SEPSIS

Dr Aung Paing Phyo

 Sepsis is a life-threatening organ dysfunction
that results from the body’s response to
infection. It requires prompt recognition,
appropriate antibiotics, careful hemodynamic
support, and control of the source of infection.
 With the trend in management moving away
from protocolized care in favor of appropriate
usual care, an understanding of sepsis
physiology and best practice guidelines is
critical
 Tools such as the Systemic Inflammatory
Response Syndrome criteria and the quick
version of the Sequential Organ Failure
Assessment can help with early diagnosis and
triage.
 The initial antibiotic should be broad-spectrum,
based on local sensitivity patterns, with daily
assessment of appropriate antibiotic de-
escalation and cessation
 Resuscitation with initial fluid boluses should
be followed by weighing benefits and risks of
additional fluid administration based on
dynamically assessed volume status, and then
aggressive fluid removal during recovery.
 During resuscitation, a goal mean arterial
pressure of 65 mm Hg is preferred, using
norepinephrine (with vasopressin if needed) to
achieve it.
 Sepsis and particularly septic shock should be
recognized as medical emergencies in which
time matters, as in stroke and acute myocardial
infarction.
 Early recognition and rapid institution of
resuscitative measures are critical.
 But recognizing sepsis can be a challenge, and
best management practices continue to evolve.
 This article reviews guidance on the diagnosis
and management of sepsis and septic shock,
with attention to maximizing adherence to best
practice statements, and controversies in
definitions, diagnostic criteria, and management.
 In 1991, sepsis was first defined as a systemic
inflammatory response syndrome (SIRS) due to
a suspected or confirmed infection with 2 or
more of the following criteria:
 Temperature below 36°C or above 38°C
 Heart rate greater than 90/minute
 Respiratory rate above 20/minute, or arterial
partial pressure of carbon dioxide less than 32
mm Hg
 White blood cell count less than 4 × 109/L or
greater than 12 × 109/L, or more than 10%
bands.
 Severe sepsis was defined as the progression of
sepsis to organ dysfunction, tissue
hypoperfusion, or hypotension.
 Septic shock was described as hypotension and
organ dysfunction that persisted despite
volume resuscitation, necessitating vasoactive
medication, and with 2 or more of the SIRS
criteria listed above.
 In 2016, the Sepsis-3 committee issued the
following new definitions:
 Sepsis—A life-threatening condition caused by

a dysregulated host response to infection,

resulting in organ dysfunction
 Septic shock—Circulatory, cellular, and
metabolic abnormalities in septic patients,
presenting as fluid-refractory hypotension
requiring vasopressor therapy with associated
tissue hypoperfusion (lactate > 2 mmol/L).
 The classification of severe sepsis was

eliminated
TOOLS FOR IDENTIFYING HIGH RISK:
SOFA AND qSOFA
 SOFA is an objective scoring system to determine major
organ dysfunction, based on oxygen levels (partial
pressure of oxygen and fraction of inspired oxygen),
platelet count, Glasgow Coma Scale score, bilirubin level,
creatinine level (or urine output), and mean arterial
pressure (or whether vasoactive agents are required).
 It is routinely used in clinical and research practice to
track individual and aggregate organ failure in critically
ill patients.
 But the information needed is burdensome to collect and
not usually available at the bedside to help with clinical
decision-making.
 qSOFA is simpler…
 Singer et al8 compared SOFA and SIRS and identified 3
independent predictors of organ dysfunction associated
with poor outcomes in sepsis to create the simplified
qSOFA:
 Respiratory rate at least 22 breaths/minute
 Systolic blood pressure 100 mm Hg or lower
 Altered mental status (Glasgow Coma Scale score < 15).
 A qSOFA score of 2 or more with a suspected or
confirmed infection was proposed as a trigger for
aggressive treatment, including frequent monitoring
and ICU admission.
 qSOFA has the advantage of its elements being easy to
obtain in clinical practice
 Although qSOFA identifies severe organ
dysfunction and predicts risk of death in
sepsis, it needs careful interpretation for defi
ning sepsis.
 One problem is that it relies on the clinician’s
ability to identify infection as the cause of
organ dysfunction, which may not be apparent
early on, making it less sensitive than SIRS for
diagnosing early sepsis.
 Also, preexisting chronic diseases may infl
uence accurate qSOFA and SOFA
measurement.
 In addition, qSOFA has only been validated
outside the ICU, with limited utility in patients
already admitted to an ICU.
 Studies have suggested that the SIRS criteria be
used to detect sepsis, while qSOFA should be
used only as a triaging tool
ANTIMICROBIAL THERAPY
 Delay in giving appropriate antibiotics is

associated with a significant increase in

mortality rate.
 Appropriate antimicrobials should be initiated

within the first hour of recognizing sepsis, after

obtaining relevant samples for culture—
provided that doing so does not significantly
delay antibiotic administration.
 The initial antimicrobial drugs should be broad-
spectrum, covering all likely pathogens.
 Multidrug regimens are favored to ensure
sufficient coverage, especially in septic shock.
 The empiric choice of antimicrobials should
consider the site of infection, previous antibiotic
use, local pathogen susceptibility patterns,
immunosuppression, and risk factors for resistant
organisms.
 Double coverage for gram-negative organisms
and for methicillin-resistant Staphylococcus aureus
(MRSA) should be considered for patients with a
high likelihood of infection with such pathogens.
 Appropriate dosing is also important, as
efficacy depends on peak blood level of the
drug and on how long the blood level remains
above the minimum inhibitory concentration
for the pathogen.
 An initial higher loading dose may be the best
strategy to achieve the therapeutic blood level,
with further dosing based on consultation with
an infectious disease physician or pharmacist,
as well as therapeutic drug monitoring if
needed
Consider antifungals
 The last few decades have seen a 200% rise in

the incidence of sepsis due to fungal

organisms.
 Antifungals should be considered for patients

at risk, such as those who have had total

parenteral nutrition, recent broad-spectrum
antibiotic exposure, perforated abdominal
viscus, or immunocompromised status, or
when clinical suspicion of fungal infection is
high.
De-escalation and early cessation
 Antibiotics are not harmless: prolonged use of broad-

spectrum antibiotics is associated with antimicrobial

resistance, Clostridium difficile infection, and even death.
 A robust de-escalation strategy is needed to balance an

initial broad-spectrum approach.

 A pragmatic strategy may involve startingwith broad-

spectrum antimicrobials, particularly in the setting of

hypotension, and then rapidly de-escalating to an
antimicrobial with the narrowest spectrum based on
local sensitivity patterns.
 If the clinical course suggests the illness is not actually

due to infection, the antibiotics should be stopped

immediately.
 Antibiotic de-escalation should be discussed
daily and should be an essential component of
daily rounds.17 A 7- to 10-day course or even
shorter may be appropriate for most infections,
although a longer course may be needed if
source control cannot be achieved, in
immunocompromised hosts, and in S aureus
bacteremia, endocarditis, or fungal infections.
 FLUID RESUSCITATION
 Sepsis is associated with vasodilation, capillary
leak, and decreased effective circulating blood
volume, reducing venous return.
 These hemodynamic effects lead to impaired
tissue perfusion and organ dysfunction.
 The goals of resuscitation in sepsis and septic
shock are to restore intravascular volume,
increase oxygen delivery to tissues, and reverse
organ dysfunction.
 A crystalloid bolus of 30 mL/kg is
recommended within 3 hours of detecting severe
sepsis or septic shock
 Some have cautioned against giving too much
fluid, especially in patients who have limited
cardiorespiratory reserve.
 Overzealous fluid administration can result in
pulmonary edema, hypoxemic respiratory
failure, organ edema, intra-abdominal
hypertension, prolonged ICU stay and time on
mechanical ventilation, and even increased risk
of death
 With this in mind, fluid resuscitation should be
managed as follows during consecutive phases
 Rescue: During the initial minutes to hours, fluid
boluses (a 1- to 2-L fluid bolus of crystalloid solution)
are required to reverse hypoperfusion and shock
 Optimization: During the second phase, the benefits
of giving additional fluid to improve cardiac output
and tissue perfusion should be weighed against
potential harms
 Stabilization: During the third phase, usually 24 to 48
hours after the onset of septic shock, an attempt
should be made to achieve a net-neutral or a slightly
negative fluid balance
 De-escalation: The fourth phase, marked by shock
resolution and organ recovery, should trigger
aggressive fluid removal strategies
 Assess volume with dynamic measures
 Clinicians should move away from using static
measures to assess volume status.
 Central venous pressure, the static measure
most often used to guide resuscitation, has
been found to be accurate in only half of cases,
compared with thermodilution using
pulmonary artery catheters to assess change in
cardiac output with volume administration
 Dynamic measures are used to estimate the
effects of additional volume on cardiac output.
 Two methods are used: either giving a fl uid
bolus or passively raising the legs.
 The latter method returns 200 to 300 mL of
blood fromthe lower extremities to the central
circulation and is performed by starting the
patient in a semirecumbent position, then
lowering the trunk while passively raising the
legs.
 With either method, the change in cardiac
output is measured either directly (eg, with
thermodilution, echocardiography, or pulse
contour analysis) or using surrogates (eg, pulse
pressure variation)
 Alternatively, changes in cardiac output can be
evaluated by heart-lung interactions in a
patient on a mechanical ventilator.
 Changes in intrathoracic pressure are assessed
during the inspiratory and expiratory cycle to
detect changes in cardiac output using pulse
pressure variation, stroke volume variation,
and variation in inferior vena cava size
 The dynamic measures mentioned above are
more accurate than static measurements in
predicting preload responsiveness, so they are
recommended to guide fluid management.
 But they do have limitations
 Although giving a fluid bolus remains the gold
standard for critically ill patients,
indiscriminate fluid administration carries the
risk of fluid overload
 Heart-lung interactions are imprecise for patients
with arrhythmias, those who are spontaneously
breathing with active effort on the ventilator, and
those with an open chest or abdomen.
 Thus, their use is limited in most critically ill
patients
 Unlike other dynamic tests, the passive leg-raise
test is accurate in spontaneously breathing
patients, for patients with cardiac arrhythmias,
and for those on low tidal volume ventilation.
 Due to its excellent sensitivity and specificity, the
passive leg-raise test is recommended to
determine fluid responsiveness
 Lactate level as a resuscitation guide
 Lactate-guided resuscitation can significantly
lessen the high mortality rate associated with
elevated lactate levels (> 4 mmol/L)
 A rise in lactate during sepsis can be due to
tissue hypoxia, accelerated glycolysis from a
hyperadrenergic state, medications
(epinephrine, beta-2 agonists), or liver failure
 Measuring the lactate level is an objective way
to assess response to resuscitation, better than
other clinical markers, and it continues to be an
integral part of sepsis definitions and the
Surviving Sepsis Campaign care bundle
 Even though lactate is not a direct surrogate of
tissue hypoperfusion, it is a mainstay for
assessing end-organ hypoperfusion
 Central venous oxygen saturation-guided
resuscitation (requiring central vascular access)
does not offer any advantage over lactate-
guided resuscitation.
 Microvascular assessment devices are
promising tools to guide resuscitation, but their
use is still limited to clinical research.
 Although optimal resuscitation end points are
not known, key variables to guide resuscitation
include a composite of physical examination
findings plus peripheral perfusion, lactate
clearance, and dynamic preload responsiveness
 Balanced crystalloids are preferred over isotonic solutions
 Crystalloid solutions (isotonic saline or balanced
crystalloids) are recommended for volume resuscitation in
sepsis and septic shock.
 The best one to use is still debated, but over the last decade,
balanced solutions have come to be favored for critically ill
patients.
 Growing evidence indicates that balanced crystalloids
(lactated Ringer solution, Plasma-Lyte) are associated with a
lower incidence of renal injury, less need for renal
replacement therapy, and lower mortality in critically ill
patients.
 Moreover, isotonic saline is associated with hyperchloremia
and metabolic acidosis, and itcan reduce renal cortical blood
flow
 No proven benefit from colloids
 The rationale for using colloids is to increase
intravascular oncotic pressure, reducing
capillary leak and consequently reducing the
amount of fluid required for resuscitation.
 But in vivo studies have failed to demonstrate
this benefit
 One can consider using albumin in sepsis if a
significant amount of resuscitative fluid is
required to restore intravascular volume
 But comparisons of crystalloids and albumin,
either for resuscitation or as a means to
increase serum albumin in critically ill patients,
have found no benefit in terms of morbidity or
mortality.
 Also its substantial cost—20 to 100 times as
much as crystalloids with an additional cost
greater than $30,000 per case with use of
albumin
 Hydroxyethyl starch, another colloid, was
associated with a higher mortality rate and a
higher incidence of renal failure in septic
patients and should not be used for
resuscitation
 EARLY SOURCE CONTROL
 Source control is imperative in managing
sepsis and septic shock.
 Inadequate source control may lead to
worsening organ function and hemodynamic
instability despite appropriate resuscitative
measures
 A thorough examination and appropriate
imaging studies should be performed to
determine the optimal way to control the
source and assess the risks associated with each
intervention
 If appropriate, source control should be
achieved within 6 to 12 hours of diagnosis,
once initial resuscitation is completed.
 The source control can range from removal of
infected intravascular devices to a chest tube
for empyema to percutaneous or surgical
intervention in cases of cholecystitis and
pyelonephritis
 RESTORING BLOOD PRESSURE
 Persistent hypotension and tissue
hypoperfusion after adequate fl uid
resuscitation are caused by loss of normal
sympathetic vascular tone, leading to
vasodilation, neurohormonal imbalances,
myocardial depression, microcirculatory
dysregulation, and mitochondrial dysfunction
 Vasopressors and inotropes restore oxygen
delivery to tissues by increasing arterial
pressure and cardiac output respectively
 Mean arterial pressure is the preferred blood
pressure to target during resuscitation.
 The recommended initial goal is 65 mm Hg.
 A higher goal of 80 to 85 mm Hg may help
 patients with chronic hypertension,while a
lower target may be better tolerated in patients
with reduced systolic function, older patients,
and patients with end-stage liver disease
 After blood pressure falls below a critical
threshold, tissue perfusion decreases linearly
 Norepinephrine is the first-line vasopressor
 Norepinephrine has shown survival benefit
with lower risk of arrhythmia than dopamine
 On the other hand, 2 systematic reviews found
no difference in clinical outcomes and
mortality with norepinephrine vs epinephrine,
vasopressin, terlipressin, or phenylephrine
 Without convincing evidence to support other
agents as first-line therapy for septic shock,
norepinephrine remains the preferred
vasopressor for achieving the target mean
arterial pressure and is strongly recommended
by the Surviving Sepsis Campaign guidelines
 Adding a second vasopressor or inotrope
 Another sympathomimetic drug such as
vasopressin or epinephrine can be used to
either achieve target mean arterial pressures or
decrease the norepinephrine requirement.
 A second vasopressor is routinely added when
norepinephrine doses exceed 40 or 50 μg/min
 Vasopressin. Septic shock involves relative
vasopressin deficiency.
 Adding vasopressin as a replacement hormone
has been shown to have a sparing effect on
norepinephrine, resulting in a lower dose
needed
 Evidence supporting the use of vasopressin
over norepinephrine as a first-line agent
remains limited, but vasopressin remains the
preferred adjunct with norepinephrine
 Epinephrine is recommended by the Surviving
Sepsis Campaign guidelines as a second-line
vasopressor. It has potent alphaand beta-
adrenergic activity, which increases mean
arterial pressure by increasing cardiac output
and vasomotor tone.
 Use of epinephrine is limited by signifi cant
risk of tachycardia, arrhythmia, and transient
lactic acidosis
 Dopamine use is discouraged in sepsis owing
to its propensity to induce tachyarrhythmia and
signifi cantly worsen outcomes in this setting
 Phenylephrine is a pure alpha-adrenergic
agonist that is routinely used in septic shock,
albeit with limited data on its effi cacy and
safety.
 Phenylephrine use should be limited to septic
shock complicated by significant
tachyarrhythmia or as an adjunct for refractory
vasodilatory shock until there is more evidence
of its benefits
 Angiotensin II was recently approved as a
vasopressor for use in septic shock. It activates
angiotensin type 1a and 1b receptors to
increase intracellular calcium in smooth
muscle, promoting vasoconstriction
 Clinical data related to its use are limited to a
recent trial that showed that the addition of
angiotensin II improved blood pressure in
patients with refractory vasodilatory shock
receiving high-dose vasopressors
 Inotropic agents may be required for patients
with inadequate cardiac output after fluid
resuscitation due to sepsis-induced
cardiomyopathy or combined shock
 Data are limited suggesting an optimal
inotropic agent in septic shock, but epinephrine
and dobutamine are most commonly used
 Milrinone and levosimendan (not approved in
the United States) have been studied, with
limited data to support their use over
dobutamine.
 The response to use of inotropes should be
monitored by measuring changes in cardiac
output, central venous oxygen saturation, or
other indices of tissue perfusion
 ROLE OF CORTICOSTEROIDS IS
QUESTIONED
 Corticosteroids downregulate the maladaptive
inflammatory response seen in sepsis and help
address relative adrenal insufficiency caused by
adrenal suppression or glucocorticoid tissue
resistance
 In septic shock, they have a vasopressor-
sparing role and reduce the duration of shock,
ventilator use, and ICU stay
 However, the evidence is not conclusive that
giving corticosteroids for sepsis improves
clinical outcomes or survival
 Rather, they can be added as adjunctive
therapy for patients requiring higher doses of
vasopressors.
 Adverse events in studies of corticosteroids
were limited to hyperglycemia, hypernatremia,
and hypertension, with no increase in
superinfections.
 The limited adverse events, along with a
uniform demonstration of shorter shock
duration, ventilator duration, and ICU stay,
suggest steroids may have a role in managing
refractory septic shock
 If corticosteroids are used in septic shock,
current guidelines recommend hydrocortisone
200 mg per day intravenously as a continuous
drip or 50 mg bolus in 4 divided doses for at
least 3 days, based on a systematic review
showing a longer course of low-dose steroids is
associated with a lower mortality rate
 There is no clear consensus on whether steroids
should be tapered or if abrupt cessation is
appropriate
 BIOMARKERS
 Biomarkers facilitate early diagnosis, identify
patients at high risk, and monitor disease
progression to guide resuscitation goals and
tailor management
 C-reactive protein and erythrocyte
sedimentation rate have been used in the past,
but with limited success
 Procalcitonin has emerged as a method to help
detect bacterial infections early and to guide
de-escalation or discontinuation of antibiotics.
 Procalcitonin-guided de-escalation of
antibiotics reduces duration of antibiotic
exposure, with a trend toward decreased
mortality.
 Galactomannan and beta-D-glucan can be
used to detect infections with fungi, specially
Aspergillus.
 Beta-d-glucan is more sensitive for invasive
Aspergillus, while galactomannan is more
specific
 Cytokines such as interleukins (eg, IL-6, IL-8,
IL-10), tumor necrosis factor alpha, acute-phase
proteins, and receptor molecules are currently
being studied to determine their utility in
sepsis care
 The limited sensitivity and specificity of single
biomarkers may be overcome by using a
combination of biomarkers, which is a current
focus of research.
 For now, the decision to initiate, escalate, and
de-escalate therapy should be based on clinical
assessment, with procalcitonin or other
biomarkers used as an adjunct to other clinical
factors
 Is SEP-1 appropriate?
 In January 2013, the State of New York
mandated that all state hospitals initiate
processes for early detection and treatment of
sepsis
 October 2015, the National Quality Forumand
CMS implemented these processes nationwide
 The resultant CMS SEP-1 quality measure
standardizes early management of severe
sepsis and septic shock with the goal of
improving outcomes
 Its elements are based on the Surviving Sepsis
Campaign guidelines and consist of a series of
steps that need to be completed within 3 and 6
hours after sepsis is recognized
 Steps to be performed within 3 hours include
measuring the serum lactate level,
drawingblood cultures, and starting
appropriate antibiotics, intravenous fluid
resuscitation, and vasopressor support if
needed
 A lactate level is repeated within 6 hours, and
static and dynamic assessment of perfusion
must be done to determine the need for
additional fluid or vasopressors to improve
end-organ perfusion
 Although SEP-1 has been adopted as a quality
measure, some question its clinical relevance,
as many of the core recommendations are not
supported by strong evidence
 Seymour et al28 collected New York State
Department of Health data for 49,331 patients
with sepsis and septic shock and found that more
rapid completion of the 3-hour bundle—
particularly of antibiotic administration but not of
fluids—was associated with decreased hospital
mortality
 A major concern about mandating SEP-1 is that
fluids and broad-spectrum antibiotics will be
overprescribed as healthcare systems try to meet
CMS-mandated quality measures.
 Indiscriminate use of these therapies has the
potential to cause harm and puts an undue strain
on healthcare resources
 A call to refine guidance
 Sepsis is a multifaceted disease, and its
management is complex.
 Simplified guidelines and quality measures
based on sound evidence are needed
 The success of optimal care initiatives requires
sustained, collaborative quality improvement
across different specialties in medicine,
nursing, and hospital administration