Sepsis and Goal directed Sepsis and Goal directed TherapyTherapy-- the first few hoursthe first few hours

Michelle JardineMichelle JardinePICU ConsultantPICU Consultant

Origins from languageOrigins from language

PepsisPepsis-- good, maturation + fermentationgood, maturation + fermentationSepsisSepsis-- bad, putrefaction + smellbad, putrefaction + smellShockShock-- “choquer” “choquer” –– to collide withto collide with

DefinitionsDefinitions

SepsisSepsis-- The host systemic response to The host systemic response to infection characterised by infection characterised by ≥≥ 2 of:2 of:TachycardiaTachycardiaElevated respiratory rateElevated respiratory rateAbnormal temperature (high or low)Abnormal temperature (high or low)Abnormal WCC (high or low)Abnormal WCC (high or low)ShockShock-- when demand for oxygen outstrips when demand for oxygen outstrips supplysupply

Definitions cont…Definitions cont…

Septic shockSeptic shock-- The systemic response to The systemic response to infection + hypotension after adequate fluid infection + hypotension after adequate fluid resuscitationresuscitationSevere sepsisSevere sepsis-- The systemic response to The systemic response to infection + evidence of end organ dysfunctioninfection + evidence of end organ dysfunctionSepsisSepsis--induced multiple organ failureinduced multiple organ failure-- The The systemic response to infection + evidence of systemic response to infection + evidence of dysfunction of two or more organ systemsdysfunction of two or more organ systems

P.I.R.O.P.I.R.O.

PPredispositionredispositionIInfectionnfectionRResponse, andesponse, andOOrgan dysfunctionrgan dysfunctionE.g.E.g.3 year old neutropenic child with a hickman line infection,3 year old neutropenic child with a hickman line infection,Tachycardia and pyrexia, Tachycardia and pyrexia, Hypotensive, acidotic and oliguric, needing oxygenHypotensive, acidotic and oliguric, needing oxygen

What kills in Sepsis?What kills in Sepsis?

Bacteria very sensitive to antibioticsBacteria very sensitive to antibiotics?Early myocardial depression?Early myocardial depression?Neurology?Neurology-- poor perfusion/ bleed into poor perfusion/ bleed into brainbrain?Mitochondria unable to use oxygen?Mitochondria unable to use oxygen?Endotoxin?Endotoxin-- starts up immune responsestarts up immune responseAntiAnti--endotoxinendotoxin-- no differenceno differenceRedundancy in systemRedundancy in system

Cell death in sepsisCell death in sepsis

Previously thought cells die by necrosisPreviously thought cells die by necrosisRecently discovered cells die by apoptosisRecently discovered cells die by apoptosisGenetically programmed cell deathGenetically programmed cell deathStress induced endogenous release Stress induced endogenous release glucocorticoidsglucocorticoidsNecrotic cellsNecrotic cells-- immune stimulation + microbial immune stimulation + microbial defencesdefencesApoptotic cellsApoptotic cells-- antianti--inflammatory cytokines that inflammatory cytokines that impair response to pathogensimpair response to pathogens

Inflammatory responseInflammatory response

Evolutionary advantageEvolutionary advantage-- Bleeding clot wellBleeding clot well-- Infection clear quicklyInfection clear quickly

Pro-inflammatory

Normal response

Immune modulation- increased risk infectionAnti-inflammatory immunosuppressive state

Anti-inflammatory

Genetic differences?Genetic differences?

Low levels TNFLow levels TNFHigh levels High levels IL10IL10Low Low monocyte surface HLAmonocyte surface HLA--DRDR expressionexpressionReduced ability to produce proReduced ability to produce pro--inflammatory inflammatory cytokine responsecytokine response60 times more likely to get infection60 times more likely to get infectionMannose binding lectinMannose binding lectin deficiencydeficiencyIncreased risk resp/meningococcal infectionIncreased risk resp/meningococcal infectionIncreased risk SIRS

TNF

IL10Die

Increased risk SIRS

Evolutionary PerspectivesEvolutionary Perspectives

Single cells obtain oxygen through diffusionSingle cells obtain oxygen through diffusionBody plans more complexBody plans more complex-- time distance time distance constraints of diffusionconstraints of diffusionCardiovascular systemCardiovascular system-- bulk flow to various bulk flow to various tissuestissuesOxygen poorly soluble in waterOxygen poorly soluble in water-- respiratory respiratory pigment that binds and carries oxygen in the pigment that binds and carries oxygen in the blood (haemoglobin in vertebrates)blood (haemoglobin in vertebrates)

Useful framework for considering Useful framework for considering Oxygen delivery to tissuesOxygen delivery to tissues

1. Increase oxygen levels environment1. Increase oxygen levels environment--Increase oxygen saturationIncrease oxygen saturation

2. Increase diffusion (lungs2. Increase diffusion (lungs--blood)blood)Increase arterial haemoglobin concentrationIncrease arterial haemoglobin concentration

3. Increase cardiac output3. Increase cardiac outputPrePre--load, Afterload, After--load, contractility, diastolic functionload, contractility, diastolic function

4. Increase diffusion (blood4. Increase diffusion (blood--tissue)tissue)

Why do cells need Oxygen?Why do cells need Oxygen?

Activities essential for survivalActivities essential for survival-- membrane membrane transport, growth, cellular repairtransport, growth, cellular repairFacultative functionsFacultative functions-- contractility, contractility, electrolyte transport, motilityelectrolyte transport, motilityIf oxygen availability falls, consumption will If oxygen availability falls, consumption will become supply dependantbecome supply dependantFacultative functions lost firstFacultative functions lost first-- organ organ dysfunctiondysfunctionObligatory functions lostObligatory functions lost-- cell deathcell death

Relationship between oxygen Relationship between oxygen delivery and consumption delivery and consumption

Oxygen consumption is independent of delivery Oxygen consumption is independent of delivery over a wide range of valuesover a wide range of valuesOxygen extraction can readily adapt to changes Oxygen extraction can readily adapt to changes in supplyin supplyWhen oxygen delivery acutely reduced (When oxygen delivery acutely reduced (↓↓CO, CO, ↓↓Hb or Hb or ↓↓O2 sats) oxygen extraction increases O2 sats) oxygen extraction increases and oxygen consumption remains stableand oxygen consumption remains stableWhen oxygen delivery falls below a critical value When oxygen delivery falls below a critical value that oxygen consumption starts to fallthat oxygen consumption starts to fallAnaerobic metabolismAnaerobic metabolism-- increase lactateincrease lactate

Septic shockSeptic shockHypovolemicHypovolemicCapillary leakCapillary leakVenodilationVenodilationLoss of cardiac fillingLoss of cardiac fillingDecrease in cardiac contractilityDecrease in cardiac contractilityIncreased pulmonary vascular resistanceIncreased pulmonary vascular resistanceAltered blood distributionAltered blood distributionShuntingShuntingCellular inability to use oxygenCellular inability to use oxygen

““Last ditch stand”Last ditch stand”--hypovolemic shockhypovolemic shock

Cerebral ischemiaCerebral ischemia-- profound sympathetic stimulationprofound sympathetic stimulationAngiotensin + vasopressin Angiotensin + vasopressin Redistribution of fluid from extravascular to intravascular Redistribution of fluid from extravascular to intravascular spacespaceCardiac output maintained (Cardiac output maintained (↑↑HR +HR +↑↑prepre--load) load) vasoconstrictionvasoconstrictionSystemic arterial constrictionSystemic arterial constrictionImpairment of flow to most tissuesImpairment of flow to most tissuesAutoregulationAutoregulation-- cerebral + coronary circulation preservedcerebral + coronary circulation preservedCompensatory mechanisms overwhelmedCompensatory mechanisms overwhelmed-- blood flow to blood flow to all tissues impaired leading to widespread cellular all tissues impaired leading to widespread cellular dysfunctiondysfunction

History of ResuscitationHistory of Resuscitation

WW1WW1-- NoneNoneEarly deathEarly deathWW2WW2-- Colloids, BloodColloids, Blood↑↑Early survival, Early survival, ↑↑acute renal failureacute renal failureVietnamVietnam-- CrystalloidsCrystalloids↑↑Early survival, Early survival, ↑↑respiratory distress syndromerespiratory distress syndrome19701970--80s Resuscitation to end points80s Resuscitation to end points↑↑Early survival, Early survival, ↑↑multi organ failuremulti organ failure

Haemodynamic states in Haemodynamic states in paediatric septic shockpaediatric septic shock

Flow = pressure Flow = pressure ÷÷ resistanceresistanceCO= (MAPCO= (MAP--CVP) CVP) ÷÷ SVRSVR58% low CO high SVR (high mortality)58% low CO high SVR (high mortality)20% high CO low SVR20% high CO low SVR22% low CO low SVR22% low CO low SVRChildren often change between statesChildren often change between states

Carcillo et al Pediatrics Aug 1998Carcillo et al Pediatrics Aug 1998

TreatmentTreatment-- FluidFluidABCABCNo more than 90 secs attempting first venous No more than 90 secs attempting first venous accessaccessUse interosseus route!Use interosseus route!> 40ml/kg 1> 40ml/kg 1stst hour hour reducesreduces mortalitymortalityFluid boluses 20ml/kg over 5Fluid boluses 20ml/kg over 5--10mins10mins(Titrate to HR, urine, CRT + consciousness level)(Titrate to HR, urine, CRT + consciousness level)

Hepatomegaly ? Hepatomegaly ? Hepatic compressionHepatic compression-- judge adequate fillingjudge adequate fillingDellinger et al Crit care Med 2004Dellinger et al Crit care Med 2004

Safe StudySafe Study7000 adults randomised to either albumin or saline for 7000 adults randomised to either albumin or saline for fluid resuscitation on ICUfluid resuscitation on ICUDiagnosed with trauma, sepsis or ARDSDiagnosed with trauma, sepsis or ARDSAlbumin group Albumin group ↓↓HR HR ↑↑CVP days 1CVP days 1--44Saline group greater volumes days 1Saline group greater volumes days 1--44Albumin group more blood days 1Albumin group more blood days 1--22No difference 28 day mortality, days in ICU, days on No difference 28 day mortality, days in ICU, days on ventilator, days of CVVHventilator, days of CVVHNot powered for subgroup analysis but clear trend to Not powered for subgroup analysis but clear trend to increased mortality with saline in the septic shock increased mortality with saline in the septic shock subgroupsubgroup(N Engl J Med; May 2004)(N Engl J Med; May 2004)

AirwayAirway-- take time to get readytake time to get ready

All children in septic shock require high All children in septic shock require high flow oxygen via reservoir maskflow oxygen via reservoir maskNBMNBMPrompt anaesthetic/ intensivist reviewPrompt anaesthetic/ intensivist reviewIntubate > 60ml/kg fluid Intubate > 60ml/kg fluid If NG tube present aspirate it!If NG tube present aspirate it!Can drop Bp on induction high SVR Can drop Bp on induction high SVR →→vasodilatevasodilate→→ ArrestArrest

AirwayAirway

PrePre--oxygenate (Parents can help)oxygenate (Parents can help)Fentanyl 2mcg/kg + ketamine 1mg/kgFentanyl 2mcg/kg + ketamine 1mg/kgDon’t use EtomidateDon’t use EtomidateRocuronium 1mg/kg or Vecuronium 100mcg/kgRocuronium 1mg/kg or Vecuronium 100mcg/kgModified RSIModified RSI-- cricoid pressurecricoid pressure-- may need to bag may need to bag to maintain satsto maintain sats? Cuffed tube? Cuffed tubeWill require PEEP once intubated (pulmonary Will require PEEP once intubated (pulmonary oedema)oedema)

Airway Airway

Monitor BP every 1Monitor BP every 1--2 minutes2 minutesPush fluid in slowly during inductionPush fluid in slowly during inductionAtropine bolus to hand (10Atropine bolus to hand (10--20mcg/kg)20mcg/kg)NGT to decompress stomachNGT to decompress stomachWill require high pressures 25/10 initiallyWill require high pressures 25/10 initiallyFind ventilatorFind ventilatorCXRCXRDon’t forget sedation!Don’t forget sedation!

AccessAccess

Insert arterial and Central linesInsert arterial and Central linesFemoral is first choice for CVLFemoral is first choice for CVLThese children are coagulopathicThese children are coagulopathic--neck lines increase risk of complicationsneck lines increase risk of complications

. . DonDon’’tt let lack of central line stop you from let lack of central line stop you from using inotropesusing inotropes

InotropesInotropesIf still low Bp after 15mins aggressive fluid If still low Bp after 15mins aggressive fluid resuscitationresuscitation→→ inotropesinotropesAnticipateAnticipate-- ask for help (lots of people) + start drawing ask for help (lots of people) + start drawing up earlyup earlyDopamine @ 5Dopamine @ 5--10mcg/kg/min is the first choice 10mcg/kg/min is the first choice vasoactive drug for children presenting in septic shockvasoactive drug for children presenting in septic shockDonDon’’t uset use dobutamine (vasodilation + tachycardia)dobutamine (vasodilation + tachycardia)If still low Bp:If still low Bp:-- Cold shockCold shock-- AdrenalineAdrenaline

Warm shockWarm shock-- Nor adrenalineNor adrenaline

.. Vasodilators/ Inodilators should not be used early in Vasodilators/ Inodilators should not be used early in resuscitationresuscitation

Clinical ParametersClinical Parameters

Sats> 93%Sats> 93%pH, COpH, CO22, Base excess, Base excessMean Bp Mean Bp ≥≥40 neonate 40 neonate ≥≥50 child 50 child ≥≥70 adult70 adult

HR appropriateHR appropriateCVP (8CVP (8--14)14)CRTCRTCoreCore--toe temperature gaptoe temperature gapLactateLactate-- trendtrend

Central Venous Oxygen SaturationCentral Venous Oxygen Saturation

Clinically useful approx Mixed Venous satsClinically useful approx Mixed Venous satsMixed venous sats measured with Mixed venous sats measured with pulmonary artery catheterpulmonary artery catheterDependent on CO, Oxygen demand, Dependent on CO, Oxygen demand, haemoglobin, arterial oxygen saturationhaemoglobin, arterial oxygen saturationNormal SVO2 70%Normal SVO2 70%Low SVO2 inadequate cardiac outputLow SVO2 inadequate cardiac outputHigh SVO2 Cells unable to use oxygenHigh SVO2 Cells unable to use oxygen

Goal directed therapyGoal directed therapyBalance oxygen supply to demandBalance oxygen supply to demandOptimise cardiac output Optimise cardiac output (manipulate Preload, Afterload and Contractility)(manipulate Preload, Afterload and Contractility)

263 patients A+E with severe sepsis or septic shock263 patients A+E with severe sepsis or septic shockRandomised to GDT or standard therapy for 72 hoursRandomised to GDT or standard therapy for 72 hoursGDT higher Bp, higher MVO2, lower lactateGDT higher Bp, higher MVO2, lower lactateGDT lower mean APACHE11 scoresGDT lower mean APACHE11 scoresIn hospital mortality 30.5% GDT Vs 46.5% standard In hospital mortality 30.5% GDT Vs 46.5% standard therapy group (p=0.009)therapy group (p=0.009)

Rivers, N Engl J Med 2001.Rivers, N Engl J Med 2001.

Oxygen, Fluid+Intubate

Arterial + centralline

CVPCrystalloid

Colloid

MAP Vasoactive agents

MVO2Transfuse and

Inotropes

CVP<8

CVP 8-12

Low Bp

Normal Bp

<70

Goals achieved

>70

Protocol for Goal Directed Therapy

Blood productsBlood productsWell child Well child ~ ~ Hb of 7Hb of 7Transfuse to achieve MVO2 ~ 70Transfuse to achieve MVO2 ~ 70transfusion related immunosuppressiontransfusion related immunosuppressionCytokines TNF, IL1, IL6, IL8Cytokines TNF, IL1, IL6, IL8Shape changes + impaired deformabilityShape changes + impaired deformabilityImpaired tissue access + entrapmentImpaired tissue access + entrapmentMicrovascular obstructionMicrovascular obstructionElevated clotting timesElevated clotting times-- FFPFFPLow fibrinogenLow fibrinogen-- cryoprecipitatecryoprecipitateDo not correct Do not correct pltsplts unless bleedingunless bleeding

SteroidsSteroids

Use when catecholamine resistanceUse when catecholamine resistanceOr proven adrenal insufficiencyOr proven adrenal insufficiencyACTH stimulation testACTH stimulation testHydrocortisone 1mg/kg qds IVHydrocortisone 1mg/kg qds IV

RCT 7 days treatment low dose hydrocortisone + RCT 7 days treatment low dose hydrocortisone + fludrocortisone reduced risk of death in 300 adult fludrocortisone reduced risk of death in 300 adult patients with septic shock and relative adrenal patients with septic shock and relative adrenal insufficiencyinsufficiencyAnnane et al; JAMA 2002Annane et al; JAMA 2002