SEPSIS

George C. Mejicano, MD Department of Medicine University of Wisconsin

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.

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 in US annually Annual cost in US estimated at $17 billion

Sepsis: Rising Incidence

Between 1979 and 1987, the incidence rose 139% (from 73.6 to 175.9 cases per 100,000 persons) in the USA Striking increase in incidence expected in the next decade

Sepsis: Mortality
Study
Brun-Buisson, 1995 Abraham, 1997

Condition
Severe sepsis Severe sepsis Septic shock Severe sepsis/ Septic shock Septic shock

Mortality Rate (N)

56-60% (1052) 36% (78) 42% (62) 38% (4356)

Natanson, 1998

Friedman, 1998

49.7% (10,694)

Sepsis: An Urgent Healthcare Challenge

More than 1400 people lose their lives to severe sepsis every day.

Sepsis Does Not Equal Shock

Shock is defined as a decrease in tissue perfusion that when untreated can lead to abnormal cellular function and multisystem organ failure.
Colletti, Dew, & Goulart [Crit Care Nursing Clin, 1993]

Classification of Shock (1)

Cardiogenic Shock z Myopathic shock z Mechanical shock z Left ventricular outflow obstruction z Arrhythmic shock

Classification of Shock (2)

Extracardiac Obstructive Shock z Pericardial tamponade z Constrictive pericarditis z Massive pulmonary embolism z Severe pulmonary hypertension z Coarctation of the aorta

Classification of Shock (3)

Hypovolemic Shock
z z

Hemorrhage Fluid depletion

Classification of Shock (4)

Distributive Shock
z z z z z

Septic shock Poisons & toxins (i.e. overdose) Anaphylaxis Neurogenic shock Endocrinologic shock

Septic Shock: Definitions

Bacteremia Sepsis Sepsis Syndrome Early Septic Shock Refractory Septic Shock Multiorgan Dysfunction Syndrome (aka Multisystem Organ Failure)

Bacteremia Bacteria in the blood

Sepsis
Clinical Evidence of Infection
PLUS
Hyperthermia/Hypothermia (> 38.4 or < 35.6) Tachycardia (> 90 beats / minute) Tachypnea (> 20 breaths / minute) WBC count abnormalities

Non-infectious Causes of Fever

Drugs (e.g. salicylates and cocaine) Thyroid storm Neuroleptic malignant syndrome Heat injury and heat stroke Injury to hypothalamus secondary to trauma or stroke

Sepsis Syndrome
Sepsis
PLUS Evidence of Altered Organ Perfusion:
z z z z

Acute mental status changes Hypoxemia (pO2 / FIO2 < 280) Oliguria (< 0.5 ml / kg / hour) Serum lactate (above normal limits)

Early Septic Shock

Sepsis Syndrome
PLUS
Hypotension or Poor Capillary Refill that Responds Promptly to IV Fluids and/or Pharmacologic Interventions

Refractory Septic Shock

Sepsis Syndrome
PLUS Hypotension or Poor Capillary Refill
that Lasts for More than 1 hour Despite IV Fluids and Pharmacologic Intervention and Requires Vasopressor Support

Multiorgan Dysfunction Syndrome (MODS)

Any Combination of:
z

z z z z

Disseminated Intravascular Coagulation (DIC) Adult Respiratory Distress Syndrome (ARDS) Acute Renal Failure Acute Hepatic Failure Acute CNS Dysfunction

MODS: Differential Diagnosis

Septic shock Pancreatitis Trauma Vasculitis Heat stroke Drugs or toxins

Systemic Inflammatory Response Syndrome (SIRS)

Focal Infection Bacteremia

Sepsis

Sepsis Syndrome

Early Septic Shock

Refractory Septic Shock

MODS

Death

Progression to Shock in Patients with Sepsis

Shock develops in 40% of patients with sepsis Onset of sepsis portends a poor prognosis
z z z

13% mortality for the sepsis syndrome 28% mortality for patients presenting with shock 43% mortality for patients who developed shock after presenting with the sepsis syndrome

Organisms and Septic Shock

Can be caused by infection with bacteria, fungi, viruses, or parasites In 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

Emergence of GNRs as a Cause of Septic Shock

Antibiotic pressure on the normal flora Increased use of invasive devices in a hostile nosocomial environment Large numbers of immunocompromised hosts (e.g. AIDS, transplants, cancer, burns, major surgery, etc.)

Sepsis: Site of Infection

Lung Abdomen or Pelvis Urinary Tract Soft Tissue Other Unknown (45-50%) (15-20%) (5-10%) (2-5%) (1-3%) (>15%)

455 patients enrolled in sepsis study [NEJM 1997; 336:912-8]

Mechanisms of Septic Shock

Excess fluid loss Myocardial failure >>> Cholera, dengue, toxic shock syndrome >>> Diphtheria, Chagas, viral myocarditis, & meningococcemia >>> Endocarditis >>> Gram negative sepsis

Valvular destruction Decreased venous return

Host Factors in Septic Shock

Asplenia Cirrhosis Alcoholism Diabetes Steroids Neutropenia T-cell dysfunction Encapsulated organisms Vibrio & Salmonella Klebsiella & S. pneumoniae Pseudomonas & Mucor TB, fungi, herpes viruses GNRs & Aspergillus Listeria, Salmonella, Mycobacteria, CMV, HSV, and VZV

Toxins and Septic Shock

Some Gram positive cocci produce exotoxins (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

Pathogenesis of Septic Shock

GNR Lipopolysaccharide (Lipid A from cell membrane) Coagulation Cascade Primary Mediators (TNF, IL-1, IFN) Complement Activation

Kallikrein-Kinin Stimulation

Endothelial Cell & PMN Activation

PMN Activation

Vasodilation & Endothelial Damage

Secondary Mediators (PAF, IL's, Eicosanoids)

Capillary Leak & Endothelial Damage

Shock

MODS

Death

Onset and Resolution of Organ Failure in Sepsis

Clinical Parameter Shock Oliguria CNS dysfunction Acute lung injury ARDS Onset & Duration (Day 0 to Day 2) (Day 0-1 to Day 3) (Day 1 to Day 7) (Day 0 to Day 9) (Day 1 to Day 11)

[NEJM 1999; 340:207-14]

Possible Therapeutic Targets

Nidus of infection Bloodstream invasion >>> Eradicate organisms >>> Neutralize microbial toxins Host defense system >>> Modulate host activated response Mediators released >>> Modulate host response Shock and multiorgan >>> Provide ICU support failure

Anti-endotoxin Therapy
Several thousand patients have now been included 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 ]

What About Steroids? It is now widely accepted that glucocorticoids should not be used in the treatment of septic shock.
Bone [Clin Micro Rev, 1993]

Steroids May Help!

300 adults with septic shock were randomized to either get placebo or the following:
z z

Hydrocortisone 50 mg IV q 6 hours x 7 days and Fludrocortisone 50 g po q day x 7 days

In patients with relative adrenal insufficiency, the group that received the steroids did better as 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]

Management of Septic Shock

Hemodynamic support with IV fluids and vasoactive agents (i.e. pressors) Oxygen and mechanical ventilation Remove the source of infection Broad spectrum antimicrobials

Drugs for Circulatory Support (Pressors)

Epinephrine (alpha and beta agonist)
z

5-20 micrograms/minute 5-20 micrograms/minute 2-20 micrograms/kg/minute 5-15 micrograms/kg/minute 2-20 micrograms/minute

Norepinephrine (alpha >> beta agonist)

z

Dopamine (dopamine and beta agonist)

z

Dobutamine (beta agonist)

z

Phenylephrine (alpha agonist)

z

Supportive Measures
Transfusions
PRBCs when hemoglobin < 7 z Platelets occasionally needed
z

Albumin
z

Consider giving when serum albumin < 2

Removing the Source is Key!

Abscess
z z

Percutaneous drainage Incision and drainage Incision and debridement Pull lines (complete catheter exchange) Consider removing artificial joints, valves, and/or grafts Remove or bypass obstruction (e.g. stones)

Necrotic tissue
z

Foreign bodies
z z z

Antibiotics and Septic Shock

Prompt administration of broad spectrum antimicrobial agents has been shown to decrease mortality by 50% in septic shock Most deaths due to septic shock occur in the first two days; moreover, culture data is typically not available for 24 - 48 hours; therefore, empiric therapy is required!

Empiric Antibiotic Therapy in Septic Shock

Antipseudomonal beta-lactam

PLUS
Antipseudomonal aminoglycoside, OR Antipseudomonal fluoroquinolone

Antipseudomonal Beta-lactams
Cefepime (Maxipime)
z

2 g IV q 12 hours (q 8 hours if neutropenic) 2 g IV q 8 hours 3 g IV q 4 hours 3 g IV q 4 hours

Ceftazidime (Fortaz, Tazidime, Ceptaz)

z

Ticarcillin (Ticar)
z

Piperacillin (Pipracil)
z

Antipseudomonal Beta-lactams
Ticarcillin-clavulanate (Timentin)
z

3.1 g IV q 4 hours 3.375 g IV q 4 hours 500 mg IV q 6 hours 1 g IV q 8 hours

Piperacillin-tazobactam (Zosyn)
z

Imipenem-cilastatin (Primaxin)
z

Meropenem (Merrem)
z

Antipseudomonal Agents (non beta- lactams)

Ciprofloxacin (Cipro IV)
z

400 mg IV q 12 hours 5 mg/kg IV q 24 hours

Tobramycin (Tobrex, Nebcin)

z

Pharmacodynamics
For beta-lactam antibiotics, efficacy depends on the time that the concentration of the drug is over the minimum inhibitory concentration (MIC)
z z

Critical parameter is time above MIC Giving higher amounts of the drug wont help, its the frequency that is important

In contrast, both aminoglycosides and fluoroquinolones are concentration dependent killers

z z z

Critical parameter is AUC/MIC High concentrations will improve efficacy Post-antibiotic effect is seen

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)

Repletion: A Novel Approach to Sepsis

Endogenous modulators of homeostasis are consumed and become deficient in sepsis Deficiency of modulators correlates with mortality and may predict sepsis progression Repletion of endogenous modulators (e.g. activated Protein C) in patients with sepsis may restore homeostasis and decrease morbidity and mortality

Conclusions (1)
Sepsis causes major morbidity & mortality Shock does not equal sepsis Host 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 cell membrane products such as Lipid A

Conclusions (2)
Pathogenesis of septic shock has suggested numerous targets for very promising, but so far unrewarding, therapeutic modalities Hemodynamic support, O2 and mechanical ventilation, prompt removal of the source of infection, and empiric broad spectrum antibiotics continue to be the best therapy for sepsis, the sepsis syndrome, & septic shock

Thank you!