Septicemia & its management

Introduction
Sepsis derives from the Greek for putrefaction and
was recognized as a frequent complication of
wounds.
As will be discussed here, the definitions of sepsis
still prove difficult, and despite significant
advances in intensive care medicine and
antimicrobial therapy, sepsis remains a common
condition with high attributable mortality.
The most seriously affected by sepsis will
require management in an intensive care
setting where available, but we will focus on
the diagnosis and immediate management of
sepsis, as this is of broad importance to all
physicians dealing with acutely ill patients.
Definition
Septicemia, blood poisoning and other vague terminology,
meaning different things to different people, were used
frequently.
This hampered attempts to properly identify septic patients
promptly, and hindered the design of trials with
standardized entry criteria.
In 1991, a consensus conference developed definitions of
sepsis that linked infection with a systemic inflammatory
response, the systemic inflammatory response syndrome
(SIRS), which was defined using simple clinical and
laboratory parameters.
This had the advantage of standardizing the
definition of sepsis across different regions
and was a significant advance. However, the
definition of SIRS, although sensitive to
detect sepsis, was rather unspecific, since
similar inflammatory responses were seen as
part of the physiological response to non-
infectious insults, such as surgery and
pancreatitis. In addition, the SIRS criteria
performed badly in identifying patients who
required critical care and who had significant
morbidity and mortality.
These issues led to a recent new consensus
definition for sepsis and septic shock.
This international task force defined sepsis as
‘life-threatening organ dysfunction caused by a
dysregulated host response to infection.’
Importantly, the task force considered how to
operationalize this definition, by analyzing what
clinical criteria best identified infected patients
with sepsis who died.
Using large datasets (>1 million patient records),
they found that an increase in 2 points or more for
a patient suspected to have infection using the
Sequential Organ Failure Assessment (SOFA) best
predicted in-hospital mortality.
The SOFA is well known within the intensive care
community, but is not so well known generally.
Therefore, the task force developed a simpler
clinical screening tool that performed very well in
identifying adult patients with suspected infection
who were likely to have poor outcomes, which they
termed ‘quick SOFA’ (qSOFA). This measures three
clinical parameters ( Box 1 ).
A patient who fulfilled two of these criteria had similar
outcomes to those who had an increase in 2 points on the full
SOFA scale.
The task force therefore considered that a qSOFA score of 2 or
more should prompt clinicians to investigate further for organ
dysfunction, consider escalation of therapy, and evaluate for
referral to critical care.
The same grouping also considered the definitions of septic
shock. Traditionally, this had been defined based on the cardinal
feature of hypotension as a marker of the cardiovascular
dysfunction associated with this condition.
 However, it has become apparent that the
application and interpretation of such a definition is
very variable. Therefore, a new consensus was
sought.
Septic shock was newly defined as ‘a subset of
sepsis in which circulatory, cellular and metabolic
abnormalities are associated with a greater risk of
mortality than sepsis alone.
Operationally, they identified septic shock as being
present when the two particular conditions were
met ( Box 2 ).
These new definitions have been adopted by
numerous international societies but are only just
entering into routine clinical practice.
They have the advantage of simplicity and are
underpinned by robust data on their performance in
identifying those patients with suspected infection
who have the worst outcomes.
They are simpler to apply, for example, than the
recent National Institute for Health and Care
Excellence (NICE) guidelines.
However, a number of problems remain. This
consensus group did not address the definition of
infection.
Despite improvements in diagnosis, only about
30–40% of patients who are suspected of having an
infection will actually have a positive
microbiological diagnosis.
Therefore, patients whose organ dysfunction is
secondary to a cause other than infection will still
potentially be misdiagnosed and unnecessary
antimicrobials administered.
Additionally, no stratification of different
degrees of sepsis is given, so targeting care for
individual patients is difficult.
In other fields, such as cancer biology, a wealth
of genetic, transcriptomic and metabolic data
are allowing ever more specific ‘personalized’
treatment.
Despite many excellent studies, there is as yet
no molecular ‘signature’ of particular
biomarkers that can unequivocally identify a
patient with infection or their likely outcome.
Such objective molecular criteria would greatly
help in diagnosis and management.
Pathogenesis
In an attempt to simplify this complex pathogenic
pathway, four main features can be highlighted –
these include the following:-

1. Endothelial dysfunction
2. Coagulopathy
3. Cellular dysfunction
4. Cardiovascular dysfunction
 1. Endothelial dysfunction
Generalized endothelial activation increases the
expression of a number of leucocyte adhesins, with
increased leucocyte transmigration into tissues.
The permeability of the endothelium is also
increased, in the lung leading to interstitial
pulmonary edema and in the gut increasing
bacterial translocation, potentially exacerbating the
inflammatory cascades already initiated by
microbial products.
2. Coagulopathy
Altered coagulation is extremely common in sepsis.
Endothelial damage removes the protective function of
the natural anticoagulation protein C pathway and
converts the endothelium into a prothrombotic surface.
In addition, bacterial products and inflammatory
cytokines activate tissue factor, the main initiator of
the extrinsic pathway of blood coagulation. This
prothrombotic state may lead to blockage of the
microvasculature, as well as giving rise to a
consumption coagulopathy (disseminated
intravascular coagulation). Gram-positive products can
also directly activate the contact clotting system.
 3. Cellular dysfunction
One of the enigmas of the field is that even in the
most severe cases of lethal sepsis, autopsy studies
show little evidence of cell death, despite
widespread organ dysfunction.
The molecular basis of this is still not clear,
although a generalized reduction in energy
expenditure by cells suggests some kind of
hibernation like process.
Concomitant with this alteration in cellular function
are numerous metabolic changes, notably increased
catabolism, insulin resistance and hyperglycemia.
4. Cardiovascular dysfunction
Many studies have shown that patients with
sepsis have a decreased systemic vascular
resistance (SVR) with a normal or increased
cardiac output, the so-called ‘hyperdynamic’
state of sepsis.
Cardiac output is maintained at the expense of
left ventricular dilation, with reduced ejection
fraction and a reduced left ventricular stroke
work index in response to left ventricular end
diastolic volume increase.
 These changes can lead to the hypotension
characterizing septic shock. Changes in SVR are
probably largely mediated by excess production
of the vasodilator nitric oxide in the
vasculature, which can be difficult to correct
with vasopressors.
Poor tissue perfusion also likely underlies the
increased lactate seen in septic shock,
although other mechanisms are possible.
Management
Survival in sepsis has improved over the last 40
years. However, we still lack a specific molecular
therapy for this condition, other than antimicrobial
therapy.
Numerous trials of promising biological agents
targeting different mediators of sepsis have failed.
This lecture will focus on the immediate
management of sepsis – the management of patients
in a critical care setting is not covered here.
Lines of Management
1. Resuscitation
2. Prompt and appropriate antimicrobial
therapy
3. Accurate fluid balance
4. Correction of Blood glucose
5. Source control
1. Resuscitation
Immediate resuscitation of a critically ill septic patient
is not appreciably different from non-septic patients.
Adequate oxygen to maintain saturations in excess of
95% should be given.
Although there is no high quality randomized controlled
trial evidence, it is considered standard care to give
intravenous saline to all patients with sepsis.
For patients with hypotension, this should be a bolus of
500 mL of saline over 15 minutes. Further fluids should
be titrated to response.
Starch based fluids should be avoided and
there is no evidence to support the use of
albumin.
Persistent hypotension despite adequate
fluid resuscitation will almost certainly
require admission to a critical care facility
and the use of vasopressors – noradrenaline
is the preferred agent.
2. Prompt and appropriate
antimicrobial therapy
Studies have shown a clear benefit of rapid use of
antimicrobials that target the likely causative
pathogens.
Although the exact timing required is not entirely clear,
every effort should be made to give such drugs as
quickly as possible, ideally within 1 hour of admission.
Prior to administering antibiotics, blood cultures should
be taken. Although there are no trials showing the
benefit or not of such cultures, identification and
characterization of antibiotic sensitivities of cultured
pathogens is crucial in further management.
3. Accurate fluid balance

Urine output should be recorded,

together with all fluids administered.
A urinary catheter should be placed if
required for patient management but it
is not essential.
4. Correction of Blood glucose

In the event of hyperglycemia, blood sugar

should be kept <10 mM with intravenous
insulin.
More aggressive blood sugar control is
contraindicated.
5. Source control
Notwithstanding the need for immediate attention to
the deranged physiological parameters, identification
and management of the source of sepsis is also
important.
From the history, full examination and appropriate
radiological investigations, a likely source of infection
may be identified; although, in around 25% of cases no
source can be identified.
However, prompt management of an infection source is
vital, such as drainage of a pleural effusion,
debridement of an infected wound, or surgical
intervention to drain an intra-abdominal Abscess.