Sepsis

Jay Green, PGY-3Dr. Jason LordOctober 2, 2008

Dr. Jason LordDr. Dan HowesDr. Trevor LanghanDr. Aric Storck

CaseDefinitionsKeys to sepsis managementRecognition!Early abxEGDTetcPut together the pocket cue card version

Severe sepsis/septic shock mortality 20-50%Incidence increasing10th most common cause of death in the US2-10% of hospital admissions

Non-infectious causes of SIRSTissue damageSurgery, trauma, DVT, MI, PE, pancreatitis, etcMetabolic Thyroid storm, adrenal insufficiencyMalignancyTumor lysis syndrome, lymphomaCNSSAHIatrogenicTransfusion rx, anesthetics, NMS, etc

72F generalized abdo pain x 3d, weak x 1dPMHRA, HTN, goutHR 109, bp 85/45, T 38.9, RR 20, SpO2 94%CVS unremarkableResp scattered cracklesAbdo tender LLQ/RLQ/suprapubic, +BSCNS AAOx3, screening exam N

SIRST38HR>90RR>20WBC12 or >10% bands

Sepsis Management

Two of:HR > 90RR > 30T > 38 or < 36WBC > 12 or

Lactic Acidosis Oliguria Altered mental statusMortality 16%SEPSISSEPSIS + Organ DysfunctionSEVERE SEPSIS

Severe Sepsis +/- hypotension despite adequate fluid resuscitationMortality 46%SEVERE SEPSISSEPTIC SHOCK

Mortality: 46%SEVERE SEPSISSEPTIC SHOCKSEPSISSIRSMortality: 10%Mortality: 16%

72F generalized abdo pain x 3d, weak x 1dHR 109, bp 85/45, T 38.9, RR 20, SpO2 94%You think shes septic?Urosepsis?


Sepsis Management 1. Recognition

#1 priority in sepsis?

Kumar et al. Crit Care Med 2006;34(6):1589

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After hypotension onsetEach hour delay = 7.6% increase mortality (first 6hrs)9.9% increase in the first hour

Mortality increases 9%/hour in hospitalized pts for every hour of delay

Kumar et al. Crit Care Med 2006;34(6):1589 Garnacho-Monero et al. Crit Care 2006;10(4):R111

Kumar et al. Crit Care Med 2006;34(6):1589

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Chest LevoAzithro + ceftriaxoneAbdoPip/tazo or AGF or ceftriaxone/FlagylGUGent or cefriaxoneSkinAncef +/- vancoHeadCeftriazone + vanco + dex

Get them in fast!!STAT, communication, check backCultures prior to abx if possibleBlood, urine, csfRemove the source if possibleFoley, cvcAbscess, necrotizing fasciitisMRSA coverage?Nursing home, other hospital, homeless, etc

AntibioticsStart within first hour of recognitionCultures before Abx if possibleSource controlExclude surgical sources within 6hCrit Care Med 2008;36(1):296


Sepsis Management 1. Recognition 2. ABX!

72F abdo pain & weaknessHR 109, bp 85/45, T 38.9, RR 20, SpO2 94%C/S 13.4

Does this patient have SIRS?Sepsis?Severe sepsis?Septic shock?

Investigations?Initial management priorities?

CBC, lytes, BUN, Cr, culturesCXR

ABCs O2, IV x 2, monitor applied ABX Fluids How much?20-30cc/kg over 30minAnything else?-Lactate!

Persistent hTN despite 2.5L NS over first 90minLabs returningU/A +nit, +leuksWBC 20.4 (3 bands), lytes/Cr N, lactate 5.2Why is lactate important?

What does she have?What evidence is there to guide you now?

You cant act earlyif you dont know theclock is ticking!

Mortality: 46%SEVERE SEPSISSEPTIC SHOCKSEPSISSIRSMortality: 10%Mortality: 16%EGDT Mortality: 30%EGDT

Prospective RCTStandard therapy vs EGDT protocol (= 4mmol/LExclusion criteriaMany

Followed pts for 60dPrimary outcomeIn hospital mortalityICU staff blinded to group

Results

46% vs 30% in hospital mortality in septic shockARR = 16%NNT = 6

Hinshaw & Cox. The Fundamental Mechanisms in Shock. Plenum Press, New York. 1972.

HypovolemicDistributiveCardiogenic Obstructive

HypovolemicDistributiveCardiogenic

You ordered NSHypovolemic

Why are patients in hypovolemic shock?Venodilation3rd spacingLosses (vomiting, diaphoresis)Recent poor PO intake

Meta-analysisSAFE trialCochrane review

Meta-analysis19 RCTs, N = 1315Trauma, surgery, burn, sepsis (1)

BMJ 1998;316:961

DBRCT, N=6997, pts admitted to ICU4% albumin vs NSVolume titrated to clinical statusPrimary outcome28d mortality18% had sepsis (predefined subgroup)NEJM 2004;350:2247

Cochrane Systematic Reviews, 2005. 19 Trials reported data on mortalityN= 7576 RR from these trials was 1.02 (0.93, 1.11).

No evidence of meaningful benefit to colloids vs crystalloids

Normal SalineCheap, availableUSE IT FIRST

Colloid or crystalloidGoalCVP >=8 (>=12 in ventilated patients)Fluid challenge technique>=1L crystalloid (300-500mL colloid) over 30minAs long as hemodynamic improvementReduce rate when CVP increases without hemodynamic improvementCrit Care Med 2008;36(1):296

How fast?1000mL crystalloid q30minHow much volume?DependsGoal: CVP 8-12Rivers study: avg 5L in first 6h

SIRST38HR>90RR>20WBC12 or >10% bandsEGDTCVP 8-12 Crystalloid (1L q30min)

Sepsis Management 1. Recognition (lactate, u/o) 2. ABX 3. EGDT (NNT=6)

BP 80/50 despite 2.5L NSYouve addressed the hypovolemic shockWhat is her MAP?What next?

Distributive

Tank is full (CVP goal reached)Need to increase vascular toneWhich vasoactive agent would you like to use?Starting dose?

Alpha adrenergic receptors:vascular walls - peripheral vasoconstrictionBeta adrenergic receptorsBeta 1: myocardium - increase inotropy (force of contraction) and chronotropy (heart rate)Beta 2: vascular walls - peripheral vasodilatation lungs - bronchodilationDopamine receptorsrenal and splanchnic arteries - vasodilatation and inc blood flow

DopaminePrecursor of epi/norepiRelease of norepi from presynaptic terminalsDosingDopaminergic 10ug/kg/minvasoconstrictionNorepinephrineAlpha >> beta agonistVasoconstriction, little inotropy/chronotropyDosingStart at 0.1 ug/kg/minDouble every five minutes to effectMaximum ~ 2ug/kg/min

Theoretical advantages to norepinephrineDirect acting, works in catecholamine depleted patientsLess dysrhythmiasMartin et al, Chest 1993;103:1826DBRCT, N=32Hemodynamic endpoints achieved with NE>dopCochrane Review (Mullner, 2004)NE vs dopamine3 studies, N=62RR mortality 0.88 (0.57-1.36)

Should we use vasopressin in sepsis?

RCT NE-resistant septic shock N=48.All pts NE>0.5 mcg/kg/minVasopressin 4U/hr + NE vs NE aloneCross-over permitted at 24hrsEndpoints: primarily HD

Either NE or dopamine as 1st lineDont use epi, phenyl or vasopressin as 1st lineUse epi next if poorly responsive to NE/dopButDose of 0.03U/min can be added to NE

Crit Care Med 2008;36(1):296

DBPRCT, N=778InclusionSeptic shock on >=5ug/min NEVasopressin 0.01-0.03U/min vs NE 5-15ug/minCould use other pressors at MD discretionPrimary endpoint28d mortalityMean time from study inclusion to drug = 12hr

We tend to add to NE/dopamine, not use alone

Likely decreases HR, increases MAP, decreases NE requirements in septic shockNo convincing mortality benefitReasonable to try in septic shock that is refractory to NE/dopamineMax/increasing dose vasopressor and doing poorly0.04U/min

SIRST38HR>90RR>20WBC12 or >10% bandsEGDTCVP 8-12 Crystalloid (1L q30min)MAP > 65 NE 0.1-2ug/kg/min OR dopamine 5-20ug/kg/min


BP 90/60 on 2ug/kg/min LevophedNext steps in EGDT?

Cardiogenic

ScvO2Measured where?SVC or RADifferent than mixed venous O2?PACaseHb 83, hct 0.26ScvO2 = 68%What does this mean?How do we increase her ScvO2?

EGDT recommends if ScvO2

Multicenter RCT of 838 ICU pts with Hb

ResultsNo difference in 30 or 60 day mortalityLower in-hospital mortality in restrictive group22.2% vs 28.1% (p=0.005)No difference in mortality in sepsis sub-groupLess sick pts (APACHE II score 100 g/L

EGDTHypovolemic patientsActual measurement of suboptimal O2 deliveryED study

TRICCEuvolemic pts enrolled within 72 hours of ICU admitOnly 6% sepsis, only 27% had any infectionSurviving Sepsis CampaignRecommends EGDTTRICC once hypoperfusion has resolved

If after pRBC her ScvO2 < 70%You want to start dobutamineMechanism?Beta-agonist (Beta1>Beta2)Inotropy/chronotropy, vasodilationBP effect??Dose?2-20ug/kg/min

After fluid resus, hypotensive septic patients may have low, normal or high cardiac outputIf CO not measured (eg. in the ED)Combined vasopressor/inotrope recommended1st line inotrope = dobutamineCrit Care Med 2008;36(1):296

SIRST38HR>90RR>20WBC12 or >10% bandsEGDTCVP 8-12 Crystalloid (1L q30min)MAP > 65 NE 0.1-2ug/kg/min OR dopamine 5-20ug/kg/minScvO2 > 70% pRBC (hct>0.30) dob 2-20ug/kg/min


Pt has had ABX, NS, pRBC, and is now on Levophed, dobutamineRepeat ScvO2 = 67%Pt is becoming more alteredWhat now?

What would be your choice of induction agent?

Predictable dosing and effectFast onset, short duration of actionMinimal respiratory depressionRelative hemodynamic stabilityMinimal histamine releaseStimulates alpha receptors

Absalom 1999, Malerba 2005, Vinclair 2007Single dose inhibits cortisol synthesis for 24-48hMohammed 2006, Ray 2007, Riche 2007Studies designed for etomidate vs no etomidateNo increase in mortalityCORTICUS (2008)>28d mort with one dose (OR 1.53 (1.06-2.26)) Etomidate non-randomized, post-hoc analysisBottom lineAvoid in sepsis

What is it?Non-cardiogenic pulmonary edemaInflammatory lung injuryWhat do you see clinically?Bilateral infiltrates on CXRPaO2/FiO2 < 200Vent settings?

RCT, N=861Pts with ARDS (27% septic)GroupsControl: 12cc/kg, plateau pressures < 50cm H2OIntervention: 6cc/kg, plateau pressures < 30cm H2OPrimary outcomesIn hospital mortalityVentilator-free days in first 28 days

Trial stopped earlyLow TV betterARR 8% (2.4%-15.3%)NNT = 11

Target TV 6cc/kgPlateau pressure

SIRST38HR>90RR>20WBC12 or >10% bandsEGDTCVP 8-12 Crystalloid (1L q30min)MAP > 65 NE 0.1-2ug/kg/min OR dopamine 5-20ug/kg/minScvO2 > 70% pRBC (hct>0.30) dob 2-20ug/kg/minARDSNetTV 6cc/kgPEEPPplateau

CaseYour pt is now intubated, ARDS vent settings, has had NS, ABX, pRBC, Levophed & dobIsnt there anything else you can do doctor?Steroids?Insulin?APC?

Early studies show no benefitVeterans administration. Effect of high-dose glucocorticoid therapy on mortality in patients wit clinical signs of systemic sepsis. N Eng J Med. 1987; 317: 659-65Bone et al. A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock. N Eng j Med. 1987; 317: 653-58Potential increased mortality at higher dosesCronin et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Crit Care Med. 1995; 23: 1430-39

DBPRCT, N=499, 52 ICUs, 9 countriesHydrocortisone 50mg q6h x 5d vs placeboPrimary outcome28d mortality in corticotropin non-respondersSecondary outcomes28d mortality in corticotropin responders1y mortality rateOthers

ConclusionsNo mortality benefit with steroids in vasopressor responsive septic shockFaster reversal of shockBut no difference in proportion of patients achieving reversal of shock

Suggest steroids in vasopressor-unresponsive patientsMax/increasing vasopressor dose and doing poorlyHydrocortisone 50mg q6hNo role for ACTH stim testHydrocortisone > dexamethasoneCan use replacement steroids if pt hx warrantsHydrocortisone 100mg q8hCrit Care Med 2008;36(1):296

Most recent labsNa = 141K = 3.3Cl = 109HCO3 = 21Cr = 178BUN = 11Glu = 18.1Any other therapy to add to the mix?

RCT N=1548, not blindedMostly surgical patients

Randomized toIntensive insulin tx (IIT)IV insulin to BG 4.4-6.1mmol/LConventional insulin tx (CIT)IV insulin to BG 10-11.1mmol/L

Primary outcomeAll-cause ICU mortality

Bacteremic patientsNo difference in mortality29.5% vs 12.5% (NS)

CriticismsGeneralizabilityMostly post-surgical patientsDoes this apply to septic or other medically sick patients?Single center trialNot blindedHyperglycemia MAY BE badHypoglycemia IS bad

In ICU IV insulin to target

VISEP trialMulticenter, RCT, 2x2 design, N=488InterventionsIIT vs CITHydroxyethyl starch vs Ringers lactatePts had severe sepsis or septic shock

Conventional therapy (BG 10.0-11.1mmol/L)Intensive therapy (BG 4.4-6.1mmol/L)Primary outcomes28d mortalityMorbidity (SOFA score)Stopped earlyHypoglycemia in IIT group (12.1 vs 2.1%, P

Glucontrol studyMulticenter PRCT, N=1,011IIT vs CIT (same definitions)Primary outcomeICU mortalityStopped for safety and protocol violations

Intensive Insulin TherapyConventional Insulin TherapyP valueICU Mortality16.7%15.2%NSHypoglycemia9.8%2.7%

BG target > 10mmol/L probably no longer acceptableSafest range below this level unresolved

Bottom lineNo need in ED unless BG markedly highBolus of insulin R preferrable to infusionAim for BG ~ 10mmol/LLikely only important in the ICU setting

APC rationale:The acute inflammatory response in sepsis is integrally related to endothelial activation and procoagulant state

rhAPC is an endogenous anti-coagulant and potent anti-inflammatory agent

DBPRCTInclusion:Severe sepsis or septic shockAll had 1 (most had 2) organs downExclusion:Many criteriaPrimary outcome:Mortality at 28d

ARR = 6.1, NNT = 16

Post hoc analysis of PROWESSDhainaut et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Int Care Med 2003; 29: 894 - 903

Concerns with PROWESSNot powered for subgroups analysisFDA 2001 report contains additional information regarding the participants and interventions that were not publishedThe trial contains 2 subtly different protocolsInitial protocol = 720 participantsAmended protocol = 970 participants 3 changes:Addition of exclusion criteria for pts with septic shockOther altered placebo from NS to 0.1% albuminSponsor introduced a change to the manufactured drug during amendment

DBPRCT, N=2613InclusionSevere sepsis and low risk of deathAPC vs placebo (NS)Stopped at 2nd interim analysisLow likelihood of efficacy and expected high risk bleeding

DBPRCT, N=477 kidsOutcomes/ResultsTime to organ dysfunction resolutionNo difference (6% vs 6%)28d mortalityNo difference (17.2% APC vs 17.5% placebo)Serious bleedingNo differenceCNS bleeding (4.6% APC vs 2.1% placebo, NS)

APC forAdults with sepsis-induced organ dysfunction and high risk of death or multiple organ failureAPACHE II scores calculated using 24h of ICU dataNo current role for APC in the EDCrit Care Med 2008;36(1):296

N=4911

RR (CI)P value28d Mortality0.92 (0.72-1.18)0.5028d MortalityAPACHE < 251.04 (0.89-1.21)0.7028d MortalityAPACHE > 250.90 (0.54-1.49)0.68Serious Bleeding1.48 (1.07-2.06)0.02

Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC

More comingPROWESS-SHOCKEXTENDRESPOND

Not for those at low risk of deathNot for kidsNot for use by ED physicians

Maybe for those with > 2 organs downMaybe for those at high risk of deathMaybe, if the ICU decides to use it

Your job as an emergency physicianRecognition!Early antibiotics!EGDT!ARDS ventilator settings

Good to know, but MUCH less important to usSteroidsInsulinAPC

*Adequate fluid resusc = 20-30mL/kg fluid over 30 minutes*Adequate fluid resusc = 20-30mL fluid over 30 minutesArtificial, as you would have someone start a line and start giving fluids before this pt gets abx*Vanco, septra, doxy for MRSA (clinda too, but have inducible resistance)*At least sepsismay be worse*Dont forget lactate!*Lactate allows for timely recognition of septic shock**Adequate fluid resusc = 20-30mL fluid over 30 minutesAge 70%*More early fluids (same after 72h), more early rbc, more early inotropes*So youre giving fluidscrystalloid or colloid?**How does it work? Stimulates V1a receptors in peripheral SM cellsBlock NO productionWorks during acidosisStudies have shown in pts with septic shock low levels of vaso

*Demonstrates that addition of vasopressin causes an increase in MAP and decrease in HR and decreased NE requirements

No mortality benefit to vasopressin*No change in adverse events including arrhythmias*Prospectively defined subgroup of less severe septic shock pts showed benefit to vasopressin*Last drug added, not titrated (background infusion), complications due to vasoC*Low ScvO2 means as the pump begins to fail it cant deliver O2 to the tissues as well, so tissues extract more O2 leaving the ScvO2 lower*Probably not for ED useACS aim for hct > 0.30 or Hb > 100*Pretreatment noInduction ketamine, avoid etomidate or meds causing hTNParalytic - *Transiently inhibits 11-B-hydroxylase (enzyme in the final step of cortisol synthesis)Presume that ketamine is safer (not studied)-causes NE release and is myocardial depressant so maybe bad choice in this patientMaybe small dose fentanyl + lido to pharynx*Leaky lung capillaries 2* to PMN activation causing endothelial damageNot truly pulmonary edema as lungs filled with inflammatory exudate rather than watery edema*Diffuse disease, Normal cap wedge, Fi02:pa02

Sepsis

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