PERM STATE MEDICAL

UNIVERSITY
TOPIC- WHAT IS THE NEW IN
TREATMENT OF SEPSIS?
BY – KOMAL JAISWAL
 Introduction
• Sepsis is one of the oldest described illnesses. The term sepsis is derived
from the ancient Greek term (“make rotten”) and was used by
Hippocrates.
• After its recognition, it took over 2,000 years to establish the hypothesis
that it is not the pathogen itself but rather the host response that is
responsible for the symptoms seen in sepsis.
• Clear definitions are of great importance in the medical field, as
appropriate treatment of illness demands a correct preceding diagnosis.
This is not always simple, and, particularly in emergency and intensive
care medicine, fast and reliable diagnosis is needed to treat acute illness.
The challenge of fast diagnosis of sepsis is that this syndrome is based on
highly complex pathophysiological pathways that may show varying
clinical signs and symptoms.
 From understanding to defining
sepsis
The former understanding of sepsis as a hyper-inflammatory
response to infection, often accompanied by a fast “cytokine
storm” 11, was the basis for former sepsis definitions: the US critical
care specialist Roger Bone organized a consensus conference in 1992
and suggested that the sepsis definition include the aspect of host
response. Here, the term systemic inflammatory response syndrome
(SIRS), which is still commonly used, was defined.
If SIRS occurs without infection (for example, in the case of burns and
pancreatitis and in the post-operative setting), the condition is defined
only as SIRS; similarly, an infection without SIRS does not equal sepsis.
Therefore, sepsis was defined as “a systemic inflammatory
response syndrome to infection” (“Sepsis-1”) that may be
seen when two or more of the following criteria are fulfilled:
✓ core temperature of more than 38°C (100.4°F) or less than 36°C
( 96.8°F)
✓ respiratory rate of more than 20 breatheart rate of more than 90
beats/minute
✓ hs/minute or partial pressure of carbon dioxide (PaCO 2) of less than
32 mmHg
✓ white blood cell count of more than 12,000/mL or less than 4,000/
mL or more than 10% immature neutrophils(abnormal white blood
cell count).
 Sepsis-2 (“PIRO” )
A classification system allowing the stratification of patients with sepsis,
“PIRO” (today called “Sepsis-2”), was developed at conference in 2001.
“P” stands for predisposition, “I” for type and extent of the primary
insult (in the case of sepsis, primary infection), “R” for type and extent
of host response, and “O” for extent of organ dysfunction.
The benefit of the PIRO model is that it enabled one to separate
morbidity due to the infection itself from secondary morbidity that
develops through the host response.
The introductions of a PIRO model, however, remained theoretical,
even though there have been several attempts to introduce a point
system that enables scoring of patients with sepsis
 Sepsis-3
A new approach (“Sepsis-3”) was developed that is based on patient
data from several validated sources and that was published in the form
of three articles in 2016.
What is new in this concept? On the one hand, it is the omission of
SIRS as a factor in the definition.
The new Sepsis-3 defines sepsis as “a life-threatening organ
dysfunction caused by a dysregulated host response to infection” 15.
Therefore, if no organ dysfunction is seen, one may speak only of an
infection, not of “sepsis”.
 Stages of sepsis
There are three stages of sepsis:
❑ sepsis
❑ severe sepsis
❑ septic shock.
The term “severe sepsis” is superfluous, as its criteria (organ
dysfunction) are already included in the new definition of sepsis. The
term “septic shock” remains; however, it now also includes an
elevated lactate level of more than 2 mmol/L as an additional factor.
 SOFA
Part of the new Sepsis-3 definitions is SOFA as a grading score for
defining acute organ dysfunction (“Sequential [Sepsis-related] Organ
Failure Assessment Score”, or SOFA score) .
This score allocates points according to pathological change in six
different organ systems; an increase in the total SOFA score by at least
two points.
In 2016 a new consensus was reached to replace screening
by systemic inflammatory response syndrome (SIRS) with the
sequential organ failure assessment (SOFA score) and the
abbreviated version (qSOFA).
 qSOFA (“quickSOFA”)is intended primarily for use in emergency
departments, peripheral wards, rest homes, and so on and not in ICUs, and
it consists of the following three criteria:
➢ respiratory rate of more than 22 breaths/minute
➢ systolic blood pressure of less than 100 mmHg.
➢ Glasgow coma scale score of less than 15 (This scale is used to determine
your level of consciousness.)
When two of these three qSOFA criteria are met, organ dysfunction should
be suspected, and the classic SOFA score should be determined by
experienced physicians, usually intensive care specialists.
Operationalization of clinical criteria identifying patients with
sepsis and septic shock
 What causes sepsis?
Any infection can trigger sepsis, but the following types of infections are more likely to
cause sepsis:
• pneumonia
• abdominal infection
• kidney infection
• bloodstream infection

According to the National Institute of General Medical Sciences, the number of sepsis
cases in the United States increases every year. Possible reasons for the increase include:
• an aging population, because sepsis is more common in seniors
• an increase in antibiotic resistance, which happens when an antibiotic loses its ability
to resist or kill bacteria
• an increase in the number of people with illnesses that weaken their immune systems
 How is sepsis diagnosed?
If you have symptoms of sepsis, your doctor will order tests to make a diagnosis
and determine the severity of your infection. One of the first tests is a blood
test. Your blood is checked for complications like:
• infection
• clotting problems
• abnormal liver or kidney function
• decreased amount of oxygen
• an imbalance in minerals called electrolytes that affect the amount of water in
your body as well as the acidity of your blood
 Depending on your symptoms and the results of your blood test, your
doctor may order other tests, including:
• a urine test (to check for bacteria in your urine)
• a wound secretion test (to check an open wound for an infection)
• a mucus secretion test (to identify germs responsible for an infection)

If your doctor can’t determine the source of an infection using the above
tests, they may order an internal view of your body using one of the
following:
• X-rays to view the lungs
• CT scans to view possible infections in the appendix, pancreas, or bowel area
• ultrasounds to view infections in the gallbladder or ovaries
• MRI scans, which can identify soft tissue infections
 Quality improvement in sepsis
management
Around 15 years ago, three international research societies founded
the SSC(Surviving Sepsis Campaign ), aiming to reduce sepsis
mortality by more than 25% (relative risk reduction) over 5 years.The
first version was published in 2004 and the third revision in 2017.

Based on the first version, “SSC Sepsis Bundles” were created,

consisting of several measurable interventions (for example,
antibiotics, blood cultures, and serum lactate measurement).
According to the initial plan, these bundles were tested in more than
30,000 cases of sepsis and septic shock worldwide over a period of 5
years (2005–2010).
As a result, it was demonstrated that
(1) the planned mortality reduction was reached and
(2) not all parts of the bundles had an intrinsic effect on patient
outcome
In more than 14,000 included patients, 90-day mortality decreased
significantly, from 64.2% to 45.0%, and the length of stay in the
hospital decreased from 44 to 36 days.
 Recent development in sepsis
management
There was a broad discussion of whether these protocols should be a
mandatory quality indicator.The way this was carried out could be decided
by the hospitals themselves, but the minimum requirement was a 3-hour
bundle with the following interventions:
(1) blood cultures before administration of antibiotics,
(2) serum lactate measurement, and
(3) infusion of broad-spectrum antibiotics.
In 2017, the results from the first 2.25 years after starting these rules were
published, presenting data from 149 hospitals, including more than 49,000
patients; 82.5% of these met the criteria for the 3-hour bundle.
Based on these impressive data, the SSC steering group recently
published newly defined “SSC Sepsis Bundles 2018”, which are now
based on a 1-hour period 30:
• Measure lactate level. Re-measure if the initial level is more than 2
mmol/L.
• Obtain blood cultures prior to the administration of antibiotics.
• Administer broad-spectrum antibiotics.
• Begin rapid administration of 30 mL/kg crystalloid for hypotension or
lactate of at least 4 mmol/L.
• Apply vasopressors if the patient is hypotensive during or after fluid
administration to maintain mean arterial pressure of at least 65 mmHg.
Since these new bundles were published
very recently, no validation studies have been
performed so far. However, the discussion
started within days; many clinicians are very
critical of this “mandatory approach”.
 Antibiotics
• Administration of effective intravenous antimicrobials within the
first hour of recognition of septic shock
• Antimicrobial regimen should be reassessed daily for potential de-
escalation.
• Empiric combination therapy should not be administered for more
than 3–5 days.
• Duration of therapy typically 7–10 days
• Antiviral therapy initiated as early as possible in patients with
severe sepsis or septic shock of viral origin
 Source control
Source control refers to physical interventions to control
a focus of infection and reduce conditions favorable to
microorganism growth or host defense impairment, such
as drainage of pus from an abscess.
Vasopressor
•Vasopressor therapy initially to
target a mean arterial pressure
(MAP) of 65 mm Hg
• Norepinephrine as the first
choice vasopressor
• All patients requiring
vasopressors have an arterial
catheter placed as soon as
practical if resources are
available.

Algorithm for treating

hypotension in septic shock
 Corticosteroids
• Indicated with persistent hemodynamic instability
• Hydrocortisone 50mg IV every 6 hours. OR Hydrocortisone 100mg
IV every 8 hours
• DO NOT use the ACTH stimulation test
• In treated patients hydrocortisone, taper when vasopressors are no
longer required
• Corticosteroids not be administered for the treatment of sepsis in the
absence of shock
• Multiple studies have shown decreased time on vasopressors. No
mortality benefit
• Complications associated with steroids
 Early goal directed
therapy
Early goal directed therapy (EGDT) is an approach to the
management of severe sepsis during the initial 6 hours after
diagnosis.
It is a step-wise approach, with the physiologic goal of
optimizing cardiac preload, afterload, and contractility. It
includes giving early antibiotics.
In the original trial, early goal directed therapy was found to
reduce mortality from 46.5% to 30.5% in those with sepsis,
and the Surviving Sepsis Campaign (SSC) has been
recommending its use.
 Activated protein C
Activated protein C(drotrecogin alpha) is an endogenous protein.
Sepsis reduces the level of protein C and inhibits conversion of
protein C to activated protein C. Administration of recombinant
activated protein C inhibits thrombosis and inflammation, promotes
fibrinolysis, and modulates coagulation and inflammation.
In 2001, the PROWESS (Recombinant Human Activated Protein C
Worldwide Evaluation in Severe Sepsis) trial demonstrated a 6.1%
absolute decrease in mortality in patients with severe sepsis.
 The updated review found no evidence suggesting that APC
should be used for treating patients with severe sepsis or septic
shock. APC seems to be associated with a higher risk of bleeding.

The drug company behind APC, Eli Lilly, has announced the
discontinuation of all ongoing clinical trials using this drug for
treating patients with severe sepsis or septic shock.
•
 Strategies to treat sepsis
(experimental)
➢ Targeting bacterial pathogens (Antistaphylococcal monoclonal,
Antipseudomonas monoclonal,Lytic bacteriophage against
Pseudomonas aeruginosa )
➢ Targeting endotoxin (Eritoran,TAK-242, Alakaline phosphatase,
Immobilized polymyxin B filter)
➢ Targeting superantigens (Superantigen antagonists)
➢ Targeting signal transduction & inflammatory response (Polyclonal
TNF Fab fragments,Vagal nerve stimulation,a7-nicotinic acetylcholine
receptor agonists,HMGB-1 inhibitors,Anti-RAGE, Suppressors of
cytokine signaling,High-volume hemofiltration,PPARg agonist, Statins)
➢ Targeting the gut (Bovine lactoferrin, Recombinant human
lactoferrin)
➢ Targeting coagulation cascade/endothelium (Transgenic
antithrombin, Activated protein C,Activated protein C variants,
Recombinant soluble thrombomodulin )
➢ Targeting complement ( Anti-C5a antibodies Repletion of protective
molecules,Inter a inhibitor proteins,Estrogen receptor binding
agonists)
➢ Targeting immunosuppression (Inhibitors of lymphocyte apoptosis,
siRNA against Fas and BIM, HIV protease inhibitors,IL-7 and -15,Anti-
PD-1 )
➢ Reversing monocyte hyporesponsiveness (GM-CSF, IFN-g)
 InnovoSep
New Research brings much-needed hope for the treatment of
sepsis. Researchers at the Royal College of Surgeons in
Ireland (RCSI) have tested a compound called cilengitide in a
preclinical trial. The drug goes by the brand name InnovoSep.
Principal investigator Steve Kerrigan of InnovoSep said, "Our
research has shown the InnovoSep candidate drug can prevent
sepsis progression early or indeed treat advanced sepsis.
The drug appears to act by preventing the bacteria from getting
into the bloodstream from the site of infection by stabilising the
blood vessels so that they cannot leak bacteria and infect the
major organs.“
In the preclinical trial, the researchers successfully used
InnovoSep to inhibit S. aureus and E. coli from binding to
human endothelial cells, both in vivo and in vitro.
Endothelial cells are “the first barrier between the blood
and the extravascular space.”
Hence,it is very new research so the trial is going on….!!
 Extracorporeal Therapies
More recently, extracorporeal techniques have been employed in both
adults and children in treating sepsis. Extracorporeal therapies include
continuous renal replacement (CRRT), plasma-based removal
techniques, and extracorporeal membrane oxygenation (ECMO).
These treatments could theoretically
1) provide immunohomeostasis of pro- and anti-inflammatory
cytokines and other sepsis mediators
2) decrease organ microthrombosis through removal of pro-
coagulant factors and modulating the impaired septic coagulation
response in sepsis
3) provide mechanical support of organ perfusion during the acute
septic episode to allow time for response to traditional sepsis
therapies and antimicrobials.
CRRT is beneficial in managing fluid overload and acute
renal failure in sepsis. Removal of sepsis mediators through
the technique is variable, and the outcome impact of CRRT
on sepsis has not been definitively determined. High-flow
CRRT has demonstrated benefit in septic adults.
Intriguing early results suggest that plasma exchange could
improve outcomes in both adults and children.
Based on experience, ECMO is recommended for
refractory septic shock in neonates and should be
considered for use in children.
Ongoing trials may help determine whether the promise of
extracorporeal therapies translates into outcome
improvement in septic children.
Extracorporeal endotoxin binding by polymyxin B
hemoperfusion
A toxic substance is associated with the membrane of bacteria,
and called it ‘endotoxin’ . Endotoxin infusion mimics many of
the inflammatory, metabolic, cardiovascular changes
observed in sepsis patients and represents one of the main
inducers of shock in sepsis.
Clinical research has shown that endotoxin is indeed circulating
in the blood of up to 50% of sepsis shock patients and
associated with impaired clinical outcome .
In view of the pivotal role of endotoxin in sepsis patients, the
idea of ‘blood purification’ emerged. Polysterene fiber filters
coated with polymyxin B are able to bind endotoxin.
The primary end-point of this
study was the change in
hemodynamic stability.
Secondary endpoints included
change in SOFA-score and
mortality.
Polymyxin B (PMX)
hemoperfusion has been
shown in numerous studies to
successfully remove endotoxin
and potentially improve
outcomes.
 Proposed prospective treatment
The proposed auxiliary therapy is based on the application of bacterial
polyvalent antibody-column (BPVAC) for neutralization of wide
spectra of blood bacterial antigens and their toxins (BATs) known as causal
agents of prevalent types of bacterial sepses.
The course of resuscitation of septic patients, BPVAC behaves as the key unit.

It would trap bacteria and remove their toxins from the blood out of the
body.
BPVACs perform as out of body detoxification for trapping of BATs from
septic blood and check them from returning back to the patient’s body.
Schematic diagram of proposed setup for
prospective auxiliary treatment of sepses.
Notes: It uses BPVAC for removing BATs from the blood
of septic patients. BPVAC would work aseptically with
the aid of a blood pump in a closed circuit. Main features
of the treatment would include (A) hand of septic
patient, (B) blood removed from artery, (C) arterial
pressure monitor, (D) inflow sampling to detect BATs
titer before processing, (E) heparin pump (to prevent
clotting), (F) peristaltic blood pump, (G) pressure
monitor indicating outflow pressure from the blood
pump, and (H) BPVAC, the central component of the
treatment, designed to trap and immobilize BATs from
infected blood. BATs would adhere to BATs-antibodies,
and hence, would be trapped inside the column. (I)
pressure monitor indicates outflow pressure from BPVAC,
(J) air detector and air trap, (K) outflow sampling to
monitor BATs titer by appropriate serological tests, and
(L) detoxified blood returns to the vein. All tubing and
BPVAC would be applied aseptically; however, they are
single-use and would be properly disposed of after
treatment.
Abbreviations: BPVAC, bacterial polyvalent antibody-
column; BATs, bacterial antigens and their toxins.
Use of BPVAC as an auxiliary therapy along with conventional
treatments would improve the therapy outcome since:
1) BPVAC diminishes BATs in blood and minimizes the duration of their
contact with internal vital organs and
2) when BPVAC is used, the major titer of BATs in blood would be
depleted rapidly, and hence, the efficacy of conventional treatments,
especially antibiotic therapies, would enhance.
Such a dual therapy may decrease sepsis side effects.

Considering that time is a key factor in resuscitation of intoxicated

patient, BPVAC may act as a lifesaving device in infectious blood diseases
when the physician has limited choice of antibiotic therapy due to
microbial resistance and/or lack of appropriate antibiotics.
 SUN AND UV LIGHT
Sepsis is a deadly disease, defined as infection of the tissues by
bacteria. It can spread throughout the body and blood, where it is
known as septicemia.
Also, it should be remembered that sunlight is said to be the
best disinfectant.
It is likely that vitamin D, produced by sun exposure, is the mechanism
by which sepsis risk is decreased in summer.
Vitamin D upregulates human cathelicidin, LL-37, which has
antimicrobial as well as anti-endotoxin activity.
Ultraviolet (UV) blood irradiation (UVBI)
UV therapy is used to treat many kinds of infections and diseases
• the following bacteria were killed by ultraviolet light: anthrax, plague,
streptococci, tubercle bacillus, cholera, staphylococcus, colon bacillus and
dysentery bacillus.
• Use to treat diseases including septicemia, pneumonia, tuberculosis,
arthritis, asthma and even poliomyelitis.
The process generally involves withdrawing a measure of blood and
running it through a machine that exposes it to ultraviolet rays. The blood
is then reintroduced into the person's body (Extracorporeal irradiation).
The process creates a response in the immune system called an
“autogenous vaccine," which "stimulates the immune system to destroy
any and all pathogens."
 LASER IRRADIATION
• Laser therapy uses a process called photobiomodulation. Photons
enter the tissue and interact with the cytochrome c complex within
mitochondria. This interaction triggers a biological cascade of events
that leads to an increase in cellular metabolism and a decrease in
both pain and inflammation.
• Late sepsis causes immunosuppression and is associated with energy
depletion in lymphocytes. Laser irradiation can promote cell
proliferation and increase cellular ATP synthesis, which may improve
the host immune response in sepsis.
• LI improves the host immune response and survival rate in sepsis. LI
may be useful as an adjuvant therapy for sepsis.
 Sepsis prevention
Taking steps to prevent the spread of infection can reduce your
risk of developing sepsis. These include:
• Staying up to date on your vaccinations. Get vaccinated for
the flu, pneumonia, and other infections.
• Practicing good hygiene. This means practicing proper wound
care, handwashing, and bathing regularly.
• Getting immediate care if you develop signs of infection. Every
minute counts when it comes to sepsis treatment. The sooner
you get treatment, the better the outcome.
 Outlook
It’s important to remember that sepsis is a medical
emergency. Every minute and hour counts, especially
since the infection can spread quickly. There’s no one
symptom of sepsis, but rather it has a combination of
symptoms. Get immediate medical attention if you
suspect that you have sepsis, especially if you have a
known infection.
QUESTION???