FROM SYSTEMIC INFLAMMATORY RESPONSE

SYNDROME (SIRS) TO BACTERIAL SEPSIS WITH

SHOCK

General Goal: To know the major causes of this disease progression, understand the basic
processes that cause the progression from SIRS to septic shock, and describe the basic
treatment plan in caring for these patients.

Specific Educational Objectives: The student should be able to:

1. recite the most likely causes of sepsis based on the knowledge of the initial site of infection
and where these organisms usually come from (sources of infection).

2. recite the most common causes of anaerobic sepsis and pediatric sepsis.

3. recite the factors that increase the risk of a patient getting sepsis and the patient types most
like to get sepsis.

4. recite the major sites of infection that can lead to sepsis.

5. describe the sequence of events that lead to septic shock (know the microbial triggers and
the host mediators that led to septic shock). A basic understanding of what types of shock are
caused by sepsis.

6. describe the differences between the following: SIRS, sepsis, severe sepsis, septic shock,
and MODS.

7. Recite the 3 treatment priorities and understand their importance.

Reading: F.S. Southwick, Infectious Diseases in 30 Days, Chapter 2: The Sepsis Syndrome,
2003, McGraw Hill.

Lecture: Dr. Neal R. Chamberlain

Resources:

eMedicine Online: Septic Shock, by J Stephan Stapczynski, MD, Chair, Associate

Professor, Department of
Emergency Medicine, University of Kentucky Chandler Medical Center (last revised
0/01/00; http://www.emedicine.com/cgi-bin/foxweb.exe/showsection@d:/em/ga?
book=emerg&topicid=533).

Balk, R.A., Casey, L.C., Sepsis and Septic Shock. Critical Care Clinics. April 2000.
Angus DC, Linde-Zwirble WT, Lidicker J, et al.: Epidemiology of severe sepsis in the United
States: analysis of incidence, outcome and associated costs of care. Crit Care Med 2001,
29:1303-1310

OVERVIEW
Septic shock is the most common cause of mortality in the intensive care unit. It is the 10th
leading cause of death overall (2003) and is the most common cause of shock encountered by
internists in the U.S. Despite aggressive treatment mortality ranges from 15% in patients with
sepsis to 40-60% in patients with septic shock. There is a continuum of clinical
manifestations from SIRS to sepsis to severe sepsis to septic shock to Multiple Organ
Dysfunction Syndrome (MODS).

ETIOLOGY

Viruses and fungi can cause septic shock. Bacterial infections are the most common cause of
septic shock. Almost any bacterium can cause bacteremia. Bacteremia is not necessary for the
development of septic shock. Only 30-50 percent of patients with sepsis have positive blood
culture results.

Escherichia coli, Klebsiella, Enterobacter, Proteus

Pseudomonas aeruginosa - associated with antibiotic therapy and burn wounds; has
very high mortality rate.

"Bacteroides fragilis" - most common cause of anaerobic septicemias

Staphylococcus aureus - Toxic Shock Syndrome (TSS) (Recent cases of "S. aureus
infection" that in some of the cases resulted in septic shock)

Streptococcus pneumoniae

Streptococcus pyogenes- Streptococcal Toxic Shock Syndrome

Enterococcus sp.

Pediatric septicemia - S. pneumoniae, Neisseria meningitidis, or S. aureus usually

causes sepsis in the child. Sepsis due to H. influenzae was very common however
since the introduction of the Hib vaccine, invasive H. influenzae infections have
virtually disappeared. Other causes include E. coli, S. agalactiae (Group B Strep),
Klebsiella sp. and Enterobacter sp. Sepsis is the 7th leading cause of death in children
1-4 years of age and is the 9th leading cause of death in children 5-14 years of age
(2003).

Sepsis in the neonate is most likely to be caused by S. agalactiae (group B strep. is

the leading cause of neonatal sepsis), E. coli, Klebsiella sp. or Enterobacter sp.
 Bloodstream infections caused by Pseudomonas aeruginosa, Candida albicans, or
multidrug resistant Enterococcus faecium is associated with increased mortality.

Fungi, viruses (HIV etc.), and protozoa can also cause septic shock. Less common
than bacterial causes.

The infection site helps in determining the most likely cause of a patient's
sepsis
Suspected Source of Sepsis
Skin/Soft Urinary
Lung Abdomen CNS
Tissue Tract
Streptococcus
pyogenes
Staphylococcu
s aureus
Streptococcus
Clostridium
Streptococcu pneumoniae
sp.
s Escherichia Neiserria
pneumoniae coli meningitidis
Major Escherichi Polymicrobial
Haemophilu Klebsiella Listeria
Communit a coli infections
s influenzae sp. monocytogene
y Acquired Bacteroide Aerobic gram
Legionella Enterobacte s
Pathogens s fragilis negative
sp. r sp. Escherichia
bacilli
Chlamydia Proteus sp. coli
Pseudomonas
pneumoniae Haemophilus
aeruginosa
influenzae
Anaerobes
Staphylococcu
s sp.

Aerobic Pseudomonas
Aerobic
gram Staphylococcu aeruginosa
Aerobic gram
Major negative s aureus Escherichia
gram negative
Nosocomial bacilli Aerobic gram coli
negative bacilli
pathogens Anaerobes negative Klebsiella sp.
bacilli Enterococcu
Candida bacilli Staphylococcu
s sp.
sp. s sp.

Special Concerns:

Elderly patients are more susceptible to sepsis, have less physiologic reserve to tolerate the
insult from infection, and are more likely to have underlying diseases, all of which adversely
impact survival. In addition, elderly patients are more likely to have atypical or nonspecific
presentations when septic.

S. pneumoniae, Neisseria meningitidis, or S aureus usually causes sepsis in the child. Sepsis
due to H. influenzae was very common however since the introduction of the Hib vaccine,
invasive H. influenzae infections have virtually disappeared.
Sepsis and septic shock in the immunocompromised patient is associated with a wide variety
of bacteria and fungi.

EPIDEMIOLOGY
Death due to this disease has increased 82.6% from 1979 to 1997 (4.2 deaths/100,000).
Around 750,000 cases of sepsis are diagnosed per year. Around 31% die each year. Shock
develops in about 40% of septic patients. The annual health care cost from caring for patients
with sepsis is $5-10 billion.

Gram-negative septic shock: comprises 1/2 of total cases of sepsis, 115,000 deaths/year. As
a group gram negative bacteria cause more deaths due to sepsis.

Gram-positive septic shock: more gram positive cases of septic shock are seen due to the
increased incidence in pneumonia and in the use of intravascular devices, 1/2 of cases sepsis.

Factors contributing to the increasing incidence of sepsis:

1. aggressive oncological chemotherapy and radiation therapy

2. widespread us of corticosteroid and immunosuppressive therapies for organ

transplants and inflammatory diseases

3. longer lives of patients predisposed to sepsis, the elderly, diabetics, cancer patients,
patients with major organ failure, and with granulocyopenia.

4. Neonates are more likely to develop sepsis (ex. group B Streptococcal infections).

5. increased use of invasive devices such as surgical protheses, inhalation equipment,

and intravenous and urinary catheters.

6. indiscriminate use of antimicrobial drugs that create conditions of overgrowth,

colonization, and subsequent infection by aggressive, antimicrobial-resistant
organisms.

Source: (usually an endogenous source of infection)

1. intestinal tract

2. oropharynx

3. instrumentation sites

4. contaminated inhalation therapy equipment

5. IV fluids.

Most frequent sites of infection: Lungs, abdomen, and urinary tract. Other sources include
the skin/soft tissue and the CNS.
The source of the infection is an important determinant of clinical outcome. Severe sepsis is
most likely to occur in patients with nosocomial pneumonia. Patients with intra-abdominal
infection and polymicrobial bacteremia or postoperative wound infections and bacteremia are
at significant risk for severe sepsis. Bacteremia associated with intravascular catheters or
indwelling urinary catheters carries a lower risk of developing septic shock.

Patients at increased risks of developing sepsis:

1. Underlying diseases: neutropenia, solid tumors, leukemia, dysproteinemias, cirrhosis
of the liver, diabetes, AIDS, serious chronic conditions.

2. Surgery or instrumentation: catheters.

3. Prior drug therapy: Immuno-suppressive drugs, especially with broad-spectrum

antibiotics.

4. Age: males, above 40 y; females, 20-45 y.

5. Miscellaneous conditions: childbirth, septic abortion, trauma and widespread burns,

intestinal ulceration.

PATHOGENESIS

Microbial triggers of disease:

1. gram-negative bacteria= endotoxin, formyl peptides, exotoxins, and proteases

2. gram-positive bacteria= exotoxins, superantigens (toxic shock syndrome toxin

(TSST), streptococcal pyrogenic exotoxin A (SpeA)), enterotoxins, hemolysins,
peptidoglycans, and lipotechoic acid

3. fungal cell wall material.

Sequence of events: Sepsis can be simply defined as a spectrum of clinical conditions caused
by the immune response of a patient to infection that is characterized by systemic
inflammation and coagulation. It includes the full range of response from systemic
inflammatory response (SIRS) to organ dysfunction to multiple organ failure and ultimately
death.

This is a very complex sequence of events and much work still needs to be done to
completely understand how a patient goes from SIRS to septic shock. Patients with septic
shock have a biphasic immunological response. Initially they manifest an overwhelming
inflammatory response to the infection. This is most likely due to the pro-inflammatory
cytokines Tumor Necrosis Factor (TNF), IL-1, IL-12, Interferon gamma (IFNgamma), and
IL-6.

The body then regulates this response by producing anti-inflammatory cytokines (IL-10),
soluble inhibitors [TNF receptors, IL-1 receptor type II, and IL-1RA (an inactive form of IL-
1)]. Which is manifested in the patient by a period of immunodepression. Persistence of this
hyporesponsiveness is associated with increased risk of nosocomial infection and death.

This systemic inflammatory cascade is initiated by various bacterial products. These

bacterial products (gram-negative bacteria= endotoxin, formyl peptides, exotoxins, and
proteases, gram-positive bacteria= exotoxins, superantigens (toxic shock syndrome toxin
(TSST), streptococcal pyrogenic exotoxin A (SpeA)), enterotoxins, hemolysins,
peptidoglycans, and lipotechoic acid, and fungal cell wall material) bind to cell receptors on
the host's macrophages and activate regulatory proteins [Nuclear Factor Kappa B (NFB)].
Endotoxin activates the regulatory proteins by interacting with several receptors. The CD
receptors pool the LPS-LPS binding protein complex on the surface of the cell and then the
TLR receptors translate the signal into the cells.

The pro-inflammatory cytokines produced are tumor necrosis factor (TNF), Interleukins 1, 6
and 12 and Interferon gamma (IFNgamma). These cytokines can act directly to affect organ
function or they may act indirectly through secondary mediators. The secondary mediators
include nitric oxide, thromboxanes, leukotrienes, platelet-activating factor, prostaglandins,
and complement. TNF and IL-1 (as well as endotoxin) can also cause the release of tissue-
factor by endothelial cells leading to fibrin deposition and disseminated intravascular
coagulation (DIC).

Then these primary and secondary mediators cause the activation of the coagulation cascade,
the complement cascade and the production of prostaglandins and leukotrienes. Clots lodge
in the blood vessels which lowers profusion of the organs and can lead to multiple organ
system failure. In time this activation of the coagulation cascade depletes the patient's ability
to make clot resulting in DIC and ARDS.

The cumulative effect of this cascade is an unbalanced state, with inflammation dominant
over antiinflammation and coagulation dominant over fibrinolysis. Microvascular thrombosis,
hypoperfusion, ischemia, and tissue injury result. Severe sepsis, shock, and multiple organ
dysfunction may occur, leading to death.

Signs and Symptoms

Symptoms of sepsis are usually nonspecific and include fever, chills, and constitutional
symptoms of fatigue, malaise, anxiety, or confusion. These symptoms are not pathognomonic
for infection and may be seen in a wide variety of noninfectious inflammatory conditions.
They may be absent in serious infections, especially in elderly individuals.

The following is the 1992 Consensus Conference's definitions for diagnosis of SIRS to
MODS.

CONSENSUS CONFERENCE DEFINITIONS*

*Data from the American College of Chest Physicians: Society of Critical Care Medicine Consensus
Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.
Crit. Care Med. 20:864-875, 1992

Systemic Inflammatory Response Syndrome (SIRS): Patient presents with two or more of
the following criteria.

1. temperature > 38C or < 36C

2. heart rate > 90 beats/minute

3. respiration > 20/min or PaCO2 < 32mm Hg

4. leukocyte count > 12,000/mm3, < 4,000/mm3 or > 10% immature (band) cells

Sepsis: SIRS plus a documented infection site (documented by positive culture for organisms
from that site). Blood cultures do NOT need to be positive. While SIRS, sepsis, and septic
shock are associated commonly with bacterial infection, bacteremia may not be present.
Bacteremia is the presence of viable bacterial within the liquid component of blood.
Bacteremia may be transient, as is seen commonly after injury to a mucosal surface, primary
(without an identifiable focus of infection), or more commonly secondary, to an intravascular
or extravascular focus of infection.

Severe Sepsis: Sepsis associated with organ dysfunction, hypoperfusion abnormalities, OR

hypotension. Hypoperfusion abnormalities include but are not limited to:

1. lactic acidosis,

2. oliguria,

3. or an acute alteration in mental status.

Septic Shock: Sepsis-induced hypotension despite fluid resuscitation PLUS hypoperfusion

abnormalities.
Organ Dysfunctions associated with Severe Sepsis and Septic Shock:

Lungs: early fall in arterial PO2, Acute Respiratory Distress Syndrome (ARDS): capillary-
leakage into alveoli; tachypnea, hyperpnea

Kidneys (acute renal failure): oliguria, anuria, azotemia, proteinuria

Liver- elevated levels of serum bilirubin, alkaline phosphatase, cholestatic jaundice

Digestive tract- nausea, vomiting, diarrhea and ileus

Skin - ecthyma gangrenosum (think Pseudomonas aeruginosa in neutropenic patients),

Petechia or purpura (think Neisseria meningitidis or Rickettsia rickettsia (if evidence of tick
bite)), Hemorrhage or bullous lesions in patient who has eaten raw oysters (Vibrio vulnificus),
generalized erythroderma (Toxic Shock Syndrome= Staphylococcus aureus or Streptococcus
pyogenes)

Heart- cardiac output is initially normal or elevated,

Brain - confusion

Multiple Organ Dysfunction Syndrome (MODS): Presence of altered organ function in an

acutely ill patient such that homeostasis cannot be maintained without intervention.

Mortality increases with increase in number of SIRS symptoms and in severity of the
disease process. (From Rangel-Frausto, M., Pttet, D., Costigan, M., et. al. The natural history
of the systemic inflammatory response syndrome (SIRS). JAMA 273:117-123, 1995)

Complications:

Adult respiratory distress syndrome (ARDS)

Disseminated Intravascular Coagulation (DIC)
Acute Renal failure (ARF)
Intestinal bleeding
Liver failure
Central Nervous system dysfunction
Heart failure
Death
The reported incidence of these complications in SIRS and sepsis in different studies is about
19% for CNS dysfunction, 2-8% for ARDS, 12% for liver failure, 9-23% for ARF, and 8-18%
for DIC.

In septic shock, ARDS has been observed in about 18%, DIC in about 38%, and renal failure
in about 50%.

DIAGNOSIS

The diagnosis of sepsis requires a high index of suspicion, the taking of an EXCELLENT
history, physical examination, appropriate laboratory tests, and a close follow-up of
hemodynamic status.

History
Helps in determining if the infection was community or nosocomially acquired and if the
patient is immunocompromised. Important details include exposure to animals, travel, tick
bites, occupational hazards, alcohol use, seizures, loss of consciousness, medications, and
underlying diseases that may predispose the patient to specific infectious agents. Some clues
to a septic event include:

1. Fever or unexplained signs with malignancy or instrumentation

2. Hypotension Oliguria or anuria

3. Tachypnea or hyperpnea Hypothermia without obvious cause

4. Bleeding

Physical Examination
A thorough physical exam is essential. In all neutropenic patients and in patients with as
suspected pelvic infection the physical exam should include rectal, pelvic, and genital
examinations. Such exams may reveal rectal, perirectal, and/or perineal abscesses, pelvic
inflammatory disease and/or abscesses, or prostatitis.

Laboratory data

Respiratory alkalosis signals impending shock that is reversible with fluid resuscitation.
Metabolic acidosis can develop just prior to hypotension or can occur at the same time.
Metabolic acidosis can signal the beginning of the end for the patient. Treatment should be
instituted before metabolic acidosis begins.

Recent studies indicate that procalcitonin (PCT) is a good nonspecific marker for
differentiating systemic bacterial inflammatory responses from nonbacterial systemic
inflammatory responses. One study (Ann Rheum Dis. 2003;62:337-340) suggests that
"patients with fever or inflammatory syndrome who have PCT levels greater than 1.2 ng/ml,
we consider that bacterial infection should be sought and antibiotic treatment started even
before the results of the bacteriological investigations are obtained. This approach is even
more strongly recommended in patients with inflammatory disease given immunosuppressive
treatment. In contrast, once tuberculosis and mycobacterial infection have been ruled out,
normal PCT levels do not argue in favor of bacterial infection."

Other tests tests include CBC with differential count, C-reactive protein, urinalysis,
coagulation profile, glucose, blood urea, nitrogen, creatinine, electrolytes, liver function tests,
lactic acid level, arterial blood gas, electrocardiogram, and a chest X-ray. Cultures of blood,
sputum, urine, and other obviously infected sites should be performed. Gram's stain of
normally sterile sites (blood, CSF, articular fluid, pleural space) by aspiration. At least 2 sets
(some believe 3) of blood cultures should be obtained over a 24hr period. Sample volume:
there is often less than 1 bacterium/ml in adults (higher in children). Draw 10-20 ml per
sampling in adults (1-5 ml in children) and inoculate both trypticase soy broth and
thioglycolate broth. Sample time: for intermittent fever spikes, the bacteremia is most
prominent 0.5 hr before the spike. If antibiotic therapy has been initiated, some antibiotics
can be deactivated in the clinical lab.

Depending on the patient's clinical status and associated risks other studies could include
abdominal X-ray, CAT scans, MRI, 2D echocardiograms, and/or lumbar puncture.

Other laboratory findings:

EARLY SEPSIS; leukocytosis with left shift, thrombocytopenia, hyperbilirubinemia, and

proteinuria. Leukopenia may occur. Neutrophils may contain toxic granulations, Dohle
bodies, or cytoplasmic vacuoles. Hyperventilation commonly induces respiratory alkalosis.
Hypoxemia correctable with oxygen. Diabetics can develop hyperglycemia. Serum lipids are
elevated.

LATER ON: Thrombocytopenia worsens with prolongation of thrombin time, decreased

fibrinogen, and presence of D-dimers suggesting DIC. Azotemia, and hyperbilirubinemia are
more prominent. Aminotranferases (liver enzymes) become elevated. When respiratory
muscles fatigue the accumulation of serum lactate occurs. Metabolic acidosis (increased
anion gap) supervenes the respiratory alkalosis. Hypoxemia not correctable even with 100%
oxygen. Diabetic hyperglycemia can precipitate ketoacidosis worsening the hypotension.

THERAPY

Three priorities.

1. Immediate Stabilization of the Patient.

The immediate concern for patients with severe sepsis is reversal of life-threatening
abnormalities (ABCs: airway, breathing, circulation). Altered mental status or depressed level
of consciousness secondary to sepsis may require immediate protection of the patient's
airway. Intubation may also be necessary to deliver higher oxygen concentrations.
Mechanical ventilation may help lower oxygen consumption by the respiratory muscles and
increase oxygen availibility for other tissues. Circulation may be compromised and
significant decreases in blood pressure may require aggressive combined empiric therapy
with fluids (with crystalloids or colloids) and inotropes/vasopressors (dopamine, dobutamine,
phenylephrine, epinephrine, or norepinephrine). In severe sepsis monitoring of the circulation
may be necessary. Normal CVP (central venous pressure) is 10-15 cm of 0.9% NaCl; normal
PAW (pulmonary arterial wedge pressure) is 14-18 mm Hg; maintain adequate plasma
volume with fluid infusion.
Patients with severe sepsis should be in ICU. Their vital signs (blood pressure, heart
rate, respiratory rate, and temperature) should be monitored. The frequency depending
on how severe the sepsis. Maintain adequate cardiac output and ventilation with
drugs. Consider dialysis to assist kidney function. Maintain arterial blood pressure in
hypotensive patients with vasoactive drugs, e.g., dopamine, dobutamine, or
norepinephrine.
2. The blood must be rapidly cleared of microorganisms.
Certain antimicrobial agents may cause the patients to get worse. It is believed that
certain antimicobials cause more LPS to be released cause more problems for the
patient. Antimicrobials that do NOT cause the patient to get worse are: carbapenems,
ceftriaxone, cefepime, glycopeptides, aminoglycosides, and quinolones.

Prompt institution of empiric treatment with antimicrobials is essential. The early

institution of antimicrobials has been shown to decrease the development of shock
and to lower the mortality rate. After the appropriate samples are obtained from the
patient a regimen of antimicrobials with broad spectrum of activity is needed. This is
because antimicrobial therapy is almost always instituted before the organisms
causing the sepsis are identified.

The drugs used depends on the source of the sepsis*.

1. Community acquired pneumonia a 2 drug regimen is usually utilized. Usually

a third (ceftriaxone) or fourth (cefepime) generation cephalosporin is given
with an aminoglycoside (usually gentamicin).

2. Nosocomial pneumonia: Cefipime or Imipenem-cilastatin and an

aminoglycoside.

3. Abdominal infection: Imipenem-cilastatin or Pipercillin-tazobactam and

aminoglycoside.

4. Nosocomial abdominal infection: Imipenem-cilastatin and aminoglycoside or

Pipercillin-tazobactam and Amphotericin B.

5. Skin/soft tissue: Vancomycin and Imipenem-cilastatin or Piperacillin-

tazobactam

6. Nosocomial skin/soft tissue: Vancomycin and Cefipime

7. Urinary tract infection: Ciprofloxacin and aminoglycoside

8. Nosocomial urinary tract infection: Vancomycin and Cefipime

9. CNS infection: Vancomycin and third generation cephalosporin or Meropenem

 10. Nosocomial CNS infection: Meropenem and Vancomycin

*Drugs will change with time. These drug choices are just to show you different
antimicrobial agents are chosen depending on the most likely cause of the patient's
sepsis.

Single drug regimens are usually only indicated when the organism causing sepsis has
been identified and antibiotic sensitivity testing has revealed which antimicrobials the
organism is sensitive to.

3. The original focus of infection must be treated.

Remove foreign bodies. Drain purulent exudate, particularly for anaerobic infections.
Remove infected organs; debride or amputate gangrenous tissues.
New Drug in Treating Severe Sepsis:
Eli Lilly and Company announced in 2001 the results of a Phase III clinical trial that
demonstrated drotrecogin alfa (recombinant human activated protein C, Xigris used to be
called Zovant) could reduce the relative risk of death from sepsis with associated acute organ
dysfunction (known as severe sepsis) by 19.4 percent. These patients had Acute Physiology
and Chronic Health Evaluation II Scores (APACHE II) of 25-53. To treat with this protein the
patient should have an APACHE II score of between 25 and 53. Please note that patients
treated with this protein also are at an increased risk of bleeding. This risk is highest during
infusion of the protein.

It is the first agent approved by the FDA effective in the treatment of severe sepsis proven to
reduce mortality. Activated Protein C (Xigris) mediates many actions of body homeostasis. It
is a potent agent for the:

1. suppression of inflammation [a. directly suppresses monocyte production of nuclear

factor-B (NF-B, b. inhibits thrombin generation which is proinflammatory, c.
minimizes the expression of E-selectin on endothelial walls, producing dose-
dependent inhibition of leukocyte adhesion at the site of infection. Reduced
leukocyte/endothelial interaction down regulates oxygen radical release, decreasing
vascular damage.],

2. prevention of microvascular coagulation [a. proteolytic inactivation of Factors Va

and VIIIa preventing thrombin formation.]

3. reversal of impaired fibrinolysis [a. binds with plasminogen activator inhibitor-1

(PAI-1), causing inactivation of PAI-1. This in turn reduces the inhibition of tissue
plasminogen activator (t-PA), allowing t-PA to stimulate fibrinolysis. Fibrin is broken
down, and microcirculation is restored.].