REVIEW ARTICLE

Sepsis: An Update on Current

Practices in Diagnosis and
Management
D1X XSnigdha Jain, D2X XMD

Division of Hospital Medicine, UT Southwestern Medical Center, Dallas, Texas

ABSTRACT
Despite several advancements in care over the last few decades, sepsis continues to carry a high morbidity and mortality bur-
den in the United States. With its varied presentations, cases of sepsis are likely to be encountered by general practitioners in
both inpatient and outpatient settings. In the recent years, there has been much debate about the appropriate criteria to diag-
nose patients with sepsis with a concurrent change in management guidelines. This article reviews definitions, diagnosis and
treatment guidelines in current practice in the management of patients with sepsis.
Key Indexing Terms: Sepsis; Infection; Sequential organ failure assessment; Severe sepsis. [Am J Med Sci 2018;356
(3):277 286.]

CASE PRESENTATION expensive cause of hospitalization in the United States.6

A
60-year-old man presented to the emergency
department with a 2-day history of chills and
dysuria. His medical history was significant for
hypertension for which he was taking amlodipine 5 mg
daily. Vital signs in the emergency department were sig-
nificant for a temperature of 38.7°C (101.5°F), heart rate
of 120 beats/minute, blood pressure of 90/60 mmHg,
respiratory rate of 20 breaths/ minute, and oxygen satu-
ration of 95% on room air. Physical examination revealed
dry mucous membranes, tachycardia without gallops,
rubs or murmurs, clear lungs and warm extremities.
Abdominal exam was significant for tenderness on pal-
pation of his suprapubic region. Laboratory testing
showed a creatinine level of 1.6 mg/dL (reference range,
0.5-1.1 mg/dL)—up from a baseline creatinine of
0.9 mg/dL 4 weeks prior, blood urea nitrogen of
56 mg/dL (reference range, 7-20 mg/dL), white-cell count
of 18,000/mm3 (reference range, 4,500-11,000 cells/
mm3), hemoglobin of 9.0 g/dL (reference range, 12.0-
15.5 g/dL) and lactate of 2 mmol/L (reference range, 0.5-
2 mmol/L). Urinalysis showed 3+ leukocyte esterase,
>100 white cells per high-power field, and many
bacteria.
Does this patient have sepsis? How would you treat
him?
INTRODUCTION
Sepsis affects more than 1 million patients in the
United States annually1,2 and more than 30 million adults
worldwide.3 The incidence of sepsis has increased sub-
stantially over the last 4 decades4,5 and with
$23.6 million in health care costs annually, it is the most
Although mortality rates for sepsis have declined signifi-
cantly over the last decade, it continues to be high at
around 20%-30%.4,5,7 Moreover, patients who survive
to discharge face rapid functional and neurocognitive
decline along with a long-term increased risk of mortal-
ity8. In the last few years, the management of sepsis has
evolved rapidly, leaving many clinicians confused about
the current practices in diagnosing patients with sepsis
and the evidence-based approach to treating them. This
article reviews the definitions of sepsis as they have
evolved over time, diagnostic criteria in practice and the
most recent guidelines to direct sepsis treatment.
THE TERM ‘SEPSIS’: A LONG TORTUOUS
HISTORY
The meaning of the term ‘sepsis’ has evolved over
time. The first use of this term can be traced back to 400
BC when Hippocrates described it as a process of biologi-
cal decay.9 Alongside the advent of germ theory, an Aus-
trian physician, Semelweiss, noted a connection between
the higher rates of puerperal sepsis in deliveries conducted
by medical students compared with those by midwives,
and the practice of performing autopsies in the hours pre-
ceding these deliveries by the former. He was one of the
first to suggest an association between germs and sepsis.9
With the expanding knowledge about the pathophys-
iology of sepsis, several additional factors related to the
host response to infection were identified to play a role in
the occurrence of this lethal syndrome. In 1991, the
American College of Chest Physicians and the Society of
Critical Care Medicine convened an international meeting
to formulate the first set of consensus definitions for

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TABLE 1. Sepsis, severe sepsis and septic shock (as defined by Bone et al., 1991).

Systemic Inflammatory Systemic inflammatory response to a variety of severe clinical insults. The response is manifested by 2 or
Response Syndrome more of the following conditions: (1) temperature >38°C or <36°C; (2) heart rate >90 bpm; (3) respiratory
(SIRS) rate >20 breaths per minute or PaCO2 of less than 32 mmHg; and (4) an alteration in the white blood cell
count, such as a count >12,000/ cu mm, a count <4,000/cu mm, or the presence of >10 percent
immature neutrophils (“bands”).
Sepsis Systemic response to infection, manifested by 2 or more of the above SIRS criteria
Severe sepsis Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion may include,
but not limited to lactic acidosis, oliguria, or an acute alteration in mental status
Septic shock Sepsis-induced with hypotension despite adequate fluid resuscitation along with the presence
of perfusion abnormalities.
Abbreviations: bpm, beats per minute; PaCO2, partial pressure of carbon dioxide in arterial blood; SIRS, systemic inflammatory response syndrome.

sepsis.10 They proposed the term ‘Systemic Inflamma-
tory Response Syndrome’ (SIRS), which was used to
designate the clinical manifestations of the host’s inflam-
matory response. This, in turn, could be triggered by a
variety of insults, including infection.
The features of SIRS were defined as (1) a body tem-
perature above 38°C or below 36°C; (2) a heart rate of 90
beats/ minute or higher; (3) tachypnea, manifested by a
respiratory rate greater than 20 breaths/minute, or hyper-
ventilation, as indicated by a partial pressure of arterial car-
bon dioxide (PaCO2) of less than 32 millimeters of mercury
(mmHg); and (4) an alteration in the white blood cell count,
defined by a cell count above 12,000/mm3, a cell count
below 4,000/mm3 or the presence of over 10% immature
neutrophils (“bands”). In this context, sepsis was defined
as the systemic host response to infection, manifested by
2 or more of the above SIRS criteria (Table 1). Further, the
septic response was classified into 3 categories—sepsis,
severe sepsis and septic shock based on the degree of
severity of clinical manifestations (Table 1).
With time, it was recognized that the existing definition
of sepsis did not adequately identify mechanisms underly-
ing its clinical presentation. It also grouped together a het-
erogenous population of patients with respect to the
source of infection, inflammatory mediators and the path-
ophysiological mechanisms behind the organ dysfunc-
tion.11 In 2001, a second large consensus conference was
therefore convened to revise these definitions. They
expanded the list of signs and symptoms to aid in the clin-
ical diagnosis of sepsis (Table 2), however, they found that
there was insufficient empirical evidence to guide a
change in definitions. Therefore, the definitions of sepsis,
severe sepsis and septic shock were not revised.12
SEPSIS-3
In 2014, an expert panel of the European Society of
Intensive Care Medicine and the Society of Critical Care
Medicine reevaluated the sepsis construct. They identi-
fied several challenges with the existing SIRS criteria,
including:
1) High sensitivity: In a large, multicenter, observational
study across 198 intensive care units (ICUs), over
90% of all patients qualify as having ‘sepsis’ based on
the SIRS criteria.13 Further, in a large retrospective
analysis of about 270,000 patients, Churpek et al14
found that on hospital wards, the cumulative propor-
tion of patients who met SIRS criteria at least once
during their stay approached 70% for those hospital-
ized for 7 days.
2) Poor discriminant validity: SIRS represents an inflam-
matory response to infection, and not necessarily a
deleterious response. The SIRS criteria, therefore, do
not effectively distinguish sepsis from uncomplicated
infection.15
3) Poor concurrent validity: In a large retrospective data-
base analysis, Kaukonen et al16 reported that 12% of
patients in the ICU with infection and organ dysfunc-
tion did not meet the SIRS criteria. In addition, they
noted that mortality increased linearly from 0 to 4
without any transition in risk at the cutoff point of 2.16
Sepsis was, therefore, redefined as a life-threatening
organ dysfunction caused by a dysregulated host
response to infection, and septic shock as sepsis with
persistent hypotension requiring the use of vasopressors
to maintain a mean arterial pressure (MAP) above 65
mmHg, and a serum lactate level above 2 mmol/L,
despite adequate volume resuscitation. The sepsis defi-
nitions suggested by Bone et al (Table 1) were retrospec-
tively identified as Sepsis-1, and the 2001 consensus
criteria (Table 2) as Sepsis-2, thereby designating the
2016 definitions, Sepsis-3.17
The diagnostic criteria in Sepsis-3 were based on a
carefully conducted study in a large electronic health
database from 12 academic and community hospitals in
the University of Pittsburgh Medical Center network
between 2010 and 2012.18 All encounters in the emer-
gency departments, wards or the intensive care units
with suspected infection were divided into 2 groups. One
of these groups was used to assess the clinical features
of sepsis that can predict worse patient outcomes, spe-
cifically death and prolonged ICU hospitalization. Among
others, 2 sets of clinical criteria/scores were evaluated in
the study: the SIRS criteria and the Sequential Organ
Failure Assessment (SOFA) Score. The latter is a score

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 Sepsis in the Current Age

TABLE 2. Diagnostic criteria of sepsis determined by 2001 sepsis
conference.
Diagnostic criteria for sepsis
Infection, documented or suspected, and some of the following:
General variables
Fever (core temperature >38.3°C)
Hypothermia (core temperature <36°C)
Heart rate >90/minute or >2 SD above the normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg body
weight over 24 hours)
Hyperglycemia (plasma glucose >120 mg/dl or 7.7 mmol/L) in
the absence of diabetes
Inflammatory variables
Leukocytosis (white blood cell count >12,000 cells/mL)
Leukopenia (white blood cell count <4,000 cells/mL)
Normal WBC count with >10% immature forms
Plasma C-reactive protein >2 SD above the normal value
Plasma Procalcitonin >2 SD above the normal value
Hemodynamic variables
Arterial hypotension (SBP < 90 mm of Hg, MAP < 70 or SBP
decrease >40 mm of Hg or <2 SD below normal for age)
ScVO2 > 70%
Cardiac index >3.5 L/minute
Organ dysfunction variables
Arterial hypoxemia (PaO2/ FiO2 <300)
Acute oliguria (urine output <0.5 mL/kg/h or 45 mmol/L for
at least 2 hours)
Creatinine increase > 0.5 mg/dL
Coagulation abnormalities (INR > 1.5 or aPTT > 60 seconds)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000 cells/mL)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL
or >70 mmol/L)
Tissue perfusion variables
Hyperlactatemia (>1 mmol/L)
Decreased capillary refill or mottling
Abbreviations: aPTT, activated partial thromboplastin time; cells/mL, cells
per microliter; ScVO2, central venous oxygen saturation; INR, International
Normalized Ratio; L/min, liters per minute; mL/kg/h, milliliters per kilogram
per hour; mL/kg, milliliters per kilogram; mg/dL, milligrams per deciliter;
mmol/L, millimoles per liter; MAP, mean arterial pressure; PaO2/FiO2, par-
tial pressure of oxygen in arterial blood divided by fraction of oxygen in the
inspired air; SBP, systolic blood pressure; SD, standard deviation.
elevated respiratory rate had a greater predictive ability
than both the SOFA score and the SIRS criteria. Figures 1
and 2 summarize the sepsis criteria proposed by Sepsis-3.
Criticism of Sepsis-3
The new sepsis and septic shock definitions have
been widely debated in the critical care and emergency
medicine communities. While endorsed by the Society of
Critical Care Medicine and the American Thoracic Soci-
ety,17 they have not been supported by a few societies
including the American College of Chest Physicians,19
the Infectious Disease Society of America20 and the Latin
American Sepsis Institute.21 A few major concerns
regarding the new criteria include:
1. An emphasis on organ failure can delay the early rec-
ognition and treatment of sepsis.19
2. This change in definition was not prompted by any
new scientific breakthrough or new clinical evidence
for sepsis.22
3. The qSOFA score was derived using a data driven
approach in a single study from 1 country.23
4. Since SIRS represent the current clinical criteria, their
lower discriminative ability for worse outcomes may
reflect their use in the recognition and initiation of
early treatment of sepsis leading to improved patient
outcomes.24
5. The requirement of hyperlactatemia poses a grave
challenge to defining septic shock in low resource
communities where lactate measurement may not be
available. Does this mean that septic shock cannot be
defined in these settings?25
6. Evidence for guidelines directing the management of
sepsis comes from trials, including the recent PRISM
trials, that enrolled patients based on previous defini-
tions. Using Sepsis-3 would put into question the
application of their results as majority of the included
patients would no longer qualify as having sepsis or
septic shock.19
7. Several other predictive scoring systems were not
considered.26

frequently used in the ICU setting to assess the risk of

end-organ damage in critically ill adults. Further, this
group of patients was used to identify a new set of crite-
ria with a good performance in predicting a higher rate of
worse outcomes. The second group of patients was
used to validate the predictive accuracy of these criteria.
In addition, these clinical criteria were cross-validated in
4 external cohorts. The study found that among patients
in the ICU setting, SOFA had a higher predictive accu-
racy for death and prolonged ICU stay, compared with
SIRS criteria. However, among patients not in the ICU, a
simple model quick SOFA or qSOFA, comprising FIGURE 1. Diagnostic criteria for sepsis proposed by the consen-
altered mentation, low systolic blood pressure and sus conference of 2015.

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FIGURE 2. Quick Sequential Organ Failure Assessment (qSOFA) as
a screening tool in patients with suspected infection outside of the
intensive care unit.
The scoring systems SOFA and qSOFA have been sub-
sequently validated in other cohorts (Table 3). They
appear to have superior predictive ability for in-hospital
mortality, compared with SIRS, consistent with the
results of the primary study supporting the Sepsis-3 cri-
teria. However, a study that evaluated the predictive
validity of SOFA and qSOFA against the modified and
the national early warning scores (MEWS, NEWS) found
the latter to be marginally superior.
MANAGEMENT OF SEPSIS
The current management of sepsis primarily
involves early resuscitation, and infection control
(Figure 3). Therapeutic strategies that target specific
aspects of the pathophysiology of sepsis are under
active investigation. While the existing guidelines on
treatment strategies are reviewed here, it is worth
keeping in mind, that evidence that shaped their devel-
opment stemmed from trials including patients based
on the old definitions of sepsis and may not be entirely
valid with the new definitions. The strength of each
recommendation and the quality of evidence guiding it
is mentioned here. Readers are encouraged to refer to
the surviving sepsis campaign guideline document for
a detailed explanation.27
Resuscitation
Targets for Resuscitation
In 2001, in a single-center randomized controlled trial
of patients with severe sepsis and/or septic shock, Riv-
ers et al found a 16% absolute reduction in in-hospital
mortality with a resuscitation strategy focused on
addressing cardiac preload, afterload, contractility and
the oxygen carrying capacity of blood to achieve a bal-
ance between oxygen demand and delivery. The latter
was measured using mixed venous oxygen saturation.28
The protocol was subsequently adopted worldwide and
incorporated into sepsis care bundles. However, given
the single-center nature of this study, there were signifi-
cant concerns regarding its generalizability, and the effi-
cacy of the specific components of this treatment
strategy.
280
In 2014-2015, 3 large multicenter trials the Protocol-
ized Care for Early Septic Shock trial in the United States29,
the Protocolised Management in Sepsis trial in the United
Kingdom,30 and the Australasian Resuscitation in Sepsis
Evaluation study in Australia and New Zealand,31 evaluated
the efficacy of EGDT, compared with usual care. Each of
these trials, as well as their patient-level meta-analysis
(PRISM),32 found no benefit of EGDT for in-hospital or 90-
day mortality. It is possible though that these differences
reflect changes in the usual care of severe sepsis over the
15 years between Rivers’ study and the PRISM trials rather
than a failure of the EGDT strategy. In their study level
meta-analysis of the PRISM trials, Angus et al note that the
amount of fluid administered to patients in the EGDT and
the control arms are remarkably similar, in contrast to the
initial study by Rivers et al, where patients in the EGDT arm
received substantially higher amount of fluids.33 This sug-
gests that aggressive fluid resuscitation has become part
of “usual care” of patients with septic shock making it diffi-
cult to show any benefit from EGDT however early fluid
resuscitation continues to be important. The results of
these studies have guided the most recent guidelines for
the management of sepsis—Surviving Sepsis Campaign
Guidelines 2016. These guidelines now do not require the
use of EGDT in the management of severe sepsis, how-
ever, do not recommend against its use since there was no
evidence of harm in the control arm in any of the trials.27
Mean Arterial Pressure
A MAP target of 65 mmHg or higher has been tradi-
tionally used in clinical settings for many years. This is
supported by evidence from a randomized controlled
trial, SEPSISPAM, a large, open-label, multicenter trial of
776 patients with septic shock that found no difference
in 28-day mortality with a target MAP of 80-85 mmHg
compared with a target of 60-65 mmHg. (36.6% in the
high-target group versus 34.0% in the low-target group).
Notably, however, patients with chronic hypertension
had a lower requirement for renal replacement therapy
when treated to higher MAP targets.34 The current guide-
lines recommend resuscitating to a target MAP of 65 mm
of Hg in patients with septic shock (strong recommenda-
tion, moderate quality of evidence).27
Lactate
High serum lactate levels have been associated with
worse outcomes.35 In a noninferiority randomized con-
trolled trial, Jones et al found that normalizing ScvO2 led
to no additional benefit in-hospital mortality compared to
normalizing lactate clearance in patients with septic
shock who were treated to normalize central venous and
mean arterial pressure.36 In another randomized study in
a wider patient population of all patients with hyperlacta-
temia on ICU admission, lactate-guided therapy reduced
ICU length of stay and mortality.37 Subsequently, 3 other
randomized trials and 2 meta-analyses demonstrated
reduction in mortality with the use of lactate directed
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TABLE 3. Predictive validity of SOFA and qSOFA compared to other scoring systems.

Study Design and time period Patient population Primary outcome Area under the receiver operating characteristic curve (95% CI)
SIRS SOFA qSOFA MEWS NEWS
38
Churpek et al, 2016 Retrospective Patients with suspected infection in ED In-hospital mortality 0.65 - 0.69 0.73 0.77
cohort 2008-2016 or wards (n = 30,677) (0.63-0.66) (0.67-0.70) (0.71-0.74) (0.76-0.79)
Raith et al, 201739 Retrospective Patients with infection—related primary In-hospital mortality 0.59 0.75 0.61 - -
cohort 2000-2015 diagnosis in ICU (n = 184,875) (0.58-0.59) (0.75-0.76) (0.60-0.61)
Freund et al, 201740 Prospective Patients with suspected infection In-hospital mortality 0.65 0.77 0.80 - -
cohort 2016 in ED (n = 879) (0.59-0.70) (0.71-0.82) (0.74-0.85)
Park et al, 201741 Retrospective Patients with suspected infection Development of organ 0.66 - 0.81 - -
cohort 2007-2016 in ED (n = 1,009) failure (Change in (0.58-0.75) 0.82 (0.72-0.91)
SOFA  2) 0.60 (0.73-0.90) 0.73
(0.51-0.69) (0.64-0.83)
Ranzani et al, 201742 Retrospective Patients with community-acquired In-hospital mortality 0.58 - 0.70 - -
cohort 2009-2011 pneumonia in ED (0.55-0.60) (0.67-0.72)
(n = 6,874)
Siddiqui et al, 201743 Retrospective Patients with diagnosis of sepsis in ICU In-hospital mortality 0.71 - 0.69 0.88* (EWS) -
cohort 2015 (n = 52)
Donnelly et al, 201744 Retrospective cohort Patients with infection requiring ED visit or In-hospital mortality 0.72 0.76 0.76 - -
(REGARDS) 2003-2012 hospital admission
Singer et al, 201745 Retrospective Patients in the ED with all vital sign data In-hospital mortality - - 0.75 - -
cohort 2014-2015 (n = 4,149 (0.71-0.78)
with suspected infection)
Wang et al, 201646 Retrospective cohort Patients diagnosed with infection in ED 28-day mortality - 0.73 0.67 - -
(n = 477) (0.68-0.78) (0.61-0.72)
Abbreviations: MEWS, Modified early warning score, NEWS, National early warning score; SOFA, Sequential organ failure assessment.

Sepsis in the Current Age

281
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therapy.47 51 Thecurrentsurvivingsepsisguidelinesthere-
forerecommendguidingresuscitationtonormalizelactatein
patientswithelevatedlactatelevels(weakrecommendation,
lowqualityofevidence).27
Fluid Therapy
The use of crystalloids at a dose of 30 mL/kg of body
weight within 3 hours of identification of sepsis is recom-
mended for the initial resuscitation of patients with
severe sepsis (strong recommendation, low quality of
evidence).27 While there is no empirical evidence to sup-
port this recommendation, this has been used in most
recent trials and is now considered standard practice. In
patient populations at risk for fluid overload, such as
those with end stage renal disease or heart failure, the
volume of fluid for initial resuscitation continues to be a
matter of debate.52-54 While there is evidence that timely
fluid administration is associated with improved mortality
regardless of comorbidities,55 volume overload as
assessed by a net positive fluid balance has also been
associated with worse outcomes.56-60 Wideman et al ini-
tially brought this to light by showing significantly better
outcomes in patients with acute lung injury with a con-
servative fluid management strategy.61 Subsequently,
multiple observational studies have found worse out-
comes in critically ill patients with higher cumulative fluid
balance.57-59 The amount of fluid appropriate for initial
resuscitation in patients at risk for volume overload
therefore remains unclear, and most clinicians exercise
caution even with the initial 30 mL/kg of fluid. To deter-
mine responsiveness to fluids, dynamic measures like
passive leg-raising and fluid challenges with concurrent
assessments of stroke volume are preferred over static
measures like central venous pressure (weak recommen-
dation, low quality of evidence). Further, variations in
pulse pressure or stroke volume with changes in intra-
thoracic pressure secondary to mechanical ventilation
can also be used.27
Type of Fluids
Crystalloids are preferred over colloids for fluid resus-
citation, with a weak recommendation for the use of 4%
albumin in patients needing a large volume of crystalloids
for resuscitation (weak recommendation, low quality of
evidence).27 In a randomized controlled trial of 7,000 criti-
cally ill patients, the Saline versus Albumin Fluid Evalua-
tion study, there was no difference in 28-day all-cause
mortality with the use of either 4% albumin or normal
saline.62 More recently, the Albumin Italian Outcome in
Sepsis study compared 20% albumin supplementation
to target serum albumin concentration >30 g/L in 1,800
patients with severe sepsis or septic shock and found no
difference in 28-day or 90-day mortality, compared with
the group receiving only crystalloids.63
Among crystalloids, evidence examining balanced
salt solutions against normal saline is limited. A
meta-analysis of observational and controlled studies
282
identified a higher risk of acute kidney injury but no differ-
ence in mortality with the use of high chloride fluids.64 In
contrast, a retrospective analysis of patients who
received large volume resuscitation found that high chlo-
ride load was not associated with the risk of hyperchlore-
mic acidosis or acute kidney injury after controlling for
fluid load and baseline illness severity, however it was
associated with worse 1 year survival.65 The recent
Saline versus Plasma-Lyte 148 for Intensive care unit
fluid Therapy trial did not find a reduction in the risk of
acute kidney injury with the use of plasmalyte, compared
with normal saline, in a heterogeneous population of criti-
cally ill patients or in the subset of patients with sepsis.66
Results were similar for the electronic health record
based Isotonic Solution Administration Logistical Testing
trial with no difference in major adverse kidney events.67
In view of inconclusive evidence favoring low or high
chloride fluids, the current guidelines do not recommend
1 crystalloid solution over the other (weak recommenda-
tion, low quality of evidence), and further randomized tri-
als are underway to provide better evidence.68,69
Vasopressors
Vasopressors are necessary for septic shock that is
refractory to fluid resuscitation. Norepinephrine is the
recommended initial pressor of choice (strong recom-
mendation, moderate quality of evidence).27 It has been
compared to dopamine in 6 RCTs, with evidence for a
lower risk of mortality (RR, 0.89; 95% CI, 0.81-0.98,
high-quality evidence) and arrhythmias (RR 0.48; 95%
CI, 0.40-0.58. high-quality evidence) compared with
dopamine, in a pooled meta-analysis of these studies.
However, comparisons between norepinephrine and
other vasopressors have not been assessed, except for
a few studies, and have not suggested superiority of nor-
epinephrine.27 The VASST trial compared norepinephrine
alone to norepinephrine and vasopressin at 0.03 U/min-
ute and found no difference in 28-day mortality with the
addition of low dose vasopressin.70 In a subgroup analy-
sis of patients with less severe septic shock, there were
trends suggesting lower mortality with low dose vaso-
pressin, however these were not statistically significant.
The use of combination vasopressors has limited sup-
port from scientific studies but is frequently needed given
limited alternative options in patients with shock refrac-
tory to single agents. The current guidelines therefore
recommend norepinephrine as the initial pressor, with a
suggestion to add either vasopressin (up to 0.03 U/min-
ute) (weak recommendation, moderate quality of evi-
dence) or epinephrine (weak recommendation, low
quality of evidence) to further augment the MAP if a tar-
get of 65 mmHg is not met with norepinephrine alone.
Recently, angiotensin II was evaluated in patients with
vasodilatory shock already receiving high doses of vaso-
pressors. Compared with placebo, angiotensin II was
associated with a significant increase in MAP, and a
decrease in the requirement for other vasopressors.71
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FIGURE 3. Cornerstones of management of sepsis and septic
shock.
Blood Transfusions
While it is plausible that the oxygen carrying capacity
of blood increases with an increase in hemoglobin con-
centration, iatrogenic correction of anemia in patients
with septic shock has not translated into improved out-
comes. In the Transfusion Requirements In Septic Shock
trial, patients with septic shock admitted to the ICU
treated to a transfusion threshold of 7 grams per deciliter
(g/dL), compared with 9 g/dL, had similar rates of 90-day
mortality, ischemic cardiovascular events and the use of
life support.72 The older target of achieving a hematocrit
of >30% proposed in the early goal directed therapy trial
is therefore no longer recommended and the current
guidelines, recommend a threshold of 7 g/dL for patients
with septic shock (strong recommendation, high quality
of evidence).27
Infection Control
Infection control is a cornerstone of sepsis treatment.
This includes both the identification and control of the
source of infection as well as adequate antimicrobial
therapy. The selection of antibiotics depends on the sus-
pected source of infection as well as host factors includ-
ing immune status, previous antibiotic therapy and
comorbidities. Empiric antibiotic therapy selection
should, therefore, be guided by a patient’s risk for bacte-
rial and fungal pathogens, and be broad enough to
include all potential pathogens (strong recommendation,
moderate quality of evidence).27 Combination therapy,
defined as the use of 2 or more antimicrobial agents from
different classes of drugs, is recommended for patients
with septic shock (weak recommendation, low quality of
evidence). However, the routine use of combination anti-
biotics for the treatment of sepsis is not recommended.
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Sepsis in the Current Age
While antimicrobial stewardship efforts are encouraged
at institutions locally, these should not prevent optimal
and broad-spectrum coverage for patients with sepsis
initially. It is prudent to de-escalate antibiotics based on
culture results and daily assessment (best practice state-
ment) and potentially, the use of procalcitonin (weak rec-
ommendation, low quality of evidence).27
Timing of antibiotics has been identified as a crucial
factor determining mortality in sepsis and septic shock in
multiple retrospective cohort studies. A large study by
Kumar et al found a nearly 8% decrease in survival with
each hour of delayed antibiotic use after the onset of
hypotension.73 However, this effect was not observed in
certain other observational studies.74 Subsequently, mul-
tiple large cohort studies, including data from the Surviv-
ing Sepsis Campaign,75 and the New York State
Department of Health,76 have found an association
between early antibiotic administration and improved
patient survival. These studies emphasize the impor-
tance of prompt antibiotic administration in patients with
sepsis and the current guidelines recommend initiation
of intravenous antimicrobials within 1-hour of recognition
of sepsis and septic shock (strong recommendation,
moderate quality of evidence).27
Targeted Therapy
Over the last few decades, many agents have been
developed to modulate the host response in sepsis, and
while several showed a benefit in animal models, they
have failed to translate into clinical practice. Targeted
therapies for sepsis can be broadly classified into 3 cate-
gories—(1) Strategies that target bacterial infection:
Besides antimicrobial therapy, this includes targeting
endotoxins in gram negative sepsis. However, 2 antien-
dotoxin monoclonal antibodies, and an endotoxin neu-
tralizing agent, failed to show benefit in clinical studies;
(2) Strategies that target inflammation: antagonists to
eicosanoids, tumor necrosis factor-alpha interleukin-1b,
interleukin-6, platelet-activating factor, bradykinin and
C5a receptor antagonist have been tried without success
in clinical trials. Ibuprofen, a nonsteroidal anti-inflamma-
tory agent, was shown to improve tachycardia, oxygen
consumption and lactic acidosis, but not survival or the
development of shock or acute respiratory distress syn-
drome in patients with sepsis.77 Steroids have been tried
for sepsis as anti-inflammatory agents at varying doses.
Initial trials of high dose corticosteroids did not show any
benefit in sepsis or septic shock.78 In a randomized con-
trolled trial by Annane et al, modest benefit was seen in
both survival and shock reversal with the use of low dose
steroids, however, these results were not reproduced in
CORTICUS, a large European trial where no difference in
mortality was noted with similar doses.79,80 Recently, the
HYPRESS trial evaluated the efficacy of steroids in
delaying progression of severe sepsis to septic shock
and found no benefit.81 The surviving sepsis guidelines
therefore give a weak recommendation supporting the
283
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use of hydrocortisone between 200 and 400 mg per day

in patients with septic shock resistant to fluids and vaso-
pressors but advise against its routine use in patients
with sepsis (weak recommendation, low quality of evi-
dence).27 It is noteworthy that in a retrospective, propen-
sity-matched analysis of patients with septic shock,
Marik et al reported a significant benefit in-hospital mor-
tality in patients treated with a combination of high dose
vitamin C, intravenous hydrocortisone and thiamine
compared to those who did not receive this treatment.82
However, this remains to be tested in a controlled set-
ting; and (3) Strategies that target the coagulation path- FIGURE 4. Surviving Sepsis Campaign bundles for patients with
way: recombinant antithrombin, recombinant tissue severe sepsis. *Either 1) Repeat focused exam (after initial fluid
resuscitation) including vital signs, cardiopulmonary, capillary refill,
factor pathway inhibitor, and human recombinant acti- pulse, and skin findings, or 2 of the following: (1) Measure central
vated protein C (drotecogrin-a) have also been assessed venous pressure (CVP), (2) Measure mixed venous oxygen satura-
in clinical trials. The drug, drotecogrin-a received tion (ScvO2), (3) Bedside cardiovascular ultrasound, and (4) Dynamic
approval from the US Food and Drug Administration for assessment of fluid responsiveness with passive leg raise or fluid
challenge.
use in severely ill patients with sepsis. However, subse-
quent studies failed to reproduce its benefit, with a signal
to both adopt and report adherence to sepsis protocols.
for higher mortality risk. Therefore, it was subsequently
The Rory Staunton Foundation, the nonprofit organiza-
withdrawn from the market. Immune system stimulating
tion that championed these regulations in New York, has
drugs have also been considered, with interferon-g,
been working to promote legislative action requiring pro-
interleukin-7 and interleukin-15 as potential targets.
tocolized sepsis care in every state. In the year 2015, the
Finally, allogeneic mesenchymal stem cells are also
Center for Medicare and Medicaid Services also adopted
being evaluated in clinical trials.83
the above surviving sepsis bundles, with a requirement
for mandatory reporting of their use in all acute care hos-
COMBINING ELEMENTS OF SEPSIS THERAPY: pitals.
BUNDLES AND MANDATES The use of these care bundles and sepsis protocols
is supported in observational studies with secular
In addition to making recommendations about indi-
improvements in sepsis outcomes. However, these data
vidual components of therapeutic strategies for sepsis
lack adequate controls.76,84,85 Therefore, while compli-
and septic shock, in the year 2004, the Surviving Sepsis
ance with sepsis bundles has been associated with
Campaign launched “sepsis care bundles.” These “bun-
improved patient outcomes, it is impossible to identify if
dles” are a set of interventions targeted to improve the
these are a result of a general improvement in care over
delivery of care in patients with presumed sepsis. The
time, or a direct benefit of sepsis-care bundles or some
original bundles were (1) a 6-hour early resuscitation
of their individual components.84 They may also be a
bundle comprising lactate measurement, blood cultures
consequence of the Hawthorne effect with improvement
before initiating antibiotic therapy, and early fluid resusci-
in outcomes being a result of close observation of perfor-
tation with a minimum of 20 mL/kg of intravenous fluids,
mance metrics. However, these mandates come at a
with or without vasopressors, with close measurement of
cost, both to the patients and to the health care system.
central venous pressures and mixed venous oxygen sat-
Given the paucity of evidence supporting the sepsis care
urations, and (2) a 24-hour bundle that consisted of strict
bundles, it is unclear if their use lead to adverse patient
glucose control, and the administration of low-dose ste-
outcomes. Further, health systems may face an addi-
roids and activated protein C in selected patients. How-
tional burden to comply with these mandates, including
ever, as new data emerged to refute some of these
a high rate of ICU bed utilization, and auditing and report-
mandated practices, the 24-hour bundle was discontin-
ing their compliance with the metrics included in the
ued in 2012, and sepsis-care bundles were reorganized
mandate.86 While the care of patients with sepsis has
into a 3-hour bundle, and a second 6-hour to focus solely
evolved over the last several decades, several questions
on the first 6 hours of resuscitation care. With the publi-
remain unanswered. It is essential that our efforts toward
cation of the PRISM trials, the bundles were further
improving sepsis outcomes are rooted in science.
revised in 2015 to include dynamic measures and physi-
cal exam to guide re-assessment for fluid resuscitation
(Figure 4).
In the last 5 years, there has been legislative support OUR PATIENT
for improved sepsis care through the use of sepsis care In our patient, criteria for sepsis were met using both
protocols. In the year 2013, following the death of a 12- Sepsis-1 and 2 and Sepsis-3 definitions. He had fever
year-old boy with sepsis, the state of New York adopted and tachycardia with evidence of urinary tract infection
“Rory’s regulations” that require all hospitals in the state meeting 2/4 SIRS criteria as well as organ dysfunction

284 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

VOLUME 356 NUMBER 3 SEPTEMBER 2018
 Sepsis in the Current Age

with hypotension and acute kidney injury. Antibiotic 22. Cortes-Puch I, Hartog CS. Opening the debate on the new sepsis defi-
treatment with piperacillin-tazobactam was started nition change is not necessarily progress: revision of the sepsis definition
should be based on new scientific insights. Am J Respir Crit Care Med.
within 1-hour of the diagnosis. He was resuscitated with
2016;194:16–18.
intravenous normal saline and his heart rate and blood 23. Gerdin M, Baker T. Clinical criteria to identify patients with sepsis. JAMA.
pressure normalized after receiving 2.5 liters of fluid. 2016;316:453–454.
Renal function returned to baseline during his admission 24. Makam AN, Nguyen OK. Clinical criteria to identify patients with sepsis.
and was normal on discharge. JAMA. 2016;316:453.
25. Hernandez G, Machado F, Ospina-Tascon G. Defining septic shock.
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Submitted December 6, 2017; accepted June 8, 2018.
Source of funding: None.
The author has no conflicts of interest to disclose.
Correspondence: Snigdha Jain, MD, Division of Hospital Medicine, UT
Southwestern Medical Center, 5939 Harry Hines Blvd, Dallas, TX 75390.
(E-mail: Snigdha.Jain@utsouthwestern.edu).
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
VOLUME 356 NUMBER 3 SEPTEMBER 2018