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Sepsis: An Update on Current

Practices in Diagnosis and
D1X XSnigdha Jain, D2X XMD

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

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

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

Copyright © 2018 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation. 277

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


Sepsis in the Current Age

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

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.

Copyright © 2018 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation. 279

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


Copyright © 2018 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.

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)
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


therapy.47 51 Thecurrentsurvivingsepsisguidelinesthere- identified a higher risk of acute kidney injury but no differ-
forerecommendguidingresuscitationtonormalizelactatein ence in mortality with the use of high chloride fluids.64 In
patientswithelevatedlactatelevels(weakrecommendation, contrast, a retrospective analysis of patients who
lowqualityofevidence).27 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 Therapy
fluid load and baseline illness severity, however it was
The use of crystalloids at a dose of 30 mL/kg of body
associated with worse 1 year survival.65 The recent
weight within 3 hours of identification of sepsis is recom-
Saline versus Plasma-Lyte 148 for Intensive care unit
mended for the initial resuscitation of patients with
fluid Therapy trial did not find a reduction in the risk of
severe sepsis (strong recommendation, low quality of
acute kidney injury with the use of plasmalyte, compared
evidence).27 While there is no empirical evidence to sup-
with normal saline, in a heterogeneous population of criti-
port this recommendation, this has been used in most
cally ill patients or in the subset of patients with sepsis.66
recent trials and is now considered standard practice. In
Results were similar for the electronic health record
patient populations at risk for fluid overload, such as
based Isotonic Solution Administration Logistical Testing
those with end stage renal disease or heart failure, the
trial with no difference in major adverse kidney events.67
volume of fluid for initial resuscitation continues to be a
In view of inconclusive evidence favoring low or high
matter of debate.52-54 While there is evidence that timely
chloride fluids, the current guidelines do not recommend
fluid administration is associated with improved mortality
1 crystalloid solution over the other (weak recommenda-
regardless of comorbidities,55 volume overload as
tion, low quality of evidence), and further randomized tri-
assessed by a net positive fluid balance has also been
als are underway to provide better evidence.68,69
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,
Vasopressors are necessary for septic shock that is
multiple observational studies have found worse out-
refractory to fluid resuscitation. Norepinephrine is the
comes in critically ill patients with higher cumulative fluid
recommended initial pressor of choice (strong recom-
balance.57-59 The amount of fluid appropriate for initial
mendation, moderate quality of evidence).27 It has been
resuscitation in patients at risk for volume overload
compared to dopamine in 6 RCTs, with evidence for a
therefore remains unclear, and most clinicians exercise
lower risk of mortality (RR, 0.89; 95% CI, 0.81-0.98,
caution even with the initial 30 mL/kg of fluid. To deter-
high-quality evidence) and arrhythmias (RR 0.48; 95%
mine responsiveness to fluids, dynamic measures like
CI, 0.40-0.58. high-quality evidence) compared with
passive leg-raising and fluid challenges with concurrent
dopamine, in a pooled meta-analysis of these studies.
assessments of stroke volume are preferred over static
However, comparisons between norepinephrine and
measures like central venous pressure (weak recommen-
other vasopressors have not been assessed, except for
dation, low quality of evidence). Further, variations in
a few studies, and have not suggested superiority of nor-
pulse pressure or stroke volume with changes in intra-
epinephrine.27 The VASST trial compared norepinephrine
thoracic pressure secondary to mechanical ventilation
alone to norepinephrine and vasopressin at 0.03 U/min-
can also be used.27
ute and found no difference in 28-day mortality with the
addition of low dose vasopressin.70 In a subgroup analy-
Type of Fluids sis of patients with less severe septic shock, there were
Crystalloids are preferred over colloids for fluid resus- trends suggesting lower mortality with low dose vaso-
citation, with a weak recommendation for the use of 4% pressin, however these were not statistically significant.
albumin in patients needing a large volume of crystalloids The use of combination vasopressors has limited sup-
for resuscitation (weak recommendation, low quality of port from scientific studies but is frequently needed given
evidence).27 In a randomized controlled trial of 7,000 criti- limited alternative options in patients with shock refrac-
cally ill patients, the Saline versus Albumin Fluid Evalua- tory to single agents. The current guidelines therefore
tion study, there was no difference in 28-day all-cause recommend norepinephrine as the initial pressor, with a
mortality with the use of either 4% albumin or normal suggestion to add either vasopressin (up to 0.03 U/min-
saline.62 More recently, the Albumin Italian Outcome in ute) (weak recommendation, moderate quality of evi-
Sepsis study compared 20% albumin supplementation dence) or epinephrine (weak recommendation, low
to target serum albumin concentration >30 g/L in 1,800 quality of evidence) to further augment the MAP if a tar-
patients with severe sepsis or septic shock and found no get of 65 mmHg is not met with norepinephrine alone.
difference in 28-day or 90-day mortality, compared with Recently, angiotensin II was evaluated in patients with
the group receiving only crystalloids.63 vasodilatory shock already receiving high doses of vaso-
Among crystalloids, evidence examining balanced pressors. Compared with placebo, angiotensin II was
salt solutions against normal saline is limited. A associated with a significant increase in MAP, and a
meta-analysis of observational and controlled studies decrease in the requirement for other vasopressors.71


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
FIGURE 3. Cornerstones of management of sepsis and septic sepsis and the current guidelines recommend initiation
shock. of intravenous antimicrobials within 1-hour of recognition
of sepsis and septic shock (strong recommendation,
Blood Transfusions moderate quality of evidence).27
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 Targeted Therapy
with septic shock has not translated into improved out- Over the last few decades, many agents have been
comes. In the Transfusion Requirements In Septic Shock developed to modulate the host response in sepsis, and
trial, patients with septic shock admitted to the ICU while several showed a benefit in animal models, they
treated to a transfusion threshold of 7 grams per deciliter have failed to translate into clinical practice. Targeted
(g/dL), compared with 9 g/dL, had similar rates of 90-day therapies for sepsis can be broadly classified into 3 cate-
mortality, ischemic cardiovascular events and the use of gories—(1) Strategies that target bacterial infection:
life support.72 The older target of achieving a hematocrit Besides antimicrobial therapy, this includes targeting
of >30% proposed in the early goal directed therapy trial endotoxins in gram negative sepsis. However, 2 antien-
is therefore no longer recommended and the current dotoxin monoclonal antibodies, and an endotoxin neu-
guidelines, recommend a threshold of 7 g/dL for patients tralizing agent, failed to show benefit in clinical studies;
with septic shock (strong recommendation, high quality (2) Strategies that target inflammation: antagonists to
of evidence).27 eicosanoids, tumor necrosis factor-alpha interleukin-1b,
interleukin-6, platelet-activating factor, bradykinin and
C5a receptor antagonist have been tried without success
Infection Control in clinical trials. Ibuprofen, a nonsteroidal anti-inflamma-
Infection control is a cornerstone of sepsis treatment. tory agent, was shown to improve tachycardia, oxygen
This includes both the identification and control of the consumption and lactic acidosis, but not survival or the
source of infection as well as adequate antimicrobial development of shock or acute respiratory distress syn-
therapy. The selection of antibiotics depends on the sus- drome in patients with sepsis.77 Steroids have been tried
pected source of infection as well as host factors includ- for sepsis as anti-inflammatory agents at varying doses.
ing immune status, previous antibiotic therapy and Initial trials of high dose corticosteroids did not show any
comorbidities. Empiric antibiotic therapy selection benefit in sepsis or septic shock.78 In a randomized con-
should, therefore, be guided by a patient’s risk for bacte- trolled trial by Annane et al, modest benefit was seen in
rial and fungal pathogens, and be broad enough to both survival and shock reversal with the use of low dose
include all potential pathogens (strong recommendation, steroids, however, these results were not reproduced in
moderate quality of evidence).27 Combination therapy, CORTICUS, a large European trial where no difference in
defined as the use of 2 or more antimicrobial agents from mortality was noted with similar doses.79,80 Recently, the
different classes of drugs, is recommended for patients HYPRESS trial evaluated the efficacy of steroids in
with septic shock (weak recommendation, low quality of delaying progression of severe sepsis to septic shock
evidence). However, the routine use of combination anti- and found no benefit.81 The surviving sepsis guidelines
biotics for the treatment of sepsis is not recommended. therefore give a weak recommendation supporting the

Copyright © 2018 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation. 283

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
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-
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


Sepsis in the Current Age

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