressure) for age, ScvO2
  gt70, and CI gt3.3, lt6.0 L/min/m2 in pediatric
  intensive care unit.

Brierley et al CCM 2009 37(1)1
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Whats New in the ACCM Guidelines?

• Start peripheral dopamine until central access is
  obtained
• Ketamine for Intubation
• Monitor Cardiac Output
• Rescue Meds Enoximone/Levosimendan
• Fluid removal strategies

Brierley et al CCM 2009 37(1)1
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ACCM Pediatric Sepsis Guidelines
Brierley et al CCM 2009 37(1)1
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Brierley et al CCM 2009 37(1)1
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When Do I Intubate?

• No good data
• Reasons to do it
• Up to 40 of Cardiac Output may be required to
  support work of breathing.
• Increased intrathoracic pressure may improve BP
• Invasive procedures/monitoring/sedation

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What Drugs Do I Use to Intubate?

• Ketamine is drug of choice
• maintains BP
• maintains spontaneous resps
• improves contractility
• antimicrobial and anti-inflammatory effect
• except - rare cases of myocardial depression

Brierley et al CCM 2009 37(1)1, Taniguchi Anesth
2001 95928, Van der Linden Anesth Anal 1990
70608
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What Drugs Do I Use to Intubate?

• Etomidate is NOT recommended
• in new ACCM guidelines
• in adult literature it is still debated
• adrenal suppression

Brierley et al CCM 2009 37(1)1
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Are Steroids Helpful?

• Sepsis can cause adrenal insufficiency
• 30 kids with fluid resistant septic shock with
  ACTH stim test
• Higher incidence of catecholamine resistant
  shock, but no difference in mortality rate

PCCM 2007 8(1)23
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Are Steroids Helpful?

• Adult Studies are conflicting
• High dose steroids associated with increased
  secondary infection, mortality and renal/hepatic
  dysfunction
• Low dose steroids have been found beneficial in
  adults with shock, not in sepsis without shock
• CORTICUS Study no improvement in 28 day
  survival or reversal of shock

Sprung NEJM 2008 358(2)111
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Are Steroids Helpful?
Sprung NEJM 2008 358(2)111
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When Should I Consider Using Steroids?

• We suggest that hydrocortisone therapy be
  reserved for use in children with catecholamine
  resistance and suspected or proven adrenal
  insufficiency (Grade 2C).
• If a child is at risk of absolute adrenal
  insufficiency or adrenal pituitary axis failure
  and remains in shock despite catecholamine
  infusion, hydrocortisone can be administered
  (Level III)

Dellinger et al CCM 2008 36(1) 315,
Brierley et al CCM 2009 37(1)1
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When Should I Consider Using Steroids?

• Chronic steroid users
• Patients with purpuric lesions
• Patients with pituitary/adrenal dysfunction
• Patients with proven low ACTH stimulation test

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When Should I Consider Blood Transfusion?

• EGDT - Hct gt 0.30 to improve O2 delivery
• Transfusions in ICU may increase mortality - not
  sepsis specific
• Transfusion level of Hgb 70 - no increase in
  complications or mortality in all-comer PICU
  study (TRIPICU)
• stabilized patients!
• 35 were septic, 15 had severe sepsis/shock

Lacroix et al NEJM 2007 356(16)1609
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When Should I Consider Blood Transfusion?

• Current recommendations differ in early vs late
  stages of sepsis
• first 6 hrs - keep 90-100, hct gt0.3
• after, if no instability, then may permit
  dropping to HGB 70.
• In the absence of data, it is reasonable to
  maintain HGB within the normal range for
  age....HGB should be maintained at a minimum of
  100

Carcillo CCM 2002 30(6)1365, Zimmerman CCM 2004
32 (11s)s542
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Future Directions

• Alberta Heritage Foundation for Medical Research
• Team Grant - Alberta Sepsis Network
• 5M over 5 years
• CAEP 2010 Pediatric Sepsis Guidelines
• Adult Guidelines presented at CAEP 2008
• Fall 2008 - initial investigation into pediatric
  guidelines

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CAEP 2010 Pediatric Sepsis Guidelines

• Niranjan (Tex) Kissoon
• Tim Lynch
• Peter Skippen
• Alan Drummond
• Gena Neto
• Elaine Gilfoyle
• Sarah Mcclennan
• Jeanette Pearce
• Francois Boucher
• Joe Carcillo
• Maala Bhatt
• Ari Joffe
• Serge Gouin

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Summary

• Early Recognition is key
• Early Access with PIV and IO
• Lots of fluids, quickly. NaCl or Colloid
• Dopamine as 1st line vasoactive drug
• Epinephrine and Norepinephrine as options

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Summary

• Ketamine for Intubation
• Steroids for those at risk
• Blood transfusions to keep Hgb 100 or Hct 30
• Have set targets to obtain
• Call for Help
• Watch of CAEP Pediatric Sepsis Guidelines

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Age Specific Vital Signs
Goldstein et al PCCM 2005 6(1)2
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Organ Dysfunction

• Respiratory
• PaO2/FiO2 lt 300 in absence of CHD or pre-existing
  lung disease
• PaCO2 gt 65 or 20mmHg over baseline
• Proven need for 50 FiO2 to maintain saturation
  gt 92
• Need for non-elective invasive or noninvasive
  mechanical ventilation
• Neurologic
• GCS lt 11
• Acute change in mental status i.e. GCS change gt3
• Hematologic
• Ptls lt80 000 or decline of 50 from highest value
  in last 3 days
• INR gt2
• Renal
• serum Cr gt2 times upper limit of normal for age
  or 2X increase from baseline
• Hepatic
• total bilirubin gt40
• ALT 2X upper limit of normal for age

Goldstein et al PCCM 2005 6(1)2
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Is there a role for Activated Protein C?

• ENHANCE and RESOLVE studies
• conflicting results in terms of bleeding
• no documented improvement in 28 day mort.
• adult recommendations only when Multi-Organ
  Failure AND high risk of death AND no
  contraindications
• We recommend against the use rhAPC in children
  (grade 1B).

Goldstein et al PCCM 2006 7(3)200, Nadel et al
Lancet 2007 369836
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Who Should Get Immunoglobulins?

• RCT 1-24 month
• significant decrease in mortality, LOS and
  coagulopathy
• 2 recent meta-analyses of adult data
• significant reduction in mortality
• OR 0.66 CI 0.53-0.83

El-Nawawy J Trop Ped 2005 51(5)271, Kreymann CCM
2007 35(12)2677, Laupland 2007 35(12)2686
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Who Should Get Immunoglobulins?

• We suggest that immunoglobulin be considered in
  children with severe sepsis (grade 2C).

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Other Therapies

• Insulin
• hyperglycemia linked to adverse outcome in adults
  (recommendation - keep lt 8.3)
• kids relatively more prone to hypoglycemic
  episodes.
• pediatric study showed hyper/hypoglycemia and
  significant variability to be risk for increased
  LOS and mortality
• GM-CSF shown to be of benefit in neonates with
  sepsis and neutropenia.