naeem ali, md assistant professor director, medical intensive care unit the ohio state university...

Naeem Ali, MD

Assistant Professor

Director, Medical Intensive Care Unit

The Ohio State University Medical Center

2008

Sepsis: still misunderstood after all these years...

Ann Surg. 1886 April; 3(4): 321–333.

Objectives

1. To identify the severe sepsis syndrome

2. To prioritize treatments for patients with septic shock

3. To understand the current controversies and upcoming studies in severe sepsis

• What is sepsis?

• How common is sepsis?

• What causes sepsis?

• How do you treat sepsis?

Pre and post-discharge

Hospitalization

24 hours

6 hours

Recognition

Resuscitation

Initial Management

Maintenance

Recovery

What is sepsis?

I shall not today attempt further to define thekinds of material…[b]ut I know it when I see it…

•Justice Potter Stewart, 1964

RECOGNITION

• 84yo Caucasian male with h/o Parkinson’s and remote history of gun shot wound

• Presents to the ED from his residence with altered mental status, fever and smelly urine

• Temp 102.3 P 118 R 32 BP 78/34 • 84% SPO2

Karol Wojtyla (1920-2005)

Sepsis: Defining a Disease Continuum

A clinical response arising from a nonspecific insult, including 2 of the following:• Temperature 38oC or 36oC• HR 90 beats/min• Respirations 20/min• WBC count 12,000/mm3 or

4,000/mm3 or >10% immature neutrophils

SIRS = Systemic Inflammatory Response Syndrome

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

Adapted from: Bone RC, et al. Chest 1992;101:1644Opal SM, et al. Crit Care Med 2000;28:S81

?


SIRS = Systemic Inflammatory Response Syndrome

SIRS with a presumed or

confirmed infectious process


Adapted from: Bone RC, et al. Chest 1992;101:1644Opal SM, et al. Crit Care Med 2000;28:S81

• 84yo Caucasian male with h/o Parkinson’s and remote history of gun shot wound

• Presents to the ED from his residence with altered mental status, fever and smelly urine

• Temp 102.3 P 118 R 32 BP 78/34 • 84% SPO2

Does he have sepsis?

Is he sick or not sick?


Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207


Sepsis with 1 sign of organ failure

Cardiovascular (refractory hypotension)

RenalRespiratoryHepaticHematologicCNSMetabolic acidosis

TachycardiaTachycardiaHypotensionHypotensionAltered CVPAltered CVP

Altered PAOPAltered PAOP

OliguriaOliguriaAnuriaAnuria

CreatinineCreatinine

PlateletsPlatelets PT/APTTPT/APTT Protein CProtein C D-dimerD-dimer

JaundiceJaundice EnzymesEnzymes AlbuminAlbumin

PT PT

Altered Altered ConsciousnessConsciousness

ConfusionConfusionPsychosisPsychosis

TachypneaTachypnea

PaOPaO22 <70 mm Hg <70 mm Hg

SaOSaO22 <90% <90%

PaOPaO22/FiO/FiO22 300 300

Neurologic

Respiratory

Hepatic

Renal

Coagulation

Cardiovascular

Wheeler et al. NEJM 1999; 340: 207-14

Sepsis:Timing of Organ Failures

Mortality increases with increasing organ failure

Hebert et al. Chest 1993;104:230-5


Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207


Sepsis with 1 sign of organ failure

Cardiovascular (refractory hypotension)

RenalRespiratoryHepaticHematologicCNSMetabolic acidosis

TachycardiaTachycardiaHypotensionHypotensionAltered CVPAltered CVP

Altered PAOPAltered PAOP

OliguriaOliguriaAnuriaAnuria

CreatinineCreatinine

PlateletsPlatelets PT/APTTPT/APTT Protein CProtein C D-dimerD-dimer

JaundiceJaundice EnzymesEnzymes AlbuminAlbumin

PT PT

Altered Altered ConsciousnessConsciousness

ConfusionConfusionPsychosisPsychosis

TachypneaTachypnea

PaOPaO22 <70 mm Hg <70 mm Hg

SaOSaO22 <90% <90%

PaOPaO22/FiO/FiO22 300 300

Neurologic

Respiratory

Hepatic

Renal

Coagulation

Cardiovascular

Mortality

Septic Shock

53-63%

20-53%Severe Sepsis300,000

7-17%Sepsis

400,000

Incidence

Balk, R.A. Crit Care Clin 2000;337:52

Mortality Increases in Septic Shock Patients

How sick is he?

• WBC 30K with 20% bands

• Shock

• ABG 7.20/28/42/15 on 100% FiO2

• Platelets normal, INR 1.7

• LFTs normal

• BUN 32, Creatinine 1.9

• Delirious

This seems kind of bad.Glad it doesn’t happen much

RECOGNITION

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Angus DC, et al. JAMA 2000;284:2762-70.Angus DC, et al. Crit Care Med 2001;29:1303-10.

Severe Sepsis is common and

increasing in incidence

Severe Sepsis is common and

increasing in incidence

800

1,000

1,200

1,400

1,600

1,800

2001 2025 2050

Year

300

400

500

600S

epsi

s C

ase

s (x

103)

To

tal U

S P

op

ula

tion

(m

illio

n)

Severe Sepsis Cases

US Population

0

50

100

150

200

250

300

Severe Sepsis Stroke Breast Cancer Lung Cancer

IncidenceMortality

Rat

e pe

r 10

0,00

0 P

opul

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*Calculated data based on information compiled from the American Heart Association, American Cancer Society, National Center for Health Statistics and the US Census Bureau (1995-1999)

Severe Sepsis Stroke Breast CA Lung CA

Severe Sepsis Case

s

US Population

At LEAST the 10th Leading

Cause of Death

Mortality rate is decreasing but more are dying overall

• 1979 – 1984 – 27.8%– 43,579– 21.9/100,000 population

• 1995 – 2000 – 17.9%– 120,491– 43.9/100,000 population

• Mortality dropped most with Gram+ infections

Martin et al, NEJM 2003:348;1546-54.

MORTALITY

215,000 deaths a year in US

~590 Deaths Every day

Severe Sepsis Costs a Lot

Angus et al, Crit Care Med 2001; 29: 1303-10

•Average LOS 19.6 days•Average cost $22,100/case

•Total national hospital cost was $16.7 BILLION$16.7 BILLION•52.3% of costs in those >64 years

•30.8% total costs in those >74 years

Age

Average per-patient cost

Total national cost

OSUMC-Specific Data:January 1995 – August 26, 2006

• ICD9 codes for sepsis – NPV 80%, PPV 90%

• 12,518 admissions– 2.9 admissions/day

• 2856 deaths (23%)– One death every 1.5

days

• Average hospital LOS 17.5 days– 219,246 hospital days– 18,807 hospital days/yr

• 4725 with ICU stay (37.7%)– Average ICU LOS 11.7 days– 4742 ICU days/yr– 13 ICU beds with septic

patients/day• Total charges of

$1,028,675,176.43• Yearly charge of $88,241,231.35• Average charge of $82,175.68

This doesn’t sound that greatMaybe we should figure out what

causes this

Risk factors and Pathogenesis

Response to Stimulus•Inflammation

•Immunosuppression•Coagulopathy

•Mitochondrial dysfunction

Susceptible Host•Co-morbidities

•Age•Genetic polymorphisms

The Pathogenesis of Sepsis

Infectious Agents•Endotoxin/LPS•Lipopeptides

•Lipoteichoic acid•DNA

•Flagellin

Infection Inflammation Cellular Failure Organ Failure MOSF Death

A Theoretical Picture of Sepsis

Infection factors

Cytokines

Dysregulated Coagulation

Apoptosis

Mitochondrial Dysfunction

Metabolic Derangement

Poor Perfusion

Host factors

Microvascular Blood Flow

Normal Septic shock

De Backer et al, AJRCCM 2002; 166:98-104.

Organisms Found in Sepsis

Only about 30% have a positive blood cultureMartin et al, NEJM 2003:348;1546-54.

Fungi

Gram positive bacteria

Gram negative bacteria

Sites of Infection in Severe Sepsis


AGE


Extremes of age are associated with higher incidence

Cases

Incidence

OR if >65 is 13!

Martin, G. S. et al. N Engl J Med 2003;348:1546-1554

Population-Adjusted Incidence of Sepsis, According to Sex, 1979-2000

659,935 cases240.4 cases/100K

Annual Increase of 8.7%

38.8% sever

e sepsis

MEN (OR 1.3)

WOMEN

Martin et al N Engl J Med 2003;348:1546-1554

Race is associated with Incidence of Sepsis

Highest incidence Youngest age at onset

Highest mortality was among

African-American men

Highest incidence Youngest age at onset

Highest mortality was among

African-American men

White

Other

Black

OR 1.9

Important Patient-Related Factors

CO-MORBIDITIES

•Immunosuppression•AIDS (OR 5.1)•Cancer

•Any (OR 2.8)•Solid (OR 1.8)•Liquid (OR 15.7)

•Cirrhosis (OR 2.6)•Alcohol dependence (OR 1.5)•Chronic catheters (OR 64)•TRANSFUSIONS (OR 6.0)•Diabetes

GENETIC PRE-DISPOSITION

•Innate immune system

•Cytokine genes

•Other polymorphisms

TREATMENT

All right, all right, I get it.But isn’t that guy dying on us?

Shouldn’t we do something about that?

Failed Strategies • High-dose corticosteroids• PLA2 inhibitors• Pentoxifylline• Prostaglandin E1• Ketoconazole• Anti-endotoxin antibodies• Anti-TNF antibodies• Interleukin-1 receptor antagonist• Tissue factor pathway inhibitor

Treatment of InflammationTreatment of Inflammation

American Association of Critical-Care NursesAmerican College of Chest PhysiciansAmerican College of Emergency PhysiciansCanadian Critical Care SocietyEuropean Society of Clinical Microbiology and Infectious DiseasesEuropean Society of Intensive Care MedicineEuropean Respiratory SocietyInternational Sepsis ForumJapanese Association for Acute MedicineJapanese Association of Intensive Care MedicineSociety of Critical Care MedicineSociety of Hospital MedicineSurgical Infection SocietyWorld Federation of Societies of Intensive and Critical Care MedicineGerman Sepsis SocietyLatin America Sepsis Institute

RESUSCITATION PHASEGOAL: Keep him alive for 24 hours

• A – Airway– Intubation

• B – Breathing– Mechanical ventilation

• C – Circulation– IV access– Goal directed therapy– Steroids

Treat the Infection

Antibiotics – Go BIG early

•Every hour in delay of appropriate atbx = 7.6% lower survival

•Median time to appropriate atbx = 6h

Kumar et al. Crit Care Med 2006; 34: 1589-96.

• Get cxs before atbx if WON’T DELAY ATBX• ≥2 blood cxs (≥1 peripheral, 1 from each

CVC), other sites as indicated• Begin IV atbx ASAP and ALWAYS within 1h of

recognizing severe sepsis/septic shock• Use broad-spectrum atbx, ≥1 agents with

activity against likely bugs and penetration into site

• Reassess choices daily• Duration can probably be 7-10d• Stop atbx if not infected

Surviving Sepsis Campaign Level 1 Recs re ATBX

N Engl J Med 2001;345:1368

CVP: central venous pressureMAP: mean arterial pressureScvO2: central venous oxygen saturation

How do you know when you’ve addressed “C” in How do you know when you’ve addressed “C” in ABCs?ABCs?

Early Goal-Directed Early Goal-Directed TherapyTherapy

49.2%

33.3%

0

10

20

30

40

50

60

Standard Therapy n=133

EGDTn=130

P = 0.01*

28-day Mortality

Early Goal-Directed Therapy Results

N Engl J Med 2001;345:1368-77.

Limitations

• Single center and a single group of investigators – Is it generalizable?

• Is the whole protocol necessary? – Blood?– Inotropes? – Continuous ScvO2 monitoring?

ProCESS Study Design

• Three Arms– Usual Care Arm– Early Goal-Directed Therapy (EGDT) Arm– Protocolized Standard Care (PSC) Arm

• 24 Centers, 1935 Subjects – 645 in each arm

ProCESS Objectives

• Aim 1: Clinical Efficacy– Is any protocolized care superior to usual care?– Is EGDT arm superior to PSC arm?

• Aim 2: Mechanisms of Action – Inflammation– Cellular hypoxia– Oxidative stress– Coagulation / thrombosis

• Aim 3: Costs and Cost-effectiveness

A Comparison of Albumin and Saline for FluidResuscitation in the Intensive Care Unit

NEJM 2004; 350: 2247-56

•N=6997

•Randomized to NS or 4% albumin for any resuscitation

•In patients with severe sepsis:

•30.7% mortality with albumin

•35.3% mortality with NS

Heart Rate Contractility Vasoconstrict

Dopamine

Low dose 0 0 1-

Med dose 2+ 2+ 0

Hi dose 2+ 2+ 3+

Dobutamine 1+ 4+ 1-

Norepinephrine 2+ 2+ 4+

Phenylephrine 2- 0 4+

Epinephrine 4+ 4+ 4+

Vasopressin 1- 1- 4+

Vasopressors In Septic Shock

Original Article Vasopressin versus Norepinephrine Infusion in

Patients with Septic Shock

James A. Russell, M.D., Keith R. Walley, M.D., Joel Singer, Ph.D., Anthony C. Gordon, M.B., B.S., M.D., Paul C. Hébert, M.D., D. James Cooper, B.M., B.S., M.D., Cheryl L. Holmes, M.D., Sangeeta Mehta, M.D., John T. Granton, M.D., Michelle M.

Storms, B.Sc.N., Deborah J. Cook, M.D., Jeffrey J. Presneill, M.B., B.S., Ph.D., Dieter Ayers, M.Sc., for the VASST Investigators

N Engl J MedVolume 358(9):877-887

February 28, 2008

Study Overview

• In a multicenter trial, 778 patients with septic shock who were being treated with catecholamine vasopressors were randomly assigned to either norepinephrine or vasopressin in addition to open-label vasopressors

Kaplan-Meier Survival Curves for Patients Who Underwent Randomization and Infusion

Russell JA et al. N Engl J Med 2008;358:877-887

Rates and Risks of Death from Any Cause According to the Severity of Shock

Russell JA et al. N Engl J Med 2008;358:877-887

• Begin resuscitation immediately if low bp or lactate >4• Goals include:

– CVP 8-12 (higher if on vent)– MAP ≥65– UO ≥0.5mL/kg/h– CvO2 ≥70% or SvO2 ≥65%

• Use crystalloids or colloids• Give “fluid challenge” and monitor response – at least 1L

crystalloid or 300mL colloid over 30min• Reduce fluid administration if filling pressures rise without

hemodynamic improvement• Norepi or dopa are initial pressors of choice• DON’T use “renal dose” dopamine• Insert an a-line in those on pressors• Use dobutamine in patients with myocardial dysfxn (elevated

filling pressures, low CO)• Do not increase CI to supranormal levels

Surviving Sepsis Campaign Level 1 Recs re Resuscitation and Pressors

Corticosteroids

Placebo

Steroids

N=300

•Sick

•Sbp<90 for 1h despite vasopressors

•Mechanical ventilation

•Another organ failure

•Treated within 8h

•77% unresponsive to ACTH

•ACTH unresponsiveness predicted benefitAnnane, D. JAMA, 2002; 288 (7): 868.

Not steroids again….

N=499

•Less Sick

•Sbp<90 or vasopressors despite fluids

•Hypoperfusion or OF due to sepsis

•Treated within 72h (77% within 12h)

•47% unresponsive to ACTH

•ACTH unresponsiveness did NOT predict benefit

•25% had misclassification of ACTH response

Sprung. NEJM, 2008; 358: 111.

• Use hydrocortisone dose ≤300mg/d• Do not use steroids without shock

LEVEL 2• Consider steroids if hypotension poorly responsive to fluids and

pressors• ACTH stim test DOES NOT identify those who will benefit from

steroids• Fludrocortisone may be included• Steroids may be weaned

Surviving Sepsis Campaign Level 1 Recs re Steroids

INITIAL MANAGEMENT PHASEGOAL: Let’s get him better

• Supportive care– Identify organ failures– Customize antibiotics

based on cultures/sensitivities

– Additional diagnostic testing

– Goals of care discussions

• Specific care– Drotrecogin alfa

(activated) [Xigris®]– Lung protective

ventilation– Conservative fluid

management

APC Links Coagulation & Inflammation

N Engl J Med 2001;344:699-709.

Coagulation cascade

InflammationInhibition of fibrinolysis

Bernard GR, et al. N Engl J Med 2001;344:699-709.

Drotrecogin Alfa (Activated) Significantly Reduced Mortality in PROWESS

Drotrecogin Alfa (Activated) Significantly Reduced Mortality in PROWESS

00 77 1414 2121 2828

70 70

80 80

90 90

100 100

Days from Start of Infusion to DeathDays from Start of Infusion to Death

Per

cen

t S

urvi

vors

Per

cen

t S

urvi

vors

P=.006 (stratified log-rank test)00

Placebo(n=840)

Drotrecogin alfa (activated) (n=850)

6% Absolute 6% Absolute mortality mortality differencedifference

NNT = 17NNT = 17

Patient selection is important

• “High risk” of dying– APACHE II score >24

• NNT = 8

– Multi-organ failure• NNT=14

– Respiratory failure• NNT=17

– Shock• NNT=15

– 40% probability of dying?

• “Low risk” of bleeding– serious bleeding: 2 to 5%– ICH: 0.2 to 0.5%– Bleeding associated with:

• Instrumentation

• Trauma

• Thrombocytopenia (<30)

• Meningitis

• INR >3

Management of Acute Lung Injury and the Acute Respiratory Distress

Syndrome…to be continued

MAINTENANCE AND RECOVERYGOAL: Don’t kill him

• Avoid nosocomial complications– Ventilator-induced

lung injury– Get tubes and lines

out of him– Clots and bleeding

• Avoid new infection– Hand washing– Semi-recumbent

position– Get tubes and lines out

of him– Minimize transfusions

GlucoseSICU

Managed by Endo fellow

Conventional Treatment

(180-200)

Intensive Treatment

(80-110)

ICU Deaths 63/783 (8.0%) 35/765 (4.6%) 0.005

Hospital Deaths 85/783 (10.9%) 55/765 (7.2%) 0.01

Hypoglycemia (<40) 6/783 (0.8%) 39/765 (5.1%) <0.0001

MICU

Managed by RN protocol

Conventional Treatment

(180-200)

Intensive Treatment

(80-110)

ICU Deaths 162/605 (26.8%) 144/595 (24.2%) 0.31

Hospital Deaths 242/605 (40.0%) 222/595 (37.3%) 0.33

Hypoglycemia 19/605 (3.1%) 111/595 (18.7%) <0.0001

Van den Berghe et al, NEJM 2001; 345:1359 and 2006;354:449.

Glucose, Part Deux

p=0.36

Brunkhorst et al., NEJM 2008; 358:125-39.

•Severe sepsis

•80-100 v 180-200

•Stopped after 488 pts

•Hypoglycemia

•17.0% v 4.1%

•Hypoglycemia was assoc with death HR 3.3

The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

Probability of Survival and Odds Ratios for Death, According to Treatment Group

• Target Hgb 7-9• Do not use epo to treat sepsis-assoc anemia• Do not use antithrombin• Use sedation protocol with goals• Use intermittent bolus sedation or daily awakenings• Avoid neuromuscular blockers• Use IV insulin to control hyperglycemia• Provide glucose and monitor every 1-2h if receiving IV insulin• Interpret with caution POC glucose• Do not use HCO3 to treat lactic acidosis with pH>7.15• Use UFH or LMWH prophylaxis• Use mechanical device when heparin contraindicated• Use H2blocker or PPI for stress ulcer prophylaxis• Discuss goals of care and set realistic expectations

Surviving Sepsis Campaign Level 1 Recs re Maintenance

What is it?• SIRS + Infection = Sepsis• Sepsis + Organ Failure = Severe Sepsis• Sepsis + Shock = Septic Shock• Mortality increases with more organ failure

How common is it?

• Significant mortality – Top 10 cause of death• Significant morbidity• Significant cost• Is getting more common

What causes it?• Inflammation• Coagulopathy• Blood flow• Cell failure• Organ failure• Death

• Host factors• Infection factors• Nosocomial

complications– VAP/BSI– Ventilators

How do you treat it?

• Recognition• Resuscitation = ABCs + Atbx

– Goal-directed therapy

• Initial Management – Customize care– Drotrecogin alfa (activated)

• Maintenance– Avoid complications

• Transfusion• Sedation• Ventilation

• For questions/comments, please feel free to contact me:

[email protected]• 292-6933

naeem ali, md assistant professor director, medical intensive care unit the ohio state university...

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