Sepsis, a 2020 review for the internist

ADRIAN PURCAREA 1, SILVIA SOVAILA 1

1
Internist.ro Clinic, 63 Nicolae Bălcescu, 500019, Brasov, Romania

Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality,
which requires urgent interventions in order to improve outcomes.
Surviving Sepsis is an international campaign that aims to improve sepsis outcomes. The 2016
guideline modifies the previous definition of sepsis and proposes some specific diagnostic and
therapeutic measures, such as the protocolized use of fluid resuscitation and antibiotics.
We aim to summarize the main recommendations of the 2016 guideline that are relevant to
the internist and evidence-base update them to the year 2020. In the current context, this review
doesn’t address patients affected by SARS-COV2 induced disease.
Key words: sepsis, diagnosis, treatment.

INTRODUCTION Directed Therapy (EGDT) approach. In order to

Sepsis is a heterogenous syndrome that
characterizes the body’s overwhelming and life-
threatening response to an infection, and it represents
the main driver of mortality from infection [1]. Its
incidence is of about 20 million cases per year with
a mortality of approximately 26%, potentially
accountable for over 5 million deaths each year [2].
Since the early 1990s an international consortium of
experts has been working to lower this heavy burden.
Their objective was to lower sepsis mortality by a
quarter through a specific agenda that included
increased awareness, improvement of time to
diagnosis and to the use of appropriate treatments,
and development of guidelines and performance
improvement programs. This program was initially
launched by the first Surviving Sepsis Campaign in
2004 [3]. At that moment, based on a 1991 consensus,
sepsis was defined as the existence of at least 2 SIRS
(systemic inflammatory response syndrome) criteria
and a suspected or proven infectious site [4], in
fact characterizing sepsis as a normal reaction to
infection. Further on, sepsis was classified according
to its gravity in sepsis, severe sepsis, and septic
shock. Therapy consisted – and still does – of
hemodynamic support, infection control and some
adjunctive measures. Later evidence emphasized
the necessity of rapid care so, 4 and 8 years later,
further guidelines based on the same evidence
were issued. These guidelines proposed almost the
same care but effected in a more urgent and highly
protocolized manner through an Early Goal
guide the proposed therapy, invasive monitoring
was suggested. Three separate trials would quickly
shed significant doubt on the benefit of the EGDT
[5–7]. Worldwide sepsis evolution trends were
better regardless of the EGDT and the vast amount
of fluids proposed by the guideline seemed to
inversely corelate with survival [6]. Synchronous
evidence testified that SIRS – and thus a sepsis
diagnosis – was present in more than half of all
hospitalized patients, without necessarily leading
to subsequent organ dysfunction and, inversely,
15% of ICU confirmed septic patients did not
reach the 2 minimum requisite SIRS criteria for
initial diagnosis [8]. Considering all this evidence,
it was clear that sepsis was too heterogenous a
syndrome and it had no validated gold standard
diagnostic or true classification. Outcomes were
more closely related to the rapidity of diagnosis
and treatment than to the specificity of the
therapeutic methods deployed. In this context, the
Surviving Sepsis Campaign Consortium replaced
the 2012 EGDT oriented guideline with the
“Sepsis-3 consensus definition for sepsis and septic
shock of 2016” [1], a statement and guideline that
took a completely new approach to sepsis. It uses a
comprehensive grading system to allow readers to
better understand the level of evidence behind each
recommendation.
We aim to summarize the main evidence
behind the Surviving Sepsis 2016 Campaign [1]
recommendations and update it in a manner
relevant for the internist.

ROM. J. INTERN. MED., 2020, 58, 3, 129–137

DOI: 10.2478/rjim-2020-0012
130 Adrian Purcarea and Silvia Sovaila 2

THE 2016 GUIDELINE SUMMARY How do we screen? Screening for sepsis

The new SEPSIS definition
The new sepsis definition of 2016 states that
“Sepsis is defined as life-threatening organ dysfunction
caused by a dysregulated host response to infection”.
Organ dysfunction is identified as a change in the
Sequential [Sepsis-related] Organ Failure Assessment
(SOFA) score of more than 2 points (Table 1)
consecutive to infection and carries a 10% in-hospital
mortality risk. These criteria render the 1992 over-
sensitive SIRS-based sepsis diagnosis obsolete and
completely abandon the intermediate “severe sepsis”
notion with some controversy due to higher specificity
but lower sensitivity. In fact, sepsis is seen now as
a severe, out of control, reaction to infection. Septic
shock is now defined as sepsis induced persistent
hypotension requiring vasopressors to maintain a
MAP of over 65mmHg or having a lactate level of
over 2 mmol/l despite adequate volume resuscitation
and carries a 40% (35–54%) in-hospital mortality.
Screening and diagnosis
Screening lowers mortality in sepsis.
Who is at risk? Risk factors for sepsis
development are an age of 65 or more, or younger
than 1 year, or the presence of concomitant chronic
conditions like lung disease, heart failure, cirrhosis,
diabetes, cancer or kidney disease or patients with
an impaired immunity.
outside of the ICU is possible with the aid of the
quick Sepsis-related Organ Failure Assessment
tool (qSOFA). It associates an altered mental status
(Glasgow coma scale of 13 or less) to an SBP of
100 mmHg or less and a respiratory rate of over
22/min. With these 3 clinical parameters, it allows
rapid use and its discriminative power is similar to
that of the original SOFA score (Table 1) and seems
superior to that of the previous SIRS criteria.
Therapy
Sepsis therapy principles comprise fluid
resuscitation and hemodynamic support, antibiotics
and source control, and a series of adjunctive
measures. Treatment of sepsis should be started as
early as possible, within the first hour after identification
of the potentially septic patient. It should be
concentrated in bundles – groups of manoeuvres with
a specific timetable – that are meant to allow the
clinician to evaluate outcomes at finite moments
during the care of the septic patient. The initial
Sepsis 3 guidelines proposed arbitrary cut-offs at 3
and 6 hours for simple goals accepted as a best
practice statement – current practice based on habit
rather than evidence but impossible to challenge in
a relevant way) the bundles of sepsis treatment: the
3-hour bundle, the 6-hour bundle (Table 2) [1].
The Sepsis 3 – 2018 update introduced the 1-hour
bundle that combines the 2 previous defined bundles
and underlines the need for immediate resuscitation.

Table 1
The SOFA score

SOFA score 0 1 2 3 4
< 200 < 100
RESPRAITORY
≥ 400 < 400 < 300 With respiratory With respiratory
PaO2 / FIO2
support support
COAGULATION
≥ 150 103/mm3 < 150 103/mm3 < 100 103/mm3 < 50 103/mm3 < 20 103/mm3
Platelets
LIVER
< 20 mol/L 20–32 mol/L 33–101 mol/L 102–204 mol/L > 204 mol/L
Bilirubin
DA > 5 DA > 15
Or Or
CARDIOVASCULAR MAP ≥ MAP < DA ≤ 5
Epinephrine ≤ 0.1 Epinephrine > 0.1
Hypotension 70 mmHg 70 mmHg Or Dobutamine
Or or
Norepinephrine ≤ 0.1 Norepinephrine > 0.1
CENTRAL NERVOUS
SYSTEM 15 13–14 10–12 6–9 <6
Glasgow Coma Scale
300–440 mol/L > 440 mol/L
RENAL
≥ 110 mol/L 110–170 171–299 or or
Creatinine or Urine Output
< 500 ml/day < 200 ml/day
3 Sepsis, a 2020 review for the internist
Table 2
Sepsis 3 “3-hour” and “6-hour” bundles and Sepsis 3 – 2018 update “1-hour bundle”
Bundle
– Hour 3 bundle [1]
– Hour 6 bundle [1]
– The 1-hour bundle update [18]
1. Antibiotics
When? Antibiotics should be initiated as
soon as possible, within the first hour bundle if
possible, after microbiological samples are obtained
What treatment? Both Gram positive and
negative bacteria should be empirically covered with
broad spectrum monotherapy (one or more molecules
with complementary spectrum) in immunocompetent
patients without risk factors for specific organisms.
Empiric broad spectrum combination therapy is
recommended in case of shock or when specific
pathogens are suspected but not in all other cases,
including neutropenic patients.
What duration? De-escalation and/or targeted
therapy is recommended once pathogen identification
and sensitivities are established or clinical improvement
is noted. A 7 to 10-day course of antibiotics is adequate
for most severe infections. Shorter periods are
appropriate in rapid responders with a possible
specific survival benefit, while longer periods are
probably necessary with specific pathogens or
persistent infectious foci. Antibiotic stewardship
measures with daily assessment for de-escalation or
stop, eventually aided by procalcitonin measurements
are recommended. When source control is impossible,
longer durations of administration are warranted.
2. Fluid resuscitation
When? Fluid resuscitation should be started
immediately and at least 30 ml/kg of fluid should
be given within 3 hours.
What treatment? Balanced crystalloids or
normal chlorine should be used to restore euvolemia.
Albumin showed additional benefits when substantial
volumes are necessary, with some inconsistencies.
Hydroxyethyl or gelatines should not be used in
sepsis and septic shock.
What duration? Treatment targets are no
longer rigid. Central venous pressure and other
131
Measures
Measure lactate, obtain blood cultures before antibiotics,
administer antibiotics, begin rapid administration of 30 ml/kg
of crystalloids if lactate >4 mmol/l or hypotension
Apply vasopressors (for hypotension that does not respond to
initial fluid resuscitation) to maintain a mean arterial pressure
(MAP) ≥65 mm Hg
Measure lactate, obtain blood cultures before antibiotics,
administer antibiotics, begin rapid administration of 30 ml/kg
of crystalloids if lactate >4 mmol/l or hypotension, initiate
vasopressors to maintain MAP > 65
invasive physiological parameters, but also lactate
clearance are no longer proposed as hard goals for
fluid resuscitation, but can still be used to guide
therapy. Initial reassessment should be completed
within 3 hours of the beginning of the resuscitation.
Fluid challenge should be continued if hemodynamic
keeps improving.
3. Source identification and control
The guideline recommends that routine
microbiological cultures (blood, urine, CSF or other
accessible fluids) should be obtained, as necessary,
in patients suspected of sepsis before antibiotics are
given, but without delaying treatment. For blood
cultures, both aerobic and anaerobic media should
be used, two separate sets being recommended,
45 minutes being an acceptable time frame for
completion. If one site is suspected, cultures form
all other sites are usually deemed unnecessary.
Anatomic diagnosis should be made as rapidly as
possible and source control should be implemented
as soon as medically and logistically practical.
If a vascular access device is the suspected
source of sepsis, it should be removed as soon as
another patent vascular access is in place.
4. Vasopressors
When? After the 3-hour bundle, vasopressor
support is recommended in non-responders to the
initial fluid challenge in order to keep a MAP of
65 mmHg but not more.
What treatment? Norepinephrine is the
preferred vasopressor. Vasopressin or adrenaline
might allow norepinephrine sparing. Terlipressin
has similar effects. Dopamine should be used only
in selected patients (low risk of arrythmia, heart
rate less than 60 bpm). Dopamine should not be
used for renal protection. In patients with low
cardiac output, dobutamine is the preferred agent.
132 Adrian Purcarea and Silvia Sovaila
Since peripheral blood pressure monitoring can be
inaccurate, invasive monitoring may be warranted
but evidence is lacking.
What duration? The targets of care are a
MAP of 65 mmHg and subsequent normalization
of lactate. As soon as hemodynamic stability is
achieved, weaning should be performed daily.
5. Corticosteroids
When? If hemodynamic stability is not obtained
in septic shock patients after fluid resuscitation and
vasopressor therapy.
What treatment? A hydrocortisone dose of
200 mg per day is suggested but lower doses might
be acceptable.
What duration? No clear recommendation
is made, usually a mean of 7 to 14 days was tested,
with shorter duration when rapid improvement is
achieved, with tapering as soon as vasopressors are
no longer needed.
6. Adjuvant measures
Hyperglycaemia should be addressed with a
target glucose of 180mg/dl and blood glucose
should be monitored every 4 hours after targets are
met. Stricter targets proved no mortality benefits and
come with more adverse events. Even less strict
ranges may be allowed in diabetic patients. POCT
glucose levels should be carefully interpreted as
they might not be reliable. Arterial rather than
capillary blood for POCT is preferred.
Blood transfusion: A haemoglobin transfusion
threshold of 7 g/dl is acceptable in septic patients
without myocardial ischemia, severe hypoxemia,
or acute haemorrhage.
Sodium bicarbonate should not be used if
pH is superior to 7.15. No benefit was observed
and side effects like hypocalcaemia and sodium
overload are expected.
Thromboprophylaxis using unfractioned or
low molecular weight heparin is recommended in
sepsis according to patient profile. Mechanical
prophylaxis can be added.
Stress ulcer prophylaxis is recommended,
with either a PPI (preferred) or an H2 antagonist in
patients with risk factors for GI bleeding but does
not lower mortality.
Nutrition. Enteral nutrition should be started
early. Parenteral nutrition alone or in association with
enteral nutrition is not recommended. Gastric residual
volume measurements are recommended only in
patients with a high risk of aspiration. Prokinetics
4
can be used, but caution is warranted since an
increased risk of arrythmia and sudden cardiac
death exists. If needed, a post-pyloric feeding tube
should be inserted. Selenium (no benefit), omega 3
fatty acids (no benefit), arginine (no benefit and
risk of hypotension), glutamine, carnitine (lack of
evidence) are not recommended.
7. Goals of care
Prognosis and goals should be discussed early
(first 72 h) with patients and families. Palliative
care should be employed when appropriate.
DISCUSSION: WHAT IS NOT IN THE 2016
GUIDELINE
Definition and classification
Even after all this effort for better classification
and speedy diagnosis and treatment, sepsis remains a
heterogenous syndrome with hard to predict outcomes.
A 2019 machine learning based large retrospective
study defines 4 different sepsis clinical phenotypes –
alpha through delta – that better define outcomes,
with mortalities within the 4 groups ranging from
less than 3% to over 30% [9]. This classification
will hopefully be incorporated in a new triage tool
for sepsis and allow better targeting of high-risk
patients, but still needs prospective validation.
Awareness and urgent intervention are the
obvious modifiers of sepsis outcomes [10] thus
screening should be a specific focus on an institutional
level. Since SIRS was abandoned, the qSOFA tool
became the mainstay of screening but as evidence
gathers, so are its limitation [11]. It is retrospectively
derived and validated with no prospective control.
Its specificity is higher when the probability of sepsis
is high, but it is far from perfect, especially in
patients with unknown sepsis pre-test probability,
like in the emergency department [12]. Until better
tools are made available, improved awareness and
sound clinical judgement [13] – relying or not on
triage tools like SIRS [14], qSOFA[15], NEWS
[16] (Table 3) or multiple other similar models –
should probably guide screening and treatment.
Therapy
Sepsis therapy is also continuously improving.
The timing of the interventions has an impact on
mortality [17]. In order to hasten interventions, some
authors advocate the sepsis bundles for 3 and 6 hours
5 Sepsis, a 2020 review for the internist
should be condensed in a “1-hour bundle”, with
antibiotics and vasopressors rapidly deployed. This
is part of the official 2018 “Sepsis 3 update” [18].
Some authors expect this to lead to an unwanted
increase in antibiotic and in vasopressor use without
sound evidence in favour of such a practice [19].
Table 3
Three easy to use sepsis prediction scores (triage): The Systemic Inflammatory Response Syndrome criteria (SIRS); the quick
Sequential Organ Failure Assessment(qSOFA), the National Early Warning Score (NEWS)
Score SIRS [14] criteria
– Temperature
– Herat rate
Variables
– Respiratory rate
– WBC count
– Mixed, clinical, and biological. Acceptable in the – Clinical, easy to use
Advantages ED or hospitals, difficult to use as office based
– Modest specificity, higher sensitivity [11]
In line with the rationale of antibiotic
stewardship programs, before antibiotic therapy,
microbiological specimens including blood cultures
should probably be drawn. Even one hour later,
once antibiotics are given, blood culture sensitivity
is significantly lower [21]. All blood culture samples
should be drawn rapidly, using large enough samples
of blood or fluids – at least 20ml and up to 60 ml
[22] –, even in the absence of fever [23], when sepsis
is suspected. A minimal number of 2 and an optimal
number of 3 samples should be drawn [24], without a
particular delay between samples. Sampling should
not hamper antibiotic administration.
Broad spectrum antibiotic therapy targeting
suspected pathogens is recommended. A third-
generation IV cephalosporin should probably cover
all community acquired infections when a specific
site cannot be identified, but evidence is limited [25].
Therapy should be guided to cover suspected sites
and should follow local ecology and disease and host
characteristics. In high-risk patients or for healthcare
acquired infections, specific pathogens like methicillin
resistant staphylococcus aureus, extended spectrum
beta lactamase producing pathogens, fungi and, when
necessary, viruses should be covered. Sepsis due to
pneumonia should be treated with a combination of
beta-lactam antibiotic and macrolide or quinolone
[26]. In intraabdominal infections, anaerobic pathogens
should also be covered [27]. Empirical combination
therapy (synergism) is no longer of first intent, except
when specific multi resistant pathogens are considered.
Aminoglycosides seem to have no mortality benefit
133
Moreover, its feasibility in the real life is doubted
because of expectedly unsurmountable systematic
delays [20]. Overall, the arbitrary “1-hour” bundle is
probably not yet primed for real life use, but early
active resuscitation interventions and protocolized
follow-up are highly recommended.
qSOFA [15] NEWS [16]
– Respiratory rate
– Oxygen saturation
– Altered mental status – Temperature
– Respiratory rate – Systolic blood pressure
– Systolic blood pressure – Altered mental status
– Pulse rate
– Oxygen use
– Clinical, easy to use
– Modest sensitivity, higher – Highest specificity and sensitivity
specificity [11] [11].
but come with significant nephrotoxicity and are
mostly abandoned as a first line empirical treatment
[28]. A duration of 3 to 10 days might suffice even
in case of septic shock if source control is obtained
early [27, 29].
Bed-side antibiotic allergy testing by nurses
in the naive patient is an empirical practice specific
mostly to Romania and Korea [30]. An intradermal
test of antibiotic is to be performed to all patients
prior to the first systemic use of an antibiotic, with
a waiting period arbitrarily set at 20 to 30 minutes.
Since the more brutal IgE mediated anaphylactic
reactions occur within the first hour and true allergy
being rare [31], such a practice leads inevitably to an
(unreasonable?) increased time from diagnosis to
treatment. In the absence of evidence in its favour,
beta lactam allergy skin test screening utility should be
questioned [30]. In selected patients with suspected
antibiotic allergy, an intradermal bed side test or oral
challenge performed prior to antibiotic administration
safely allowed the use of the suspected antibiotic in
most patients [31].
Fluid resuscitation with crystalloid fluid
challenges with balanced solutions seem to offer better
outcomes than saline and Ringers’ lactate is now
preferred [32]. Moderate quality evidence supports
that lower quantities (less than 30 ml/kg) of fluids
can be offered, especially when fluid challenges
are continued outside the initial hour 1 to hour 3
bundle [33].
Treatment should be guided with repeated lactate
[34, 35] and procalcitonin measures. Venous lactate is
134 Adrian Purcarea and Silvia Sovaila 6

as useful as arterial lactate in the follow up of sepsis
[36]. Point of care portable devices are available.
Passive leg raise offers an easily available
bedside method to assess pressure and cardiac output
response to fluid challenges. It can be used alone or
in combination with transthoracic echocardiography
[37]. Capillary refill time (of less than 3 seconds) is
another non-invasive and easily available method
that can aid diagnose and evaluate response to initial
fluid challenge in sepsis [38]. It is noteworthy
that fluid challenges should aim to re-establish
homeostasis and renal perfusion and excess is
probably deleterious [39].
Adjuvant therapy
According to current guidance, corticosteroids
should only be used in case of persistence of septic
shock albeit vasopressors use. Still, corticosteroids
carry direct indications for treatment of specific
infections like pneumonia (for 5 days) [40] and
cellulitis (for 8 days) [41] regardless of the existence
of sepsis. Recently, a cocktail of corticosteroids,
thiamine and vitamin C in high doses seemed to
massively lower sepsis mortality [42]. The quality
of evidence of this anecdotal mixture was low and
contradictory results of equal quality have emerged
[43, 44]. Multiple well conducted randomized trials
are ongoing and, although VICTAS [45] has yet to
present results, the CITRIS-ALI [46] and VITAMINS
[47] trials showed no mortality improvement from
the vitamin cocktail as compared to corticosteroids
alone. Until all results are available, vitamin C is still
sometimes empirically used as adjuvant to infection
[48] treatment with low risk of adverse effects and
unknown benefits. Thiamine lacks solid proofs of
efficacy in sepsis [49]. As for corticosteroids, a
2019 Cochrane meta-analysis finds, with moderate
quality evidence, a small 28-day sepsis survival
benefit in favour of a moderate to high dose of
corticosteroids. It also finds a shorter ICU stay and
lower in-hospital mortality when corticosteroids
are deployed [50]. In this context, evidence should
continue to be gathered as per dose, timing,
duration of treatment. Their use, independently of
hemodynamic instability, in septic patients might
be warranted.
CONCLUSION
An important number of the “Sepsis 3”
recommendations rely on controversial or low-quality
data. We should continue improving the current level
of evidence and, hopefully, patient outcomes. Until the
many faces of sepsis and its putative mechanisms are
clearly identified, institutional, urgent, evidence-based
approach to sepsis care will increase awareness and
can still improve outcomes.
TAKE AWAY MESSAGE:
 Sepsis and septic shock are severe,
overwhelming and heterogenous reactions to infection.
 Awareness, early recognition, and timely
interventions lower sepsis mortality.
 qSOFA – a score that includes respiratory
rate, mental status, and arterial pressure – is the
recommended screening tool, but others might be
as valid.
 Biomarkers like procalcitonin and lactate
hasten diagnosis and guide therapy, but bedside
manoeuvres like the passive leg raise test and the
capillary refill time could also be useful.
 A raised lactate should prompt the initiation
of treatment even in the absence of hypotension.
 Broad spectrum antibiotics and balanced
crystalloid solutions are the mainstay of therapy.
 Care is grouped in bundles that aim to give
a time frame for efficacy evaluation.
 Rapid ICU care and vasopressors should
be proposed if no response to initial measures or
persistently high lactate values.

Septicemia – reacția exagerată și necontrolată a corpului în fața unei infecții –

este o patologie care asociază o mortalitate și morbiditate înaltă și necesită
intervenții rapide în scopul ameliorării prognsoticului.
Surviving sepsis este o campanie internațională care are ca scop ameliorarea
prognosticului în septicemie. Noul lor ghid terapeutic, emis în 2016, modifică
definiția septicemiei și aduce precizări specifice in ce privește diagnosticul și
terapia, cum ar fi folosirea protocolizată a antibioticelor și restabilirea volemiei.
7 Sepsis, a 2020 review for the internist 135

În lucrarea de față încercăm să rezumăm cele mai relevante recomandări ale

campaniei pentru medicul internist și să le aducem la zi, bazându-ne pe dovezi, la
nivelul anului 2020. În contextul actual, lucarea nu acoperă recomandări rezervate
pacienților suferind de infecția cu virusul SARS-COV2.

Correspondence to: Adrian Purcarea, MD, Internist.ro Clinic, 63 Nicolae Bălcescu, 500019, Brasov, Romania
Email: adrian.purcarea@internist.ro
Tel: 0040733911513

Acknowledgements: Ioana, for her English skills

Conflict of interest disclosure: The authors declare there is no conflict of interest.

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Received 15th April 2020