脓毒血症的抗生素治疗(英文)Antibiotics-for-Severe-Sepsis-and-Se.ppt

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1、Early Goal Directed Therapy and Antibiotics for SepsisFaheem Guirgis MDObjectives:nDefine SIRS,Sepsis,and Septic ShocknEpidemiology,PathophysiologynHistory of EGDTnRefining EGDTnSurviving Sepsis CampaignnImplementing EGDT in the EDnFocus on AbxnGOAL:Clinically Useful,Evidence-Based Guidelines for tr

2、eating your Septic ptsDefinitionsnSIRS?HR 90,Temp 38 C,RR 20,WBC 12nSepsis?SIRS+Suspected InfxnnSevere Sepsis?+End Organ DysfunctionnSeptic Shock Hypotension(not responsive to IVF)Change in ManagementSevere Sepsis and ShocknThe Problem Mortality of Severe Sepsis-28.6%,or 215,000 pts nationally(Angus

3、 et al,Crit Care Med 2001;29:13031310)Septic Shock has lower survival rate of 43.7%(Kumar et al,Chest.2009 Nov;136(5):1237-48.)and mortality of 40 to 70%OkaySo we know the mortality is highMODSnMulti-Organ Dysfunction SyndromeHost inflammatory response triggered by physical,chemical,or infectious in

4、sult.Inflammatory response generates noxious substances(proteolytic enzymes,O2 radicals)to fight insult.When host loses protective mechanisms inflammations results in host injury which triggers more inflammation MODS.Our Goal=Prevention of MODSWhen does MODS occur?nUpstairs in the ICUnDeath usually

5、occurs later in the course of disease even if they present in septic shocknSeptic patients rarely die in the ED,but if they dothey CRASHTrying to Reduce Mortality from Severe Sepsis and Septic ShocknShoemaker WC surgical intensivist from CalifornianFocused on hemodynamic resuscitation in the critica

6、lly illnTheorized that adjustment of physiologic parameters predicted oxygenation and would affect mortalityPublished over 40 Papers on Hemodynamic Resuscitation in Septic PatientsnShoemaker WC,Appel PL,Kram HB,Waxman K,Lee TS.Prospective trial of supranormal values of survivors as therapeutic goals

7、 in high-risk surgical patients.Chest 1988;94:1176-1186.nShoemaker WC,Kram HB,Appel PL,Fleming AW.The efficacy of central venous and pulmonary artery catheters and therapy based upon them in reducing mortality and morbidity.Arch Surg 1990;125:1332-1339.nVelmahos GC,Demetriades D,Shoemaker WC,et al.E

8、ndpoints of resuscitation of critically injured patients:normal or supranormal?A prospective randomized trial.Ann Surg.2000 Sep;232(3):409-18.nShoemaker WC,et al.Hemodynamic and oxygen transport monitoring to titrate therapy in septic shock.New Horiz.1993 Feb;1(1):145-59.nShoemaker WC,et al.Sequence

9、 of physiologic patterns in surgical septic shock.Crit Care Med.1993 Dec;21(12):1876-89.nShoemaker WC,et al.Temporal hemodynamic and oxygen transport patterns in medical patients.Septic shock.Chest.1993 Nov;104(5):1529-36.The PointGoal Directed Therapy is NOT a New ConceptRivers,et al2001nSIRS crite

10、ria(2 of 4)plus lactate 4 and/or Systolic BP 65UO 0.5ml/kg/hrSVO2 70%How Did They Do it?Meet Criteria Central Line and A-line placedPan-culturedAntibiotics per physician discretion(well talk about this later)RCT-263 Pts 130 EGDT,133 Standard TxnBaseline Characteristics-HR,CVP,MAP,SVO2,Lactate,Base D

11、eficit,Arterial pHDifferences In TreatmentnFirst 6 hrs-EGDT group received increased IVF,PRBCs,and Inotropes.Use of Pressors and Mech Vent were equal.nOver 72 hrs no difference in total IVF or Inotropes;Standard Tx group received more Pressors,Mech.Vent.,PA Cath but less PRBCs.Differences During Tre

12、atmentnGoals?SVO2 70 94.9%for EGDT,60.2%Standard Tx(p.001)CVP,MAP,UO goals 99.2%EGDT,86.1%Standard Tx(p 2 SIRS criteria+suspected infxn and lactate 4nBut Dont Forget!How Do We Do It?nBoard to ICU immediatelynObtain Blood Cultures(1C)and culture indwelling catheters(48 hrs)nAntibiotics within the 1st

13、 hour for severe sepsis(1D)and septic shock(1B)How Do We Do It ContdnDont need to be hypotensive to place Central line Place Central line early!nAttain goals of EGDT CVP 8-12,MAP 65,UO 0.5 mL/kg/hr,SvO2 70%nPressors if MAP 65 Norepinephrine and Dopamine(1C)are initial pressors of choicenSome evidenc

14、e that Norepinephrine may be superiorHow Do We Do It ContdnAdd fixed dose Vasopressin at.03 U/min if persistently hypotensive(2B)nIf SVO2 70,transfuse PRBCs to Hct of 30(2C)nIf SVO2 still 70,add Dobutamine to max of 20 mcg/kg/minnFoley catheter to measure UOHow Do We Do It ContdnConsider intravenous

15、 hydrocortisone for adult septic shock when hypotension responds poorly to adequate fluid resuscitation and vasopressors(2C)nACTH stimulation test is NOT recommended to identify the subset of adults with septic shock who should receive hydrocortisone(2B)n Hydrocortisone is preferred to dexamethasone

16、(2B)Surviving Sepsis CampaignnFunding from Eli Lilly?Yes;Wont discuss APCnGuidelines accepted by ACEP and SCCMAntibiotics for SepsisAvoiding PitfallsWest Side at Montefioren62 yo NH pt w/multiple medical problems,alert but demented NH note says“r/o sepsis”nT102F,HR 115,R 24,BP 90/50,Sat 94%on 2L NCn

17、2 Peripheral IVs placed,IVF boluses started,Tylenol givenWest Side at MontefiorenLactate=6nChemistry still pendingnCXR PendingnFoley placed minimal urinePitfall No.1“I SHOULD WAIT FOR A SOURCE BEFORE STARTING ANTIBIOTICS”How to Kill Your PatientnWithhold the Antibiotics for a whileSurviving Sepsis 2

18、008“Begin IV antibiotics as early as possible and always within the first hour of recognizing severe sepsis(1D)and septic shock(1B).”Kumar et al,CCM 2006 2100 pts-Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was asso

19、ciated with a survival rate of 79.9%.Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%.Kumar et al,Intens Care Med 2009-4,532 pts-A longer duration to antimicrobial therapy was also associated an increase in incidenc

20、e of AKI AND AKI was associated with significantly higher odds of death What Causes this Delay?“Excuse me ID,Id like approval for Zosyn please”Pitfall No.2“I MUST KNOW THE CREATININE BEFORE GIVING THE FIRST DOSE OF ABX”Does Kidney Function Matter for Initial Antibiotic Dosing?Surviving Sepsis 2008 “

21、All patients should receive a full loadingdose of each antimicrobial.”Kidney FunctionnPea,et al Retrospective Study in which therapeutic drug monitoring(TDM)results were analyzed in critically ill patients over a 7-year periodn“the percentage of patients receiving appropriate loading was inversely c

22、orrelated with their degree of renal function,decreasing from 60.4%in the case of normal renal function to 26.8%and 5.5%,respectively,in cases of moderately or totally impaired renal function.”nAccording to Pea,et al“the need for appropriate loading at the commencement of therapy is independent of t

23、he patients renal function”and that“in the absence of loading,several days may be required to achieve therapeutically effective concentrations”nThese patients had suboptimal concentrations persisting at Day 4 of treatmentKidney FunctionnZimmerman,et al Retrospective review of kidney function and Van

24、c levels-No statistically significant correlation between nephrotoxicity and initial serum creatinine,days of hospital stay,or days of vancomycin therapy.Pitfall No.3UNDERESTIMATING THE IMPORTANCE OF THE LOADING DOSEHydrophilic vs Lipophilic*Pea F,Viale P.Bench-to-bedside review:Appropriate antibiot

25、ic therapy in severe sepsis and septic shock-does the dose matter?Crit Care.2009;13(3):214.Epub 2009 Jun 10.(Vanc,Teicoplanin)Hydrophilic Abxn=PCNs,Aminoglycosides,CephalosporinsnDiffuse more slowly into deep-seated sites of infxn(PNA,intra-abdominal,etc)=Loading Dose is MORE Important!Hydrophilic A

26、bxnAffected by Volume of DistributionnTarget plasma concentration(Ct)that is achieved with the first dose-loading dose(LD)-depends solely on the volume of distribution(Vd)of the drugnCt=LD/VdnSo if you increase your Vd,you decrease the chance of achieving the optimal CtPts in Septic Shock have high

27、Vd because of third spacing(capillary permeability)and IV hydration!Hydrophilic AbxnThis means thatTarget plasma conc(Ct)may be reduced when using the standard LD=“Third Spacing Phenomenon”nJoukhadar and company showed that the peak levels of piperacillin after a single standard 4 g IV dose were sev

28、eral fold lower,either in plasma or in the interstitium of soft tissues,in patients with septic shock than in correctly matched healthy volunteers.*nInitial peak plasma concentrations of gentamycin and tobramycin following a 3 mg/kg LD in critically ill surgical patients with life-threatening Gram n

29、egative infections were found to be lower than desired(8.3 mg/l)in about half of the patients and greater LDs-by at least 20%to 25%-were advocated.*Joukhadar C,Frossard M,Mayer BX,Brunner M,Klein N,Siostrzonek P,Eichler HG,Muller M:Impaired target site penetration of beta-lactams may account for the

30、rapeutic failure in patients with septic shock.Crit Care Med 2001,29:385-391.*Dorman T,Swoboda S,Zarfeshenfard F,Trentler B,Lipsett PA:Impact of altered aminoglycoside volume of distribution on the adequacy of a three milligram per kilogram loading dose.Critical Care Research Group.Surgery 1998,124:

31、73-78.The Full LDs of-lactams,aminoglycosides or glycopeptides(Vanc,Teicoplanin)should be administered to ensure optimal exposure at the infection site whenever treatment is begun in patients with severe sepsis or septic shock.Lipophilic Abxn=Macrolides,Quinolones,Rifampin,LinezolidnLess affected by

32、 Vd,act on intracellular pathogens,hepatically metabolizednConsider adding one of these in deep tissue infection(eg Moxi for PNA,Cipro for abdominal infxns)Pitfall No.4“NARROWER COVERAGE IS FINE IF I HAVE A SUSPECTED SOURCE”Inadequate Antibiotics A Clean Killn“Restriction of antibiotics as a strateg

33、y to reduce the development of antimicrobial resistance or to reduce cost is not an appropriate initial strategy in this patient population.”Surviving Sepsis Guidelines 2008nIbrahim,et al,Chest 2000 147 pts w/inadequate antibiotics(29.9%)for bloodstream infections.Hospital mortality 61.9%versus 28.4

34、%in group with adequate antibiotics.nFraser et al,AJM 2006-Inappropriate initial antibiotic treatment was prescribed in 36%of patients(N=319).All-cause 30-day mortality rates were 20.1%(N=64)and 11.8%(N=68)in patients who received inappropriate and appropriate treatment,respectively.nKumar et al,Che

35、st 2009-5,715 patients with septic shock in three countries.Overall mortality 43.7%.The survival rates after appropriate and inappropriate initial therapy were 52.0%and 10.3%,respectively(odds ratio OR,9.45;95%CI,7.74 to 11.54;p 0.0001)Pitfall No.5INAPPROPRIATE SELECTION OF ANTIBIOTICS FOR PNEUMONIA

36、Pneumonia Break it down!nCAP Not hospitalized or in ECF for 14 days prior andDoes not meet the criteria for HCAPnHCAP Hospitalization for 2 days or longer w/in last 90 days From ECFAnyone who received IV Abx,chemotherapy,or wound care within last 30 daysAnyone on HDnHAP new infection occurring 48 ho

37、urs after hospital admissionnVAP-pneumonia occurring 48 to 72 hours after endotracheal intubationNazarian,et al.Clinical Policy:Critical Issues in the Management of AdultPatients Presenting to the Emergency Department With Community-Acquired Pneumonia.Ann Emerg Med.2009;54:704-731.CAP IDSA,ATS Guide

38、linesInpt Resp Quinolone or B-lactam+AzithroICU-B-lactam+Azithro or Resp QuinolonePseudomonas Anti-Pseudo PCN+(Cipro/Levo or AG and Azithro or Antipneumococcal Quinolone)Pneumonia IDSA,ATS GuidelinesTreat HCAP,HAP and VAP the samenIDSA 2005 guidelines pts admitted after recent hospitalization or fro

39、m NH,Dialysis etc should be treated for MDR pathogensnMDR Pathogens-P.aeruginosa,E.coli,Klebsiella pneumoniae and Acinetobacter,MRSA*Taken from 2005 IDSA/ATS GuidelinesEmpiric Coverage for HCAP,HAP and VAPnAnti-Pseudomonal+Vanc/LinezolidnAlso,cover Legionella w/a Macrolide or a Quinolone if suspecte

40、d*Taken from 2005 IDSA/ATS GuidelinesAbx Dosing*Taken from 2005 IDSA/ATS GuidelinesDouble Gram Negative Coverage?nSafdar,et al Meta-analysis of 3077 pts across 17 studies 2 out 17 studies found benefit,1 found increased mortality,14 showed no benefit*nProspective Studies were separated out and still

41、 no benefitnCochrane Review of 7586 pts comparing PCN+AG to PCN alone for Gram neg sepsis No mortality benefit*Safdar,et al.Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia?A meta-analysis.Lancet Infect Dis.2004 Aug;4(8):519-27.*Paul M,et al.Beta lactam antibiotic

42、 monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.Cochrane Database Syst Rev.2006 Jan 25;(1):CD003344.Why No Benefit?nLikely due to increased potency of newer antibioticsnStudies that showed benefit were older studies comparing older drugsnSurviving Sepsis Guid

43、elines No evidence for double coverage butWhat about Pseudomonas?nRecently hospitalized patientsnNH patientsnVent dependent patientsnIndwelling tubes/linesDouble Pseudomonas Coverage?nSafdar,et al Same study in 3077 pts found benefit to double coverage when Pseudomonas was isolatednSurviving Sepsis

44、Guidelines double cover if suspecting Pseudomonas(2D)Neutropenic PatientsnIDSA double gram neg coverage is recommended*nSurviving Sepsis Guidelines double gram neg coverage is recommended(2D)*Hughes WT,Armstrong D,Bodey GP,et al:2002 Guidelines for the use of antimicrobial agents in neutropenic pati

45、ents with cancer.Accessed July 10,2007Klastersky J:Management of fever in neutropenic patients with different risks of complications.Clin Infect Dis 2004;39(Suppl 1):S32S37In SummaryThe Evidence SaysnRecognize Severe Sepsis and Septic ShocknGet Appropriate Antibiotics on board earlynBroad coverage r

46、ecommendednFull LD regardless of kidney functionnDouble coverage if suspected pseudomonas or neutropenic ptsIn SummaryThe Evidence SaysnPlace the Central Line early!nBelieve in EGDT Achieve your goalsnR/O CRASH Diagnoses Asplenic PNA,Liver dz,Meningiococcemia,Nec Fasc,Neutropenic fever,MRSA PNAnSour

47、ce control and R/O Surgical Problems SAVE A LIFE!Whats With this 4 Hour Time to Abx?nHouck,et al retrospective study of 13,771 pts w/CAP decreased 30 day mortality,in-hospital mortality,and Hospital LOS in pts Tx in 4 hrsnWeaknesses post-hoc 4 hr cut-off chosen;More pts in 4 hr cut-off grp received

48、appropriate abx;Same mortality in any of the pts treated between 3 and 8 hrs*nThis does not apply to sepsis in which case pts should receive prompt Abx w/in 1 hr*Nazarian,et al.Clinical Policy:Critical Issues in the Management of Adult Patients Presenting to the Emergency Department With Community-Acquired Pneumonia.Ann Emerg Med.2009;54:704-731.