Sepsis 2003

7/27/2019 Sepsis 2003

1/50

SEPSIS

George C. Mejicano, MDDepartment of Medicine

University of Wisconsin

7/27/2019 Sepsis 2003

2/50

Case:

A 71 year old woman who is dialysis dependent

presents with fevers, malaise, and hypotension(SBP < 70 mm Hg). Blood cultures grow out

S. aureus. Within hours of admission, she goes

into florid pulmonary edema and enzymes are

positive for an acute myocardial infarction. The

next day her liver enzymes skyrocket and she

goes into DIC. The patient dies within 48 hours

of presentation despite aggressive intervention.

7/27/2019 Sepsis 2003

3/50

Epidemiology of Sepsis

Major cause of morbidity and mortality

Leading cause of death in non-coronary ICUs

13th leading cause of death in the US overall

More than 700,000 cases of severe sepsis inUS annually

Annual cost in US estimated at $17 billion

7/27/2019 Sepsis 2003

4/50

Sepsis: Rising Incidence

Between 1979 and 1987, the incidence

rose 139% (from 73.6 to 175.9 cases

per 100,000 persons) in the USAStriking increase in incidence expectedin the next decade

7/27/2019 Sepsis 2003

5/50

Sepsis: Mortality

Study Condition Mortality Rate (N)

Brun-Buisson, 1995 Severe sepsis 56-60% (1052)

Abraham, 1997 Severe sepsis 36% (78)Septic shock 42% (62)

Natanson, 1998 Severe sepsis/ 38% (4356)

Septic shock

Friedman, 1998 Septic shock 49.7% (10,694)

7/27/2019 Sepsis 2003

6/50

Sepsis: An UrgentHealthcare Challenge

More than 1400 people

lose their lives to severe

sepsis every day.

7/27/2019 Sepsis 2003

7/50

Sepsis Does Not Equal Shock

Shock is defined as a decrease in tissue

perfusion that when untreated can lead

to abnormal cellular function andmultisystem organ failure.

Colletti, Dew, & Goulart

[Crit Care Nursing Clin, 1993]

7/27/2019 Sepsis 2003

8/50

Classification of Shock (1)

Cardiogenic Shockz Myopathic shock

z Mechanical shock

z Left ventricular outflow obstruction

z Arrhythmic shock

7/27/2019 Sepsis 2003

9/50


Extracardiac Obstructive Shockz Pericardial tamponade

z

Constrictive pericarditisz Massive pulmonary embolism

z Severe pulmonary hypertension

z Coarctation of the aorta

7/27/2019 Sepsis 2003

10/50


Hypovolemic Shock

z Hemorrhage

z Fluid depletion

7/27/2019 Sepsis 2003

11/50


Distributive Shock

z Septic shock

z Poisons & toxins (i.e. overdose)z Anaphylaxis

z Neurogenic shock

z Endocrinologic shock

7/27/2019 Sepsis 2003

12/50

Septic Shock: Definitions

BacteremiaSepsis

Sepsis Syndrome

Early Septic Shock

Refractory Septic Shock

Multiorgan Dysfunction Syndrome(aka Multisystem Organ Failure)

7/27/2019 Sepsis 2003

13/50

Bacteremia

Bacteria in the blood

7/27/2019 Sepsis 2003

14/50

Sepsis

Clinical Evidence of InfectionPLUS

Hyperthermia/Hypothermia (> 38.4 or < 35.6)

Tachycardia (> 90 beats / minute)

Tachypnea (> 20 breaths / minute)

WBC count abnormalities

7/27/2019 Sepsis 2003

15/50

Non-infectiousCauses of Fever

Drugs (e.g. salicylates and cocaine)

Thyroid storm

Neuroleptic malignant syndromeHeat injury and heat stroke

Injury to hypothalamus secondary totrauma or stroke

7/27/2019 Sepsis 2003

16/50

Sepsis SyndromeSepsis

PLUS

Evidence of Altered Organ Perfusion:z Acute mental status changes

z Hypoxemia (pO2 / FIO2 < 280)

z Oliguria (< 0.5 ml / kg / hour)z Serum lactate (above normal limits)

7/27/2019 Sepsis 2003

17/50

Early Septic Shock

Sepsis SyndromePLUS

Hypotension or Poor Capillary Refill

that Responds Promptly to IV Fluids

and/or Pharmacologic Interventions

7/27/2019 Sepsis 2003

18/50


Sepsis Syndrome

PLUS

Hypotension or Poor Capillary Refill

that Lasts for More than 1 hour Despite

IV Fluids and Pharmacologic Interventionand Requires Vasopressor Support

7/27/2019 Sepsis 2003

19/50

Multiorgan DysfunctionSyndrome (MODS)

Any Combination of:z Disseminated Intravascular Coagulation (DIC)

z Adult Respiratory Distress Syndrome (ARDS)z Acute Renal Failure

z Acute Hepatic Failure

z Acute CNS Dysfunction

7/27/2019 Sepsis 2003

20/50

MODS: Differential Diagnosis

Septic shockPancreatitis

Trauma

Vasculitis

Heat stroke

Drugs or toxins

7/27/2019 Sepsis 2003

21/50

Systemic InflammatoryResponse Syndrome (SIRS)

Death

MODS


Early Septic Shock

Sepsis Syndrome

Sepsis

Bacteremia

Focal Infection

7/27/2019 Sepsis 2003

22/50

7/27/2019 Sepsis 2003

23/50

Organisms and Septic ShockCan be caused by infection with

bacteria, fungi, viruses, or parasitesIn the pre-antibiotic era, septic shock

was typically caused by Gram positive

bacteria such as S. pneumoniae,S. aureus, and S. pyogenes

More recently, Gram negative bacteria

have become the most common pathogens

7/27/2019 Sepsis 2003

24/50

Emergence of GNRs asa Cause of Septic Shock

Antibiotic pressure on the normal floraIncreased use of invasive devices in a

hostile nosocomial environmentLarge numbers of immunocompromised

hosts (e.g. AIDS, transplants, cancer,

burns, major surgery, etc.)

7/27/2019 Sepsis 2003

25/50

Sepsis: Site of Infection

Lung (45-50%)Abdomen or Pelvis (15-20%)

Urinary Tract (5-10%)

Soft Tissue (2-5%)Other (1-3%)

Unknown (>15%)

455 patients enrolled in sepsis study

[NEJM 1997; 336:912-8]

7/27/2019 Sepsis 2003

26/50

Mechanisms of Septic Shock

Excess fluid loss

Myocardial failure

Valvular destruction

Decreased venousreturn

>>> Cholera, dengue,

toxic shock syndrome

>>> Diphtheria, Chagas,

viral myocarditis, &

meningococcemia>>> Endocarditis

>>> Gram negative sepsis

7/27/2019 Sepsis 2003

27/50

Host Factors in Septic Shock

Asplenia Encapsulated organisms

Cirrhosis Vibrio & Salmonella

Alcoholism Klebsiella & S. pneumoniae

Diabetes Pseudomonas & Mucor

Steroids TB, fungi, herpes virusesNeutropenia GNRs &Aspergillus

T-cell dysfunction Listeria, Salmonella,

Mycobacteria, CMV,HSV, and VZV

7/27/2019 Sepsis 2003

28/50

Toxins and Septic Shock

Some Gram positive cocci produceexotoxins (e.g. S. aureus & TSST-1)

All Gram negative rods have endotoxin,

comprised of a highly conserved

lipopolysaccharide (lipid A) in their

bacterial cell membrane

7/27/2019 Sepsis 2003

29/50

7/27/2019 Sepsis 2003

30/50

Pathogenesis of Septic Shock

GNR Lipopolysaccharide

(Lipid A from cell membrane)

Vasodilation &

Endothelial Damage

Kallikrein-KininStimulation

CoagulationCascade

Secondary Mediators

(PAF, IL's, Eicosanoids)

Shock

Death

MODS

Endothelial Cell& PMN Activation

Primary Mediators(TNF, IL-1, IFN)

Capillary Leak &

Endothelial Damage

PMNActivation

ComplementActivation

7/27/2019 Sepsis 2003

31/50

Onset and Resolution ofOrgan Failure in Sepsis

Clinical Parameter Onset & Duration

Shock (Day 0 to Day 2)

Oliguria (Day 0-1 to Day 3)CNS dysfunction (Day 1 to Day 7)

Acute lung injury (Day 0 to Day 9)

ARDS (Day 1 to Day 11)

[NEJM 1999; 340:207-14]

7/27/2019 Sepsis 2003

32/50

Possible Therapeutic Targets

Nidus of infection

Bloodstream invasion

Host defense system

activatedMediators released

Shock and multiorgan

failure

>>> Eradicate organisms

>>> Neutralize microbialtoxins

>>> Modulate host

response>>> Modulate host

response

>>> Provide ICU support

7/27/2019 Sepsis 2003

33/50

Anti-endotoxin Therapy

Several thousand patients have now beenincluded in clinical trials of new agents

for sepsis... none of the interventions has

has shown efficacy in prospectively defined

study groups...

Abraham & Raffin

[JAMA 1994 ]

7/27/2019 Sepsis 2003

34/50

What About Steroids?

It is now widely accepted thatglucocorticoids should not be

used in the treatment of septicshock.

Bone [Clin Micro Rev, 1993]

7/27/2019 Sepsis 2003

35/50

Steroids May Help!300 adults with septic shock were randomizedto either get placebo or the following:

z Hydrocortisone 50 mg IV q 6 hours x 7 days and

z Fludrocortisone 50 g po q day x 7 days

In patients with relative adrenal insufficiency,

the group that received the steroids did betteras measured by 28 day survival

z 73 deaths (63%) in the placebo arm compared

to 60 deaths (53%) in the treatment arm

[JAMA 2002; 288(7):862-871]

7/27/2019 Sepsis 2003

36/50

Management of SepticShock

Hemodynamic support with IV fluids

and vasoactive agents (i.e. pressors)

Oxygen and mechanical ventilationRemove the source of infection

Broad spectrum antimicrobials

7/27/2019 Sepsis 2003

37/50

Drugs for Circulatory

Support (Pressors)Epinephrine (alpha and beta agonist)z 5-20 micrograms/minute

Norepinephrine (alpha >> beta agonist)z 5-20 micrograms/minute

Dopamine (dopamine and beta agonist)z 2-20 micrograms/kg/minute

Dobutamine (beta agonist)

z 5-15 micrograms/kg/minutePhenylephrine (alpha agonist)z 2-20 micrograms/minute

7/27/2019 Sepsis 2003

38/50

Supportive Measures

Transfusions

z PRBCs when hemoglobin < 7

z Platelets occasionally neededAlbumin

z Consider giving when serum albumin < 2

7/27/2019 Sepsis 2003

39/50

Removing the Source is Key!

Abscessz Percutaneous drainagez Incision and drainage

Necrotic tissue

z Incision and debridementForeign bodiesz Pull lines (complete catheter exchange)

z Consider removing artificial joints, valves, and/orgrafts

z Remove or bypass obstruction (e.g. stones)

7/27/2019 Sepsis 2003

40/50

Antibiotics and SepticShockPrompt administration of broad spectrum

antimicrobial agents has been shown to

decrease mortality by 50% in septic shock

Most deaths due to septic shock occur inthe first two days; moreover, culture data

is typically not available for 24 - 48 hours;therefore, empiric therapy is required!

7/27/2019 Sepsis 2003

41/50

Empiric AntibioticTherapy in Septic Shock

Antipseudomonal beta-lactam

PLUSAntipseudomonal aminoglycoside, OR

Antipseudomonal fluoroquinolone

7/27/2019 Sepsis 2003

42/50

AntipseudomonalBeta-lactams

Cefepime (Maxipime)z 2 g IV q 12 hours (q 8 hours if neutropenic)

Ceftazidime (Fortaz, Tazidime, Ceptaz)

z 2 g IV q 8 hoursTicarcillin (Ticar)z 3 g IV q 4 hours

Piperacillin (Pipracil)z 3 g IV q 4 hours

7/27/2019 Sepsis 2003

43/50

AntipseudomonalBeta-lactams

Ticarcillin-clavulanate (Timentin)z 3.1 g IV q 4 hours

Piperacillin-tazobactam (Zosyn)

z 3.375 g IV q 4 hoursImipenem-cilastatin (Primaxin)z 500 mg IV q 6 hours

Meropenem (Merrem)z 1 g IV q 8 hours

7/27/2019 Sepsis 2003

44/50

Antipseudomonal Agents(non beta- lactams)

Ciprofloxacin (Cipro IV)

z 400 mg IV q 12 hours

Tobramycin (Tobrex, Nebcin)z 5 mg/kg IV q 24 hours

7/27/2019 Sepsis 2003

45/50

PharmacodynamicsFor beta-lactam antibiotics, efficacy depends onthe time that the concentration of the drug is

over the minimum inhibitory concentration (MIC)z Critical parameter is time above MIC

z Giving higher amounts of the drug wont help,its the frequency that is important

In contrast, both aminoglycosides and fluoro-quinolones are concentration dependent killersz Critical parameter is AUC/MIC

z High concentrations will improve efficacy

z Post-antibiotic effect is seen

7/27/2019 Sepsis 2003

46/50

Georges Favorite

Cefepime 2 g IV q 8 hours

and

Tobramycin 5 mg/kg IV q 24 hours

(but substitute ciprofloxacin 400 mg IV q 12 hours

for tobramycin if renal insufficiency is present)

7/27/2019 Sepsis 2003

47/50

Repletion: A NovelApproach to Sepsis

Endogenous modulators of homeostasis areconsumed and become deficient in sepsis

Deficiency of modulators correlates with

mortality and may predict sepsis progressionRepletion of endogenous modulators (e.g.activated Protein C) in patients with sepsis

may restore homeostasis and decreasemorbidity and mortality

7/27/2019 Sepsis 2003

48/50

Conclusions (1)Sepsis causes major morbidity & mortality

Shock does not equal sepsisHost factors are important predictors of

which patients will progress to septic shock

SIRS (the systemic inflammatory response

syndrome) is caused by a complex cascade

that begins with exposure to bacterial cellmembrane products such as Lipid A

7/27/2019 Sepsis 2003

49/50

Conclusions (2)Pathogenesis of septic shock has suggested

numerous targets for very promising, but sofar unrewarding, therapeutic modalities

Hemodynamic support, O2 and mechanical

ventilation, prompt removal of the source of

infection, and empiric broad spectrum anti-

biotics continue to be the best therapy forsepsis, the sepsis syndrome, & septic shock

7/27/2019 Sepsis 2003

50/50

Thank you!

Documents

Sepsis 2003