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SEPSIS

Author: Nicolene Naidu

Bachelor of Biological Science (Cellular Biology), Bachelor of Medical Science (Medical Microbiology) (Honours)

SEPSIS AT A GLANCE...

The term “sepsis” was coined in the 19th century and refers to an infection of the

bloodstream by pathogenic micro-organisms (bacteria, viruses or fungi). It is

characterized by acute inflammation of the whole body as a result of the host’s

immune response to infection.

The host’s response is also known as Systemic Inflammatory Response

Syndrome (SIRS) and is characterized by elevated or lowered body temperature,

abnormal white blood cell count and elevated respiratory and heart rates. Sepsis is

differentiated from SIRS by the presence of a suspected or proven pathogen.

Usually a localized infection, for example in the lung, urinary tract, abdomen, central

nervous system, skin, bone or other tissue spreads from the primary site of infection

into the bloodstream which carries it throughout the body, thereby spreading the

infection. Sepsis is also associated with infections acquired during surgery.

Activation of acute phase proteins form part of the body’s immune response to

infections. In the case of sepsis, these proteins cause widespread damage by

disrupting the coagulation and complement pathways.

Symptoms used to help diagnose sepsis include:

Elevated heart rate and breathing

Elevated or lowered body temperature

Mental confusion

The symptoms of original infection

Skin spots (eg. Petechiae or purpura)

Abnormal white blood cell count

White blood cells in normally sterile fluid (eg. Urine or CSF)

perforated viscous

decrease in urine output

low blood pressure

Systemic Inflammatory Response Syndrome with two or more of the above

symptoms are used in conjunction with positive results for laboratory tests like blood

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cultures and CSF’s and in some cases even x-rays (to show a perforated viscous or

chest infection), to give a positive diagnosis for sepsis. Sepsis is an extremely

serious and rapidly progressive medical condition with possible complications

including Adult respiratory distress syndrome, Septic shock and death. Prognosis

often depends on how soon a patient is diagnosed and how soon treatment begins.

Treatment usually begins before confirmation via blood culture with the use of broad

spectrum antibiotics and once blood culture results are received, broad spectrum

antibiotics are swapped for antibiotics specific to the pathogen causing the infection.

Patients may also be given oxygen and fluids intravenously to help maintain blood

pressure. Sometimes surgery may be required to remove sources of infection such

as abscesses. Treatment is often in a hospitals high care unit like the ICU.

While sepsis can be an extremely life threatening disease if left untreated or even if

treatment is prolonged, it can also be prevented altogether by receiving the S.

pneumoniae and Haemophilus influenza B vaccines, cleaning wounds and receiving

appropriate treatment for infections as well as taking preventative antibiotics when in

close contact with septicaemia patients.

Elderly people, patients with co-morbidities like cancer and diabetes as well as

patients that are immune-suppressed have the greatest risk of contracting sepsis.

With advances in medical science, sepsis still remains a deadly disease mainly due

to drug resistant microbes and delay in diagnosis and treatment.

PATHOPYSIOLOGY OF SEPSIS

When host tissue is injured or infected, the host’s initial response is to localize and

control the pathogenic invasion and initiate tissue repair. While this task may seem

simple enough, the actual process consists of a number of complex pathways that

work in unison to bring about equilibrium or homeostasis by eliminating invading

pathogens without causing damage to its own tissues, organs or other systems.

Sepsis occurs when the host’s inflammatory response extends to involve healthy

tissue, usually remote from the initial site of invasion or infection.

Sepsis can originate from an infection anywhere in the body and its pathophysiology

can be initiated by the outer membrane component of gram-negative or gram-

positive organisms as well as parasitic, viral or fungal components

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FIGURE 1: The inflammatory response

(http://www.inflammationreliefguide.com/tag/natural-anti-inflammatory/)

The inflammatory response drives the physiological changes that become

apparent in the Systemic inflammatory Response Syndrome. In the normal

inflammatory response (a response meant to localise and contain infection),

leukocytes are attracted to the site of infection by the expression of adhesion

molecules on the endothelium. Polymorphonuclear leukocytes (PMN’s) are

simultaneously activated and express adhesion molecules which cause them to

aggregate at the vascular endothelium. Diapedesis (ie.the outward passage of blood

cells through intact vessel walls) occurs and the PMN’s migrate to the site of

infection where invading bacteria and debris from tissue injury are phagocytosed.

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FIGURE 2 : From bacteria to infectious diseases. Interaction of microbial derived molecules with

host's cells leads to the production of cytokines, a prerequisite for innate immunity. Overwhelming

production is associated with severe inflammation while the concomitant anti-inflammatory response

may be associated with increased susceptibility to nosocomial infection (Annane D, Bellissant E,

Cavaillon J-M (2005) Septic Shock. The Lancet 365: 63-78).

(http://www.pasteur.fr/recherche/RAR/RAR2007/Cytoinf-en.html)

During the inflammatory response (A process involving adherence, chemotaxis,

phagocytosis and bacterial killing), blood vessels around the site of infection dilate to

allow increased blood flow to the infected area and gaps appear in the cell wall

enabling the larger immune cells and proteins to pass through. The increase in blood

flow increases body temperature. These characteristic signs of inflammation (ie.

local vasodilation and hyperaemia along with increased microvascular permeability)

are a direct result of the release of mediators by the Polymorphonuclear leukocytes.

Macrophages are triggered by invading micro-organisms to secrete cytokines (eg.

tumor necrosis factor and interleukins) which leads to the activation of other pro-

inflammatory mediators like eicosanoids (prostaglandins and leukotrienes -

Prostaglandins dilate blood vessels and produce fever while leukotrienes attract

certain leukocytes.), platelet activating factor, interleukin-1 (IL-1) , IL-2, IL-6, IL-8,

IL-10 and interferon.

The end result is clearing of tissue debris and bacteria, followed by tissue repair.

This is the normal outcome of the host’s response to infection, however in some

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cases, the inflammatory response goes beyond the boundaries of its local

environment to effect otherwise healthy tissue. This process is called sepsis when it

occurs in association with an infection and Systemic Inflammatory Response

Syndrome when it is induced by non- infectious conditions (eg. Severe trauma or

pancreatitis).

Sepsis represents an exaggeration of the normal inflammatory response, where

instead of intercellular interactions in the interstitial space, the process becomes

intravascular (spreading through the blood). It is uncontrolled, unregulated and self

sustaining.

Coagulopathy is a term used to describe any blood disorder that impairs the bloods

ability to clot. During inflammatory conditions like sepsis, the cells that regulate the

coagulation system and the system itself are altered on multiple levels. The clotting

cascade involves a complex process. Here is a brief overview...

FIGURE 3: The clotting cascade

(http://upload.wikimedia.org/wikipedia/commons/b/b6/Coagulation_full.svg)

Sepsis disrupts the fine balance needed to maintain the homeostasis that allows

blood to remain free flowing within the blood vessels and to control bleeding (when

appropriate) by clotting. This altered homeostasis among other things clogs blood

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vessels and reduces blood flow. Due to the inflammatory cytokines Interleukin-1 and

TNF-α, tissue factor (the first step in the extrinsic pathway of coagulation) is

expressed on the endothelial and monocyte surfaces. Tissue factor leads to the

production of another pro-inflammatory substance – thrombin. Thrombin leads to

the formation of fibrin clots in the microvasculature. Interleukin-1 and TNF-α also

play a role in the production of plasminogen activator inhibitor-1 which inhibits

fibrinolysis (Vervloet et al).

Activated Protein C (APC) and anti-thrombin are the body’s naturally occurring

modulators of inflammation and coagulation. Protein C circulates as an inactive

enzyme precursor (zymogen) that is converted to the enzyme-activated Protein C by

the presence of thrombomodulin (a protein bound to the endothelial surface) and

thrombin. Pro-inflammatory cytokines disrupt the modulation activity of APC and anti-

thrombin. Anti-thrombin leads to the production of prostacyclin (anti-inflammatory)

when bound to the endothelial surface of gylcosaminoglycans. During sepsis, the

anti-inflammatory action of anti-thrombin is limited by the cleaving of

gylcosaminoglycans off the endothelial lining surface by neutrophil elastase(Jordan

et al.). Pro-inflammatory cytokines can prevent the activation of protein C via down-

regulation of thrombomodulin as well as by shearing this molecule of the endothelial

surface (Boehme et al).

Early during the sepsis process, CD4 lymphocytes (TH1 phenotype) produce pro-

inflammatory mediators including interferon γ, IL-2 and TNF-α, later with the release

of stress hormones (eg. catecholamines), CD4 lymphocytes evolve (TH2

phenotype) to produce ant-inflammatory mediators including IL-10, IL-4 and IL-13

that suppress the immune response and may lead to monocyte deactivation (Reddy

et al).

The elevation of circulating TNF- α levels as observed in septic patient’s (Pinksy et

al), may be a result the transfer of endotoxin (bound to lipopolysaccharide protein) to

macrophages which in turn stimulate this pro-inflammatory mediator (Lamping et al).

Metabolic auto-regulation, the process that ensures that the blood supplies the

exact amount of oxygen to meet tissue requirements, is also disrupted. Maximal

oxygen extraction is reduced by the decrease in capillarity associated with sepsis

(Neviere et al). Causes for reduced capillarity include extrinsic capillary compression

via plugging of the capillary lumen by for example white blood cells, endothelial

swelling and protein rich tissue edema (ie. tissue fluid retention). As mentioned, the

endothelial dysfunction upregulates adhesion molecules and impairs anticoagulant

properties. During sepsis, erythrocytes lose their ability to “deform” and remain

“rigid”, which makes it difficult to navigate in impaired circulatory conditions.

Septic patients commonly present with Disseminated Intravascular Coagulation

(DIC) with platelet consumption and prolonged clotting times.

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During sepsis, activation of the endothelial cells by the presence of endotoxins and

inflammatory cytokines (Tumor Necrosis Factor and IL-1) causes production of

vasoactive mediators like nitric oxide and prostacyclin. Larger quantities of nitric

oxide are produced via inducible nitric oxide synthase (a group of flavin containing

ezymes), prostaglandins and endothelin. The relative proportions of these three

determine vascular response. Nitric oxide is believed to play a vital role in the

vasodilation that accompanies septic shock (Parrat et al).

Damaged mitochondrial electron transport can be directly linked to the cytotoxicity of

TNF- α, endotoxin and nitric oxide. This may contribute to the disruption of energy

metabolism in sepsis.

Once an infection has subsided apoptosis is the termination step in the

inflammatory response. Apoptosis refers to a natural process that leads to

programmed cell death. In septic patients the inflammatory response may be

prolonged and apoptosis delayed by pro-inflammatory cytokines, which often

contributes to the development of multiple organ failure. Apoptosis may also aide in

pathogenesis by the early removal of cells like lymphocytes which should not be

removed and the delayed removal of cells like neutrophils which should be removed

early (Marshall et al).

Sepsis comes down to a battle between two opposing forces – pro-inflammatory and

anti-inflammatory mediators that disrupt the body’s homeostasis in a range of

varying ways (cellular and coagulatory).

DIAGNOSING SEPSIS

A simple definition for sepsis was established in 1989 by Bone et al. It was based

on specific clinical symptoms and a known source of infection. The problem was that

patients without discernable levels of bacteria in the blood and those presenting with

for example acute pancreatitis or trauma, shared the same clinical symptoms.

In 1992, the Society of Critical Care Medicine and the American College of Chest

Physicians took this discrepancy into account at a consensus conference where the

term Systemic Inflammatory Response syndrome was coined along with several

other terms to distinguish between the varying stages of sepsis (table 1).

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(From: Niels C. Riedemann, Ren-Feng Guo, Peter A. Ward. The enigma of sepsis. J Clin

Invest. 2003; 112(4):460–467 doi:10.1172/JCI19523 ).

Many non-infectious illnesses can produce the systemic inflammatory response and

organ dysfunction witnessed in sepsis. Among these are hematoma, venous

thrombosis, transplant rejection, pancreatitis, hyperthyroidism, myocardial or

pulmonary infarcts, malignancies, drug or blood product reaction and central nervous

system hemorrhages among other things. These illnesses should be considered by

any diagnosing physician when making a differential diagnosis for sepsis.

Clinical signs that may allow the diagnosing physician to consider sepsis include:

hyper or hypothermia (body temperature that is higher or lower than the core

body temperature)

unexplained tachycardia (faster than normal heart rate)

unexplained tachypnea (abnormally rapid breathing)

mental status changes and shock

signs of peripheral vasodilation

increased cardiac output

low systemic vascular resistance

abnormalities in the complete blood count

Laboratory test results as seen in table 2, aide in the differential diagnosis of sepsis.

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Table 2: Laboratory Indicators of Sepsis

Laboratory Test Findings Comments

White blood cell count

Leukocytosis or leukopenia Endotoxemia may cause early leukopenia

Platelet count Thrombocytosis or thrombocytopenia

High value early may be seen as acute-phase response; low platelet counts seen in overt DIC

Coagulation cascade Protein C deficiency; antithrombin deficiency; elevated D-dimer level; prolonged PT and PTT

Abnormalities can be observed before onset of organ failure and without frank bleeding.

Creatinine level Elevated from baseline Doubling-indicates acute renal injury Lactic acid level Lactic acid > 4 mmol/L (36 mg/dL) Indicates tissue hypoxia Liver enzyme levels Elevated alkaline phosphatase,

AST, ALT, bilirubin levels Indicates acute hepatocellular injury caused by hypoperfusion

Serum phosphate level

Hypophosphatemia Inversely correlated with proinflammatory cytokine levels

C-reactive protein (CRP) level

Elevated Acute-phase response

Procalcitonin level Elevated Differentiates infectious SIRS from noninfectious SIRS

(http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/infectious-

disease/sepsis/ )

As mentioned previously, sepsis refers to the systemic inflammatory response

system with a presumed or known site of infection. Severe sepsis includes organ

dysfunction.

The diagnosing physician will use two or more of the clinical symptoms already

mentioned (eg. tachycardia) as evidence of a systemic inflammatory response, but

what would he or she use as an indicator of infection (known or presumed)?

Indicators of known or presumed infection in suspected sepsis patients, as used in

past clinical trials, include positive blood culture, lymphocytes in normally sterile

body fluid, evidence of infected medical hardware or an infected collection as

noted by radiographic or physical exam, perforated viscous (noted by spillage of

bowel contents during an operation), a chest radiograph showing new infiltrates that

cannot be explained by a non-infectious process or a purulent respiratory sample or

sputum.

Indicators of sepsis induced organ failure:

A mean arterial pressure of 60 mm Hg or lower and the need for vasopressors to

maintain blood pressure despite the presence of sufficient intravascular volume (or

after adequate fluid challenge has been given) is an indication of cardiovascular

failure.

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An indicator of respiratory dysfunction is an arterial oxygen pressure to fraction of

inspired oxygen ratio of < 200 in patients with pneumonia and < 250 in patients

without pneumonia.

Renal failure is characterised a doubling of serum creatinine levels and decreased

urine output (0.5 ml/kg per hour for 2 hours) despite the adequate intravascular

volume (or after adequate fluid challenge).

Hematologic dysfunction is also noted by thrombocytopenia (< 80, 000

platelets/mm2) or a 50 % drop from baseline during acute illness.

Sepsis induced organ failure may be accompanied by plasma lactate levels greater

than one and a half times that of the laboratories normal limit and pH values of < 7.3

(ie. metabolic acidosis).

TREATMENT

A universally agreed upon treatment plan for sepsis has not yet been established. In

general treatment usually involves administering a broad spectrum or empirical

antibiotic, while tests are done to determine the causative pathogen/s and site of

infection. A clinical trial of patients with severe sepsis showed that the lungs were the

most common site of infection. The abdomen and urinary tract were a close second

and third (Bernard et al.) Administering the appropriate antibiotic requires a sound

knowledge of the most common organisms that infect different sites in the body.

Candida, Psuedomonas, Enterobacter and Serratia spp infections are known to

contribute to morbidity in sepsis (Miller et al.).Recent studies on animals and humans

have demonstrated a statistically significant incremental rise in mortality per hour

delay in the administration of appropriate antibiotic therapy from the onset of septic

shock (Kumar et al.)

As important as antimicrobial treatment is as the first line of defence in the treatment

of severe sepsis, controlling the source of infection is just as important. This includes

surgical drainage of abscesses or infected fluid collections and removing infected

foreign bodies (some of which may have been introduced through surgery).

As mentioned, metabolic auto-regulation is disrupted during sepsis hence optimizing

oxygen delivery to critical organs is a priority during sepsis treatment. Lactic acidosis

can be used as an indicator of the body’s inability to meet its tissue oxygen

requirements and in such cases Early Goal Directed Therapy (EGDT) has been

shown to reduce mortality (Rivers et al), with the aim being to achieve a central

venous oxygen saturation of 70% or higher.

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Early Goal Directed Therapy involves:

monitoring central venous saturation via a central venous catheter

crystalloid boluses of 500ml are administered every half hour to achieve a

central venous pressure of between 8 to 12 mm Hg.

Mean arterial pressure is measured and if still below 65 mm Hg,

vasopressors are added.

If central venous oxygen saturation remains below 70 % despite these

interventions, then red blood cells are transfused to reach a hematocrit of

30 %.

Finally, dobutamine is administered if the target has not yet been achieved

((Rivers et al)).

Treatment may also include fluid resuscitation. Data would suggest that aggressive

fluid management should occur in the acute phase of sepsis, followed by more

conservative resuscitation thereafter. Trials using this strategy in patients with acute

lung injury, were associated with a fewer number of ventilator and intensive care unit

days (National Heart, Lung and Blood institute ARDS clinical trials network, 2006).

Clinical trials using a recombinant form of activated protein C have been shown

to have considerable success in the treatment of sepsis (Bernard et al.), but this is

not without complications.The main complication being its association with bleeding

(particularly in patients displaying gastro-intestinal lesions and severe

thrombocytopenia).

Due to its beneficial effects on vascular tone and anti-inflammatory properties, low

dose corticosteroids may be used to treat septic shock. Clinical evidence suggests

only treating patients with shock refractory to vasopressors with low doses of

corticosteroid over an extended period of time (Minneci ,et al.).

Glycemic control is another factor that might be used in the treatment of sepsis.

Advantages of maintaining strict glucose control include a reduction in infections,

muscle wasting, acute renal failure and anaemia. Potential complications include the

cost associated with constant close monitoring and hypoglycaemia.

Sepsis shock can be treated with vasopressors as mentioned previously. These

include dopamine, norepinepherine and vasopressin.

Three additional components include adequate nutrition (best accomplished

enterically), providing deep vein thrombosis (via subcutaneous heparin) and

providing gastric ulcer prophylaxis (via sucralfate), (Dellinger, et al).

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Treatment in general...

Antibiotic treatment should begin within an hour of presenting with acute

sepsis

Early goal directed therapy should be used on patients presenting with lactic

acidosis

Patients with established acute lung injury should be treated with a

conservative fluid strategy and low tidal volume ventilator

Patients presenting with an APACHE II score of >25 (greatest disease

severity) or two or more organ failures, should be considered with treatment

with recombinant human activated protein C.

Patients with septic shock refractory to fluid resuscitation and vasopressors

should be considered for low dose corticosteroid therapy.

PREVENTION

One of the most common infections leading to sepsis is pneumonia. Thus reducing

the incidence of pneumonia via vaccinations against H.influenza and S.pneumonia

would significantly reduce the number of new sepsis cases.

Cleaning wounds and receiving appropriate treatment for infections could prevent

sepsis altogether. Stricter medical procedures, involving sterile insertion of catheters

and chlorhexidine dressings could diminish catheter related blood stream infections.

Many microbes have developed drug resistance due to the incorrect use of

antibiotics, which could turn a potentially simple infection into a potentially lethal one.

Thus educating people on the proper use of antibiotics (for example always

completing an antibiotic course – even when you feel better) could lower the number

of severe sepsis infections.

CONCLUSION

Although numerous advancements have been made in the sepsis arena, much work

remains to be done. Sepsis is still one of the deadliest diseases around and its

altered pathophysiology is not yet fully understood. Several studies continue to

research the devastating processes involved in sepsis in an attempt to better

understand this disease and maybe answer questions like – are septic patient’s

immune-compromised or hyper-inflammatory.

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Thus far patients with co-morbidities like cancer and diabetes, the aged, immune-

suppressed patients and patients undergoing surgical procedures involving

equipment being left in place for any length of time are at greatest risk of contracting

sepsis.

Procalcitonin has been suggested as a marker for infection as it is more specific than

inflammation, but like everything else in sepsis requires further research.

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