ICU Case PresentationICU Case Presentation

Treatment of Septic Treatment of Septic ShockShock

Leah Jackson, Leah Jackson, BScPhmBScPhmPharmacy ResidentPharmacy Resident

April 17, 2007April 17, 2007

Learning ObjectivesLearning Objectives

At the end of the presentation, the audience At the end of the presentation, the audience will be able to:will be able to:–– Describe the meaning of sepsis, SIRS, and septic Describe the meaning of sepsis, SIRS, and septic

shockshock–– Explain the basic Explain the basic pathophysiologypathophysiology of sepsis and of sepsis and

how it presentshow it presents–– List the interventions available to treat sepsis List the interventions available to treat sepsis

(toolkit)(toolkit)–– Understand the basis for the preprinted ICU order Understand the basis for the preprinted ICU order

set (adjuvant therapy for sepsis) and access 3 set (adjuvant therapy for sepsis) and access 3 landmark studies for further information if landmark studies for further information if desireddesired

Mr. C, 77 Mr. C, 77 yoyo ♂♂PMHPMH–– HTN (20+ years)HTN (20+ years)–– CAD CAD →→ 1998, 20051998, 2005–– CHF (grade 2/3 ventricle)CHF (grade 2/3 ventricle)–– A fib (pacemaker 2002)A fib (pacemaker 2002)–– AVR, MVR 1997 AVR, MVR 1997

(mechanical)(mechanical)–– AAAAAA–– PVD (bilateral bypasses PVD (bilateral bypasses

2004)2004)–– TIATIA–– ESRD (peritoneal ESRD (peritoneal

dialysis)dialysis)–– BPHBPH–– HypothyroidismHypothyroidism–– DM type 2 (recent DM type 2 (recent dxdx; ;

dietdiet--controlled)controlled)

Home medicationsHome medications–– MetoprololMetoprolol 50mg BID50mg BID–– AmiodaroneAmiodarone 200mg daily200mg daily–– DigoxinDigoxin 0.125mg daily0.125mg daily–– AtorvastatinAtorvastatin 10mg daily10mg daily–– WarfarinWarfarin–– Ferrous Ferrous fumaratefumarate 300mg 300mg

dailydaily–– DarbepoetinDarbepoetin 50mcg q 2 50mcg q 2

wkwk–– Ca carbonate 625mg am Ca carbonate 625mg am

and 1250mg noonand 1250mg noon–– ReplaviteReplavite dailydaily–– LevothyroxineLevothyroxine 0.1mg 0.1mg

dailydaily–– ??metolazonemetolazone, ?ASA, ?ASA

TimelineTimeline

Mar 21Mar 21: : admadm. for . for tPAtPA treatment of ischemic treatment of ischemic leglegMar 22Mar 22: : admadm. to CCU . to CCU →→ UA/NSTEMIUA/NSTEMIMar 25Mar 25: PCI : PCI →→ stentstent to LADto LADMar 28Mar 28: R leg above: R leg above--knee amputation knee amputation Apr 1Apr 1: : admadm. to ICU: BP 68/40, CXR changes. to ICU: BP 68/40, CXR changes–– sepsis sepsis vsvs cardiac sourcecardiac source–– Rx pipRx pip--tazotazo for possible HAPfor possible HAP

Apr 5Apr 5: stabilized : stabilized →→ SDUSDUApr 8Apr 8: : readmreadm. to ICU with likely sepsis. to ICU with likely sepsis

What is Sepsis?What is Sepsis?

Systemic inflammatory response to Systemic inflammatory response to infectioninfectionSIRS criteria:SIRS criteria:–– T >T > 3838°°C or <36C or <36°°CC–– HR > 90 HR > 90 bpmbpm–– RR > 20 breaths/min or PaCORR > 20 breaths/min or PaCO22 < 32 mmHg< 32 mmHg–– WBC >12 or <4 or >10% immature WBC >12 or <4 or >10% immature

neutrophilsneutrophilsResources:Resources:1. 2007 UHN Guidelines for Antimicrobial Use (pg 2211. 2007 UHN Guidelines for Antimicrobial Use (pg 221--2)2)2. 2. KodaKoda--Kimble, MA. Ch 56: Principles of Infectious Diseases in Kimble, MA. Ch 56: Principles of Infectious Diseases in Applied Therapeutics: The Applied Therapeutics: The

Clinical Use of Drugs 8Clinical Use of Drugs 8thth EditionEdition. 2005 Lippincott Williams & Wilkins, Baltimore, . 2005 Lippincott Williams & Wilkins, Baltimore, Maryland.Maryland.

3. 3. VenesVenes, D. Sepsis in , D. Sepsis in TaberTaber’’s s CyclopedicCyclopedic Medical Dictionary Edition 20Medical Dictionary Edition 20. 2005 F.A. Davis . 2005 F.A. Davis Company, Philadelphia, PA. Company, Philadelphia, PA.

PathophysiologyPathophysiologyPathogenic organisms (Pathogenic organisms (endo/exotoxinsendo/exotoxins, , cell wall components) cell wall components) Host response Host response →→ rrelelease of TNF, ease of TNF, interleukins, nitric oxide; complement interleukins, nitric oxide; complement activationactivationIncreased endothelial permeability (Increased endothelial permeability (↓↓SVR, SVR, vasodilationvasodilation))NeutrophilNeutrophil activationactivation

Manifestations and complicationsManifestations and complications

SIRSSIRS–– T >T > 3838°°C or <36C or <36°°CC–– HR > 90 HR > 90 bpmbpm–– RR > 20 breaths/min or PaCORR > 20 breaths/min or PaCO22 < 32 < 32

mmHgmmHg–– WBC >12 or <4 or >10% immature WBC >12 or <4 or >10% immature

neutrophilsneutrophils

↑↑ blood glucoseblood glucose↓↓ platelets, platelets, ↑↑ INR INR →→ DICDIC

Manifestations and complicationsManifestations and complications

↓↓ BP, BP, ↓↓ perfusion perfusion →→ shock shock (BP = SVR x (BP = SVR x CO)CO)–– altered mental statusaltered mental status–– global tissue hypoxia (global tissue hypoxia (↑↑ lactate)lactate)–– low central venous oxygen saturation (low central venous oxygen saturation (ieie/ <70%)/ <70%)–– organ dysfunction (“severe” sepsis)organ dysfunction (“severe” sepsis)–– oliguriaoliguria (u/o < 0.5 (u/o < 0.5 mLmL/kg/hr), /kg/hr), ↑↑ ScrScr, , ↑↑ BUNBUN–– acute respiratory distress syndrome acute respiratory distress syndrome –– shock liver (shock liver (↑↑ transaminasestransaminases, , ↓↓ albumin, albumin, ↑↑ INR)INR)–– ischemic bowelischemic bowel

40% mortality rate40% mortality rate

ShockShockShock:Shock: an acute, generalized state of an acute, generalized state of inadequate perfusion of critical organs that inadequate perfusion of critical organs that can produce can produce pathophysiologicpathophysiologic consequences, consequences, including deathincluding deathDipiroDipiro, JT. Ch 23: Use of , JT. Ch 23: Use of VasopressorsVasopressors and and InotropesInotropes in the Pharmacotherapy of Shock in in the Pharmacotherapy of Shock in

Pharmacotherapy 6Pharmacotherapy 6thth EditionEdition. 2005 The McGraw. 2005 The McGraw--Hill Companies, Inc. New York, NY.Hill Companies, Inc. New York, NY.

Septic shockSeptic shock–– sepsis with SBP <90 mmHg (hypotension)sepsis with SBP <90 mmHg (hypotension)–– vasodilationvasodilation (BP = SVR x CO); “warm”(BP = SVR x CO); “warm”

HypovolemicHypovolemic shock and shock and cardiogeniccardiogenicshockshock–– ↓↓ CO; CO; ““coolcool””

How did Mr. C present?How did Mr. C present?77 y.o. male, in hospital x 2.5wks; DM, 77 y.o. male, in hospital x 2.5wks; DM, ESRD (PD), hypothyroidism, ++CV ESRD (PD), hypothyroidism, ++CV conditionsconditions

April 8:April 8:CNS CNS –– ↓↓ LOCLOCRespResp –– new infiltrates on CXR, purulent new infiltrates on CXR, purulent

sputum (?aspiration pneumonia), RR 26sputum (?aspiration pneumonia), RR 26CVSCVS –– HR 120, BP 75/50, ScvOHR 120, BP 75/50, ScvO2 2 49%49%

How did Mr. C present?How did Mr. C present?

GIGI –– abdomen distended (ischemic bowel abdomen distended (ischemic bowel vsvsintraintra--abdominal infection)abdominal infection)

GUGU –– anuricanuric (as usual); PD (as usual); PD ∆∆’’d d to CVVHDto CVVHD

IDID –– T 36.4T 36.4°°, WBC 27.8; cultures sent , WBC 27.8; cultures sent (blood x 2, sputum, PD (blood x 2, sputum, PD dialysatedialysate, IV , IV catheter tip)catheter tip)

Abnormal labs Abnormal labs –– lactate 7.4, pH 7.23, AST lactate 7.4, pH 7.23, AST 400, ALT 270, INR 1.85400, ALT 270, INR 1.85

Consistent with septic shock?Consistent with septic shock?

Source of infection Source of infection (lungs, possibly (lungs, possibly abdomen)abdomen)SIRS criteria (3/4)SIRS criteria (3/4)–– T >38T >38°°C or <36C or <36°°C (36.4)C (36.4)

HR > 90 HR > 90 bpmbpm (120)(120)RR > 20 breaths/min (26)RR > 20 breaths/min (26)WBC >12, <4, or >10% WBC >12, <4, or >10% (WBC 27.8)(WBC 27.8)

BP BP ↓↓ (75/50 mmHg)(75/50 mmHg)altered mental statusaltered mental status↑↑ lactate(7.4),lactate(7.4),↓↓ pH (7.23)pH (7.23)↓↓ ScvOScvO2 2 (49%)(49%)↑↑ liver liver transaminasestransaminases and and INR (400, 270, 1.85)INR (400, 270, 1.85)?ischemic bowel?ischemic bowel

Clinical questionClinical question

How do we treat a patient with septic How do we treat a patient with septic shock?shock?

Therapeutic alternatives: Therapeutic alternatives: Sepsis toolkitSepsis toolkit

1.1. Appropriate antibioticsAppropriate antibiotics2.2. InsulinInsulin3.3. Early goalEarly goal--directed therapy directed therapy →→

fluids, blood, fluids, blood, vasoactivevasoactive agents, agents, inotropesinotropes

4.4. SteroidsSteroids5.5. Activated protein CActivated protein C

Appropriate antibioticsAppropriate antibiotics

Sepsis is an infectious process Sepsis is an infectious process →→ treat treat the sourcethe source

High mortality, esp. due to sudden High mortality, esp. due to sudden circulatory collapse circulatory collapse →→ start promptly start promptly ((ieie/ <24 hours)/ <24 hours)1,21,2

Empiric Empiric txtx based on site of (suspected) based on site of (suspected) infection; adjust ASAP when C & S infection; adjust ASAP when C & S reportedreported

Appropriate antibioticsAppropriate antibiotics

New New NosocomialNosocomial Pneumonia guidelines Pneumonia guidelines in UHN antimicrobial handbook (pages in UHN antimicrobial handbook (pages 127127--131)131)–– NosocomialNosocomial bugs: enteric GNB, S. bugs: enteric GNB, S. aureusaureus, S. , S.

pneumoniaepneumoniae, H. , H. influenzaeinfluenzae

–– ICU/VAP bugs: resistant GNB ICU/VAP bugs: resistant GNB →→ pseudomonas, pseudomonas, ESBL producing E.coli and ESBL producing E.coli and KlebsiellaKlebsiella, bugs with , bugs with inducible chromosomal betainducible chromosomal beta--lactamaseslactamases; ; legionellalegionella

*Q: how would you empirically treat *Q: how would you empirically treat Mr.CMr.C??

Insulin Insulin –– in briefin brief

In sepsis, blood glucose can In sepsis, blood glucose can ↑↑Tight glucose control has been Tight glucose control has been studied in various populations studied in various populations –– some benefits shown (cardiac some benefits shown (cardiac sxsx pts pts

and various mixed populations)and various mixed populations)

Insulin Insulin nomogramsnomograms used in ICUused in ICU

Sugar study ongoing!Sugar study ongoing!

Sepsis toolkitSepsis toolkit

Appropriate antibioticsAppropriate antibioticsInsulinInsulinEarly goalEarly goal--directed therapy directed therapy →→fluids, blood, fluids, blood, vasoactivevasoactive agents, agents, inotropesinotropesSteroidsSteroidsActivated protein CActivated protein C

Early goalEarly goal--directed therapy in the treatment directed therapy in the treatment of severe sepsis and septic shockof severe sepsis and septic shock

Rivers et al. NEJM 2001;345:1368Rivers et al. NEJM 2001;345:1368--77.77.

Sepsis: peripheral Sepsis: peripheral vasodilationvasodilation, intravascular , intravascular volume depletion, myocardial depression, volume depletion, myocardial depression, and increased metabolismand increased metabolism–– OO22 demand > delivery, tissue hypoxia, shock; can demand > delivery, tissue hypoxia, shock; can

lead to lead to multiorganmultiorgan failure and deathfailure and death

Resuscitation needed; past studies of Resuscitation needed; past studies of ““hemodynamichemodynamic optimization” enrolled optimization” enrolled patients up to 72hrs after patients up to 72hrs after admadm. to ICU . to ICU (neutral)(neutral)

Early goalEarly goal--directed therapydirected therapyRivers et al. NEJM 2001;345:1368Rivers et al. NEJM 2001;345:1368--77.77.

Standard Standard hemodynamichemodynamic assessment assessment (physical findings, VS, central venous (physical findings, VS, central venous pressure, urinary output) fails to detect pressure, urinary output) fails to detect persistent global tissue hypoxiapersistent global tissue hypoxia

“Golden hours” before serious illness may “Golden hours” before serious illness may elapse early onelapse early on

11°° efficacy outcome: inefficacy outcome: in--hospital mortalityhospital mortality

Rivers et al.Rivers et al.

Results: primary outcomeResults: primary outcome

Rivers conclusionsRivers conclusions

Early, aggressive resuscitation is Early, aggressive resuscitation is very importantvery important

Practically speaking, we may not Practically speaking, we may not always have access to all parameters always have access to all parameters measured (they were equipped in ER measured (they were equipped in ER for early goalfor early goal--directed therapy)directed therapy)

InotropesInotropes and and vasoactivevasoactive drugsdrugs3,4,53,4,5

--refractory sepsis (refractory sepsis (splanchnicsplanchniccirculation)circulation)--powerful powerful vasopressorvasopressor, , inotropeinotrope

--start at 0.01 start at 0.01 ugug/kg/min /kg/min ((ββ1, 1, ββ2 2 →→ αα1)1)

EpinephrineEpinephrine

--vasopressorvasopressor; natural hormone ; natural hormone deficient in septic shockdeficient in septic shock

0.01 0.01 –– 0.04 units/min 0.04 units/min (V1 receptors)(V1 receptors)

VasopressinVasopressin

--inotropeinotrope, vaso, vasodilatordilator--improves CO; may need comboimproves CO; may need combo

2 2 –– 20 20 ugug/kg/min (/kg/min (ββ11, , ββ2)2)

DobutamineDobutamine

--vasopressorvasopressor--often used if arrhythmias with often used if arrhythmias with DA or NEDA or NE

0.5 0.5 –– 9 9 ugug/kg/min (/kg/min (αα1)1)PhenylephrinePhenylephrine

--primarily used as a primarily used as a vasopressorvasopressor((inotropicinotropic effects)effects)

2 2 -- 20 20 ugug/min (/min (ββ1,1,αα11))NorepinephrineNorepinephrine“LEVOPHED” “LEVOPHED”

--inotropeinotrope, , vasopressorvasopressor--low doses not proven to low doses not proven to prevent/treat renal failureprevent/treat renal failure

<3 <3 ugug/kg/min (DA)/kg/min (DA)3 3 -- 10 10 ugug/kg/min (DA, /kg/min (DA, ββ11))>10 >10 ugug/kg/min (/kg/min (ββ1,1,αα11))

DopamineDopamine

Common useCommon useCommon doseCommon doseDrugDrug

Sepsis toolkitSepsis toolkit

Appropriate antibioticsAppropriate antibioticsInsulinInsulinEarly goalEarly goal--directed therapy directed therapy →→fluids, blood, fluids, blood, vasoactivevasoactive agents, agents, inotropesinotropesSteroidsSteroidsActivated protein CActivated protein C

Effect of Treatment with Low Doses of Effect of Treatment with Low Doses of Hydrocortisone and Hydrocortisone and FludrocortisoneFludrocortisone on on Mortality in Patients with Septic ShockMortality in Patients with Septic Shock

AnnaneAnnane et al. et al. JAMA 2002;288:862JAMA 2002;288:862--7171

Sepsis is an inflammatory processSepsis is an inflammatory process–– high doses/short courses not high doses/short courses not favourablefavourable

Observation: severe sepsis may be Observation: severe sepsis may be associated with relative adrenal associated with relative adrenal insufficiency insufficiency –– replacement therapy proposed to treat replacement therapy proposed to treat

septic shockseptic shock

AnnaneAnnane et al.et al.

11°° objective: objective: –– to assess whether low doses of to assess whether low doses of

corticosteroids improve 28corticosteroids improve 28--day survival day survival in patients with septic shock and in patients with septic shock and relative adrenal insufficiencyrelative adrenal insufficiency

MethodsMethodsAnnaneAnnane et al.et al.

Very sick patients: site of infection, Very sick patients: site of infection, hyper or hypothermia, HR > 90, SBP < hyper or hypothermia, HR > 90, SBP < 90 mmHg, 90 mmHg, oliguriaoliguria, lactate > 2, mech. , lactate > 2, mech. ventilationventilation

CorticotropinCorticotropin stimulation test: blood stimulation test: blood immediately before, 30 & 60 min postimmediately before, 30 & 60 min post–– Take highest Take highest cortisolcortisol level as responselevel as response–– Increase of at least 250 Increase of at least 250 nmolnmol/L = /L =

responderresponder

MethodsMethodsAnnaneAnnane et al.et al.

Intervention:Intervention:–– Hydrocortisone 50mg IV q6h x 7 daysHydrocortisone 50mg IV q6h x 7 days–– FludrocortisoneFludrocortisone 50ug NG daily x 7 days50ug NG daily x 7 days

Note: Steroid equivalencies (CPS)Note: Steroid equivalencies (CPS)

12512510mg10mgFludrocortisoneFludrocortisone

115mg5mgPrednisonePrednisone

2220mg20mgHydrocortisoneHydrocortisone

MineralocorticoidMineralocorticoidequivalencyequivalency

AntiAnti--inflammatory inflammatory dosedose

ResultsResultsAnnaneAnnane et al.et al.

Sepsis toolkitSepsis toolkit

Appropriate antibioticsAppropriate antibioticsInsulinInsulinEarly goalEarly goal--directed therapy directed therapy →→ fluids, fluids, blood, blood, vasoactivevasoactive agents, agents, inotropesinotropesSteroidsSteroidsActivated protein C (Activated protein C (XigrisXigris®®))

Efficacy and Safety of Recombinant Human Efficacy and Safety of Recombinant Human Activated Protein C for Severe SepsisActivated Protein C for Severe Sepsis66

Bernard et al. NEJM 2001;344:699Bernard et al. NEJM 2001;344:699--709709

Severe sepsis (=sepsis with acute Severe sepsis (=sepsis with acute organ dysfunction) results from organ dysfunction) results from generalized inflammatory and generalized inflammatory and procoagulantprocoagulant response to infectionresponse to infection

Inflammatory and Inflammatory and procoagulantprocoagulant host host responses are closely relatedresponses are closely related–– Cytokines can activate coagulation and Cytokines can activate coagulation and

inhibit inhibit fibrinolysisfibrinolysis–– Thrombin can stimulate inflammatory Thrombin can stimulate inflammatory

pathwayspathways

PurposePurposeBernard et al.Bernard et al.

Activated protein C (APC) has Activated protein C (APC) has antithromboticantithrombotic, , antiinflammatoryantiinflammatory and and profibrinolyticprofibrinolytic propertiesproperties

11°° Outcome: death from any cause Outcome: death from any cause 28 days after the initiation of the 28 days after the initiation of the infusioninfusion

InterventionInterventionInclusion: source of infection, 3/4 SIRS Inclusion: source of infection, 3/4 SIRS criteria, and dysfunction of criteria, and dysfunction of ≥≥ 1 organ or 1 organ or system within 24 hours of study system within 24 hours of study enrollmentenrollment

IV IV drotrecogindrotrecogin alfaalfa (APC) 24ug/kg/hr x (APC) 24ug/kg/hr x 96h or placebo96h or placebo

Protocol did not standardize approach to Protocol did not standardize approach to abxabx, fluids , fluids pressorspressors, , ventilatoryventilatory supportsupport

ResultsResults

Conclusions and issuesConclusions and issuesTreatment with APC reduces mortality in Treatment with APC reduces mortality in patients with severe sepsis and may be patients with severe sepsis and may be associate with risk of bleedingassociate with risk of bleeding

Adverse events: serious bleeding higher in Adverse events: serious bleeding higher in APC group; only during infusion period and APC group; only during infusion period and primarily if predisposed (GI ulcer, primarily if predisposed (GI ulcer, pltplt <30)<30)

Optimal duration not known (? incomplete Optimal duration not known (? incomplete resolution of resolution of procoagulantprocoagulant state after 96 hrs)state after 96 hrs)

SummarySummary

All 3 studies (early goalAll 3 studies (early goal--directed directed therapy, steroid replacement, and therapy, steroid replacement, and APC) showed a MORTALITY benefitAPC) showed a MORTALITY benefit

Interventions for Mr. C Interventions for Mr. C -- abxabx

Apr 8: continued on pipApr 8: continued on pip--tazotazo (began (began Apr 1)Apr 1)–– added added vancovanco briefly (?line infection)briefly (?line infection)

Apr 9: ischemic bowel Apr 9: ischemic bowel →→ OROR–– 1m small bowel 1m small bowel resectedresected–– jejunostomyjejunostomy and mucus stoma createdand mucus stoma created–– added added fluconazolefluconazole

Interventions for Mr. C Interventions for Mr. C -- abxabx

Apr 10: “GNB” in sputumApr 10: “GNB” in sputum–– ∆∆’d pip’d pip--tazotazo to to meropenemmeropenem

Apr 11: Apr 11: KlebsiellaKlebsiella pneumoniaepneumoniae–– R: amp, R: amp, cefazolincefazolin, , cefuroximecefuroxime, pip, pip--tazotazo–– S: S: ceftriaxoneceftriaxone, , ciprocipro, gent, , gent, SeptraSeptra, ,

meropenemmeropenem (called lab)(called lab)

Did not narrow spectrum with new Did not narrow spectrum with new abdoabdo processprocess

HAP/VAP GuidelinesHAP/VAP Guidelines

For your For your refencerefence::

American Thoracic Society. Guidelines for American Thoracic Society. Guidelines for the Management of Adults with Hospitalthe Management of Adults with Hospital--acquired, Ventilatoracquired, Ventilator--associated, and associated, and HealthcareHealthcare--associated Pneumonia. Am J associated Pneumonia. Am J RespirRespir CritCrit Care Med 2005;171:388Care Med 2005;171:388––416.416.UHN Antibiotic Handbook 2007UHN Antibiotic Handbook 2007

Mr. C Mr. C –– GlycemicGlycemic ControlControl

ICU insulin ICU insulin nomogramnomogram

Mr. C Mr. C –– goalgoal--directed therapydirected therapy

Fluid resuscitation, Fluid resuscitation, norepinephrinenorepinephrine, , transfusions; ultimately transfusions; ultimately intubatedintubatedComplicated by ORComplicated by ORCVP 11, MAP 59, SaOCVP 11, MAP 59, SaO2 2 94%, ScvO94%, ScvO2249%49%

General monitoring of NE: General monitoring of NE: hypertension, arrhythmias, ischemic hypertension, arrhythmias, ischemic injury (injury (ieie/ extremities, gut)/ extremities, gut)

Mr. C Mr. C –– steroids steroids CosyntropinCosyntropin stimulation test April 8stimulation test April 8Began hydrocortisone 50mg IV q6hBegan hydrocortisone 50mg IV q6h–– StimStim test results later reported (test results later reported (cortisolcortisol

levels):levels):1209h: 1507 1209h: 1507 nmolnmol/L/L1250h: 1813 1250h: 1813 nmolnmol/L/L1330h: 2010 1330h: 2010 nmolnmol/L/L

**Responder or not? What to do **Responder or not? What to do with hydrocortisone?with hydrocortisone?

No No fludrocortisonefludrocortisone

Steroid monitoringSteroid monitoring

ShortShort--term term txtx::–– PsychosisPsychosis–– ↑↑ Blood sugarBlood sugar–– HypokalemiaHypokalemia–– Sodium and fluid retention; HTN, CHFSodium and fluid retention; HTN, CHF–– ↑↑ WBCWBC–– Gastric irritation, ulcerationGastric irritation, ulceration–– ……

Mr. C Mr. C –– APC APC Inclusion criteria likely met April 8:Inclusion criteria likely met April 8:

Serious infection managed with supportive careSerious infection managed with supportive careCommitment to aggressive Commitment to aggressive txtx by team/familyby team/family3 or more SIRS criteria3 or more SIRS criteriaNew onset (<48h) sepsisNew onset (<48h) sepsis--induced organ induced organ dysfunction of at least 2 organs (CV, acidosis)dysfunction of at least 2 organs (CV, acidosis)No absolute contraindicationsNo absolute contraindications

April 9 to OR (CI if concern for active major April 9 to OR (CI if concern for active major bleeding)bleeding)Relative CI’sRelative CI’s

Need for therapeutic anticoagulation (on heparin Need for therapeutic anticoagulation (on heparin for valves)for valves)

OutcomeOutcomeSlow improvements until April 12, then:Slow improvements until April 12, then:–– bowel bowel →→ stomas dusky, stomas dusky, ØØ BS, BS, ØØ output, output,

foul smellingfoul smelling–– became hypothermic (T 34.9became hypothermic (T 34.9°°CC))–– WBC WBC ↑↑ 17.717.7–– lactate lactate ↑↑ 3.7, pH 7.333.7, pH 7.33–– platelet drop (186 platelet drop (186 →→ 94), INR 94), INR ↑↑ 1.301.30–– CVP 1, ScvOCVP 1, ScvO22 54% 54% –– levophedlevophed ↑↑ 20ug/min to maintain BP20ug/min to maintain BPWithdrawal of care April 13Withdrawal of care April 13

ReferencesReferences1.1. Rivers E, Nguyen B, Rivers E, Nguyen B, HavstadHavstad S et al. Early goalS et al. Early goal--directed therapy directed therapy

in the treatment of severe sepsis and septic shock. NEJM in the treatment of severe sepsis and septic shock. NEJM 2001;345:13682001;345:1368--77.77.

2.2. AnnaneAnnane D, D, SebilleSebille V, V, CharpentierCharpentier C, et al. Effect of treatment C, et al. Effect of treatment with low doses of hydrocortisone and with low doses of hydrocortisone and fludrocortisonefludrocortisone on on mortality in patients with septic shock. JAMA 2002;288:862mortality in patients with septic shock. JAMA 2002;288:862--71.71.

3.3. DipiroDipiro, JT. Ch 23: Use of , JT. Ch 23: Use of VasopressorsVasopressors and and InotropesInotropes in the in the Pharmacotherapy of Shock in Pharmacotherapy of Shock in Pharmacotherapy 6Pharmacotherapy 6thth EditionEdition. . 2005 The McGraw2005 The McGraw--Hill Companies, Inc. New York, NY.Hill Companies, Inc. New York, NY.

4.4. Beale R, Beale R, HollenbergHollenberg S, Vincent JL, S, Vincent JL, ParrilloParrillo J. J. VasopressorVasopressor and and inotropicinotropic support in septic shock: An evidencesupport in septic shock: An evidence--based review. based review. CritCrit Care Med 2004;32(Suppl.);S455Care Med 2004;32(Suppl.);S455--65.65.

5.5. BassiBassi G, G, RadermacherRadermacher P, P, CalziaCalzia E. E. CatecholaminesCatecholamines and and Vasopressin During Critical Illness. Vasopressin During Critical Illness. EndocrinolEndocrinol MetabMetab ClinClin N Am N Am 2006;35:8392006;35:839--57.57.

6.6. Bernard G, Vincent JL, Bernard G, Vincent JL, LaterreLaterre PF, et al. Efficacy and Safety of PF, et al. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. Recombinant Human Activated Protein C for Severe Sepsis. NEJM 2001;344:699NEJM 2001;344:699--709709