INTENSIVE CARE

Sepsis in 2024: a review Learning objectives

Jeffrey Wayland After reading this article, you should be able to:
J Pedro Teixeira C define sepsis and septic shock using the most contemporary
(Sepsis-3) criteria
Nathan D Nielsen
C describe clinical criteria required for the early diagnosis of sepsis

C formulate an initial treatment plan for the critically ill patient with

sepsis
Abstract
C describe secondary and adjunctive therapies presently available
Sepsis is responsible for tremendous morbidity, mortality, and health-
for refractory sepsis
care expenditure worldwide. Over the past decade, the conceptualiza-
tion of sepsis has shifted from one based upon an inflammatory
response to one defined by a dysregulated immune response to
infection and resulting organ dysfunction. The definitions of sepsis
and septic shock were revised to improve their diagnostic specificity regionally, data from the NHS showed 244,158 cases of sepsis
and facilitate accurate and timely diagnoses at the bedside. The with 48,000 deaths in the UK during the same time period. The
core of sepsis management remains early identification and diagnostic annual economic burden (both direct and indirect) is estimated
testing, early antimicrobial therapy, and early haemodynamic resusci- at a staggering £7.42 billion.2 More timely and accurate recog-
tation. Recently, there has been additional movement towards nition of patients at risk for sepsis is essential to improving pa-
classifying and treating sepsis based on genotype, phenotype, and tient care and health system outcomes. To that end, this article
endotype, though these methods are not yet widely accessible or will review the most recent definitions and clinical guidelines for
adopted. Current guidelines recommend that the first steps in treat- the treatment of sepsis.
ment and resuscitation take place within 1 hour from when septic
shock is suspected. Additional essential elements in the current sepsis Pathophysiology of sepsis
management guidelines include using dynamic parameters to assess At its onset, sepsis manifests as an overwhelming release of in-
fluid responsiveness, a conservative fluid strategy following initial flammatory mediators (sometimes referred to as ‘cytokine
resuscitation (with subsequent de-resuscitation when possible), serial storm’) in response to an infection. An analogy can be drawn
reassessments of haemodynamic status, and adaptable treatment between the immune response to infection and national de-
plans. This review provides a summary of the most recent clinical trials fences. Components of the innate immune system or ‘citizens’
and practice guidelines for the diagnosis and treatment of sepsis in the (epithelial cells, macrophages, mast cells, innate lymphocytes) at
critical care setting. the site of pathogen exposure activate and recruit circulating
Keywords Critical care; intensive care; sepsis; septic shock immune cells or ‘troopers’ (neutrophils, Natural Killer (NK) cells,
dendritic cells, platelets, monocytes, eosinophils). These cells
Royal College of Anaesthetists CPD Skills Framework: ICM and emergency
have pathogen-recognition receptors (PRRs) on their surface
management
which bind to and are activated by pathogen-associated molec-
ular patterns (PAMPs) on bacterial cell walls or damage-
associated molecular patterns (DAMPs) e host biomolecules
Introduction released when danger is sensed from a pathogen, burn, trauma,
etc. This receptor binding initiates an intracellular signalling
In 2017 alone, the global incidence of sepsis was estimated to be
cascade resulting in the activation of cytosolic transcription fac-
48.9 million cases and was associated with 11 million deaths,
tors such as nuclear factor-kB and activator protein 1 (AP-1),
thus representing 19.7% of all deaths worldwide.1 More
which in turn leads to the production of several acute phase re-
actants, among them cytokines, coagulation factors, and induc-
ible nitric oxide synthetase, thus initiating the immuno-
Jeffrey Wayland MD is a Fellow at the Division of Pulmonary, Critical inflammatory cascade. A subsequent chain reaction involves
Care and Sleep Medicine, Department of Internal Medicine, the activation of even stronger ‘armed forces’, the adaptive im-
University of New Mexico School of Medicine, Albuquerque, USA.
mune response. This explosive activation and resultant immune
Conflicts of interest: none declared.
‘cytokine storm’ are believed to be the causative pathway for
J Pedro Teixeira MD is an Associate Professor at the Divisions of septic shock.3
Nephrology and Pulmonary, Critical Care and Sleep Medicine, The end-response to an infection is often a combination of
Department of Internal Medicine, University of New Mexico School of
pro- and anti-inflammatory cascades. Once infection resolves, a
Medicine, Albuquerque, USA. Conflicts of interest: Outset Medical
(consulting fees). balance is established between immune up-regulating and
down-regulating processes, and immune memory is generated
Nathan D Nielsen MD MSc is an Associate Professor at the Division of
to protect against future exposures. However, when the initial
Pulmonary, Critical Care and Sleep Medicine, Department of Internal
response is excessive or dysregulated, this balancing process
Medicine & Section of Transfusion Medicine and Therapeutic
Pathology, Department of Pathology University of New Mexico becomes dysfunctional. As sepsis persists, by about 24e48
School of Medicine, Albuquerque, USA. Conflicts of interest: hours a shift towards a hypoinflammatory state is observed, and
Inotrem, Adrenomed (advisory board). patients develop features consistent with immunosuppression.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 25:10 642 Ó 2024 Published by Elsevier Ltd.
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This phase is known as sepsis-induced immunoparalysis,4 and Management

the majority of septic shock-related deaths occur during this
The cornerstone of effective sepsis management is indisputably
immunoparalytic phase. These patients are often not able to
the timely identification of sepsis and the prompt initiation of
clear the initial infection and, in addition, are predisposed to
aggressive and appropriate treatment. Successful treatment re-
new infections from nosocomial pathogens. T-cell and B-cell
quires fluid resuscitation with a focus on perfusion and the early
exhaustion, apoptosis, and anergy are now recognized immu-
administration of antibiotics. The 2018 Surviving Sepsis
nosuppressive mechanisms observed in patients with fatal
Campaign (SSC) bundle update introduced the ‘1-Hour Bundle’,
sepsis.5,6 Although the pattern of hyperinflammation/hyper-
which was largely retained for patients with septic shock in the
immunity followed by hypoinflammation/hypoimmunity is the
2021 SSC guidelines.10 This bundle combines elements of the
most common presentation of sepsis, it should be noted that
prior 3- and 6-Hour Bundles into an algorithm that emphasizes
some patients present as hypoinflammatory/hypoimmune from
the immediate treatment of septic shock patients. The first ele-
the outset.7
ments of the bundle are diagnostic: measuring a lactate level and
obtaining blood cultures prior to administration of antibiotics.
Definitions
The remainder of the bundle addresses management: early
Over the course of the last few decades, considerable effort has antimicrobial administration, fluid resuscitation, and, if required,
been expended in improving the recognition, categorization, and vasopressor support (see Box 2).
algorithmic treatment of sepsis. From the early 1990s until the The ‘1-Hour Bundle’ was met with some resistance, however,
mid-2010s, sepsis was defined as a proven or suspected infection and, despite observational data suggesting the importance of
accompanied by a pronounced systemic inflammatory response timely treatment of septic shock, there is a lack of high-quality
syndrome (SIRS). Patients were further categorized as having prospective evidence supporting the shift.11 Additionally, in the
sepsis, severe sepsis, or septic shock based on organ dysfunction era of quality metrics, many groups have expressed concerns that
and fluid responsiveness. Though widely accepted at the time, it compression of the timeline could lead to the overdiagnosis of
failed to detect many cases of sepsis (as many as 1 in 8) and a sepsis and thus an overuse of antibiotics and excessive volume
more precise definition was required.8 resuscitation.12 The Effect of the 1-hour Sepsis Bundle on In-
The Third International Consensus Definitions for Sepsis and hospital Mortality in Patients With Sepsis in the Emergency
Septic Shock (‘Sepsis-3’), jointly developed by the Society of Department: a Randomized Controlled Trial (1BED) is an
Critical Care Medicine (SCCM) and the European Society of ongoing multicentre randomized controlled trial (RCT) that aims
Intensive Care Medicine (ESICM), were released in 2016 and to address this concern specifically.13
noted that sepsis is far more complex than an inflammatory
response, involving both pro- and anti-inflammatory processes Early antimicrobial therapy and source control
and non-immunologic systems in the disease process.4 The For patients with presumed sepsis, early empiric broad-spectrum
term ‘severe sepsis’ was eliminated, and sepsis was formally antibiotic therapy should be initiated within 1 hour of presenta-
redefined as ‘life-threatening organ dysfunction caused by a tion, especially in patients with septic shock. Ideally, microbio-
dysregulated host response to infection’. Septic shock was logical samples from all suspected foci of infection should be
redefined as a ‘subset of sepsis in which profound circulatory obtained prior to administering antibiotics. However, if obtaining
failure, cellular, and metabolic abnormalities are associated these samples would delay antibiotic administration, antibiotic
with a greater risk of mortality than with sepsis alone’. therapy should always take priority. Though this finding has not
In addition to the new definitions, the consensus committee been reproduced in all studies, especially those analysing pa-
also established a set of practical clinical guides to facilitate the tients with sepsis without shock, the prompt administration of
diagnosis of sepsis at the bedside. Although earlier versions of antibiotics has been independently associated with improved
these guidelines recommended the Sequential Organ Failure sepsis survival in multiple studies.14,15 Appropriate empiric
Analysis (SOFA) score or a ‘qSOFA’ variant (Box 1),4 more recent
studies have shown that these tools are sensitive but not specific
for patients at risk for increased mortality from sepsis9 and more
recent guidelines have recommended against using these as Surviving Sepsis Campaign-1 Hour Bundlea
single screening tools.10 C Measure lactate level (follow serial measurements if initial level
>2mmol/litre)
Quick Sequential Organ Failure Analysis (qSOFA) scorea C Obtain blood cultures prior to administering antibiotics
C Administer broad spectrum antibiotics
qSOFA criteria:
2 of the following: C Begin rapid administration of 30 ml/kg of crystalloid for hy-
C Respiratory rate >22/minute
potension or lactate
4mmol/litre
C Change in mental status
C Start vasopressors if patient is hypotensive during or after fluid
C Systolic blood pressure <100 mmHg
resuscitation to maintain a mean arterial pressure (MAP)
65
mmHg
a
Adapted from: Singer M, Deutschman CS, Seymour CW, et al. The Third
a
International Consensus Definitions for Sepsis and Septic Shock Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle:
(Sepsis-3). JAMA. 2016;315(8):801e810. 2018 update. Intensive care medicine. 2018 Jun 1;44(6):925e8.

Box 1 Box 2

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 INTENSIVE CARE

antimicrobial therapy is essential for decreasing sepsis mortality Source control has been increasingly recognized as an
and should be guided by the clinical presentation and local important element of optimal sepsis treatment. The removal of
antimicrobial resistance patterns, as well as the patient’s risk potentially infected invasive devices is highly recommended,
factors for particular organisms (see Table 1).15,16 Chronic particularly urinary and central venous catheters. Prompt
comorbidities (e.g. human immunodeficiency virus, combined consultation with surgical or interventional radiology services is
variable immunodeficiency, diabetes mellitus) and the presence required to address scenarios such as an empyema, septic
of invasive medical devices (e.g. central venous catheters, uri- arthritis, cholecystitis, or intra-abdominal abscess. Generally, the
nary catheters) should also be taken into account when selecting least invasive intervention method of source control is preferred,
initial antibiotic regimens. though timeliness is also a major factor in selecting between
When the source of infection is unclear, empiric broad- competing options. A multidisciplinary approach to early inter-
spectrum antimicrobial therapy should be administered. For vention (<6 hours) is associated with improved patient
most patients, empiric antibiotic coverage should include survival.20
either an extended spectrum penicillin, a third- or fourth-
generation cephalosporin, or a carbapenem. Additional Fluid resuscitation
consideration should be paid to risk factors for meticillin- Prompt fluid resuscitation should be initiated upon the diagnosis
resistant Staphylococcus aureus (MRSA) and, if present, of sepsis. Previous guidelines strongly recommend initiating the
empiric vancomycin administration is advised. Combination infusion of 30 ml/kg of intravenous (IV) crystalloid fluid within 1
therapy (the use of multiple antibiotics with different phar- hour of sepsis identification if hypotension is present. However,
macodynamic profiles and mechanisms of action to treat the recent updates have downgraded the strength of this recom-
same organism) is a topic of some debate, though some early mended fluid volume.10
studies reported a synergistic effect with the addition of an
aminoglycoside to a b-lactam,17 and later studies assessed the Fluid choice e colloid versus crystalloid: in 2004, the SAFE
addition of a fluoroquinolone. Combination therapy has been trial compared clinical outcomes in critically ill patients receiving
associated with improved survival in the most critically ill volume resuscitation with either normal saline or albumin.21 No
patients,18 though RCT data are lacking. In the appropriate significant difference in all-cause mortality was noted between
clinical context (e.g. suspected influenza), empiric anti-viral the two groups, though a subgroup analysis showed increased
therapy is appropriate. In the setting of immunosuppression, mortality with albumin in patients with traumatic brain injury.
total parenteral nutrition, or recent abdominal surgery, empiric The combination of the significantly increased expense of albu-
anti-fungal therapy can also be considered. Once microbial min infusion and an absence of data to support a clear benefit led
data are available, prompt de-escalation to a targeted antimi- the SSC to recommend crystalloids as the initial volume resus-
crobial is safe and is associated with lower mortality rates.19 citation agents of choice.

Comparison of Sepsis-2 and Sepsis-3a

Sepsis-2 Sepsis-3

Publication year 2001 2016

Mechanism (pathophysiology) Physiological inflammatory response (SIRS) to Dysregulated immune response to infection
infection
Spectrum SIRS / Sepsis / Severe Sepsis / Septic Sepsis / Septic shock
shock / MODS
Predictive validity for in-hospital mortality 0.64 (95% CI, 0.62e0.66) 0.74 (95% CI, 0.73e0.76)
(area under the curve, p <0.001)
Sensitivity/specificity [ Sensitivity Y Sensitivity
Y Specificity [ Specificity
Definition of septic shock Acute circulatory failure characterized by Subset of sepsis in which underlying
persistent arterial hypotension unexplained by circulatory and cellular metabolism
other causes abnormalities are profound enough to
substantially increase mortality
Practical considerations 3 of 4 SIRS criteria obtainable at bedside Multiple laboratory test results required to
without need for laboratory testing calculate SOFA score; qSOFA can be used as
substitute prior to test availability

MODS, multiple organ dysfunction syndrome; qSOFA, quick sequential organ failure analysis; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ
failure analysis.
a
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801e810.

Table 1

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Fluid choice e saline versus balanced crystalloid: which

crystalloid to use is also a matter of active debate. Two large
single-centre cluster RCTs, including SMART which focused
specifically on critically ill patients, found decreases in the
composite outcome of mortality, renal dysfunction, and need for
renal replacement therapy (RRT) with the use of balanced salt
solutions such as Ringer’s lactate or Plasma-Lyte when compared
to 0.9% saline solution.22,23 However, the more recent BaSICS
and PLUS trials demonstrated no significant differences in 90-day
mortality between the two arms, though a meta-analysis of 13
RCTs and more than 35,000 intensive care unit (ICU) patients
(the majority of which came from the SMART, BaSICS, and PLUS
trials) showed a small mortality benefit in favour of balanced
solutions.24e26 Figure 1 The four phases of fluid therapy in sepsis or other critical illness:
‘ROSE’. Optimal fluid resuscitation strategies should parallel the phases
Fluid balance: while adequate resuscitation is essential, fluid of septic shock or other critical illness. The first phase (e.g. first 6 hours) is
Resuscitation, when initial aggressive resuscitation, recommended to be
overload is associated with increased mortality,27 making
30 ml/kg ideal body weight of crystalloid in most patients,34 should be
perfusion assessment essential to the treatment algorithm. provided. The second phase is Optimization, when additional fluids are
Careful attention to fluid management with a transition to con- given specifically targeting fluid responsiveness (i.e. increased stroke
servative fluid management 24e48 hours after successful resus- volume or cardiac output) or other specific haemodynamic endpoints to
citation is associated with reduced ICU lengths of stay and improve organ function. The third phase is Stabilization, also referred to
increased ventilator-free days. Additionally, Silversides et al. as the ‘tone and time’ phase, in which patients remain on vasopressors
but vasopressor requirements are no longer increasing, patients are no
found that a positive fluid balance at day 3 was an independent
longer fluid responsive, organ function is stable or improving, and further
risk factor for increased mortality.28 The CLASSIC and CLOVERS
fluids are withheld. The fourth phase is Evacuation, also known as the
RCTs suggested that more conservative approaches to fluid de-resuscitation or mobilization phase, when patients with volume
administration have little to no effect on mortality in ICU patients overload are treated with diuretics or ultrafiltration to expedite the return
with septic shock but did demonstrate the safety of relative fluid to euvolaemia in hopes of accelerating recovery from critical illness.35e37
restriction.29,30 Several ongoing studies including ARISE FLUIDS, The time at which a given patient transitions between phases varies and
EVIS, and FRESHLY will generate additional data on the potential repeated insults may substantially disrupt this sequence. Reproduced
with permission from Hoste et al. Br J Anaesth 2014.36
benefits of conservative fluid strategies and early vasopressor use
in septic shock.31e33 In the meantime, based on the observational
data that fluid overload is associated with mortality and accu- However, persistent alterations of microcirculatory blood flow
mulating RCT data that conservative fluid management is at despite the restoration of macro-haemodynamic parameters can
worst safe, a reasonable modern approach to fluid management lead to organ failure. At least one study has shown that micro-
includes aiming to achieve an even to net negative fluid balance circulatory perfusion alterations predicted mortality during
at 72 hours and keeping cumulative fluid balances low to avoid serious infection, whereas mean arterial pressure and cardiac
end-organ dysfunction resulting from volume overload. output did not.38
This dissociation between microcirculatory and microcircu-
De-resuscitation: the practice of fluid mobilization, evacuation, latory flow underscores the need to assess end-organ tissue
or ‘de-resuscitation’ has gained traction in recent years as a way perfusion in patients with septic shock and to develop tools to
to minimize adverse effects of volume overload and potentially analyse microcirculatory blood flow. For example, persistent
decrease duration of illness (Figure 1). Although minimal pro- hyperlactatemia has been traditionally considered as a signal of
spective literature on this approach currently exists in the realm tissue hypoperfusion or hypoxia. Consequently, lactate normal-
of sepsis, the REDUCE trial aims to explore the feasibility of a ization is recommended as a resuscitation target in recent
protocol for in-ICU de-resuscitation. With the ongoing RELIEVE- guidelines.14 However, the pathogenesis of lactic acidosis is
AKI and Probe-Fluid trials that are studying fluid management sepsis metabolically complex, and many have recently criticized
using RRT in patients with acute kidney injury (AKI) in the ICU, the use of lactate as a haemodynamic endpoint of resuscitation,
we may soon have more guidance into optimal strategies for especially when used as a trigger for further IV fluid
managing fluid overload in critical illness.33,38,39 administration.39
Peripheral perfusion is a promising alternative target. There is
Perfusion assessment particular interest in the scientific community for using the skin,
In the assessment of perfusion in sepsis, intensivists have his- an easily accessible organ, as a surrogate for deeper organ
torically focused on normalizing macro-haemodynamic param- perfusion by using skin temperature gradients, capillary refill
eters. The targeted goals for resuscitation have evolved from time (CRT), the extent of mottling, and the peripheral perfusion
static haemodynamic targets (e.g. heart rate, mean arterial index.
pressure, central venous pressure) to dynamic variables such as In the first major RCT using peripheral perfusion as an assay
pulse pressure variation, stroke volume variation, plethysmog- for microcirculatory dysfunction (ANDROMEDA-SHOCK), a
raphy variability index, and others obtained through bedside CRT-targeted resuscitation strategy did not demonstrate a sta-
echocardiography measurements. tistically significant reduction in all-cause 28-day mortality when

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 INTENSIVE CARE

compared to lactate-targeted fluid resuscitation, though there There are extremely limited clinical trial data about the use of
was a trend (p ¼ 0.06) towards benefit. This trial also demon- phenylephrine in septic shock, with observational data suggest-
strated that CRT could be used to reliably follow dynamic ing that phenylephrine in septic shock is associated with higher
changes in regional and microcirculatory flow parameters and mortality rates when compared to noradrenaline.55,56 As such, its
hypoxia surrogates during sepsis resuscitation.40 A much larger use should be limited in patients with sepsis.53
follow up trial (ANDROMEDA-SHOCK-2) is in progress and aims Angiotensin II (ATII) is the most recent vasopressor to receive
to further stratify patients in septic shock in order to more pre- European Medicines Agency and US Food and Drug Administra-
cisely guide CRT-based resuscitation efforts.41 tion approval following the 2017 ATHOS-3 trial. In this multi-
Given the subjectivity of CRT, several new technologies have centre RCT the group treated with ATII demonstrated a signifi-
been developed to more objectively measure CRT, and other cant increase in blood pressure and no significant increase in
methods for the objective assessment of peripheral perfusion are adverse events.57 ATII appears to be particularly effective in pa-
in development, all in the hope of identifying better microcircu- tients with AKI, as a subgroup analysis of the ATHOS-3 demon-
latory targets for resuscitation.42 The overall efficacy of strated a mortality benefit in patients with AKI requiring RRT.58
microcirculation-targeted resuscitation remains to be deter- Additionally, results from a recent observational pilot study sug-
mined, however. gest that ATII may be effective when used as a first-line vaso-
pressor for vasodilatory shock, but additional data to define which
Vasopressors patients are most likely to derive benefit from ATII are needed.59
Mean arterial pressure (MAP) is the primary driving factor A subset of patients with septic shock will develop septic
behind systemic perfusion. When hypotension persists despite cardiomyopathy. These patients typically have little cardiac
adequate IV fluid resuscitation, vasopressors should be promptly reserve at baseline and are unable to generate a compensatory
administered. At present, the SSC recommends noradrenaline cardiac output during vasodilatory shock. If cardiac output re-
(norepinephrine) as the first-line vasopressor.43 If a second agent mains low despite use of vasopressors, initiation of inotropic
is necessary to achieve MAP goals, vasopressin is recommended. therapy is appropriate. The 2021 SSC guidelines recommend the
Patients with septic shock are hypothesized to have a ‘relative addition of dobutamine to noradrenaline or switching from
vasopressin deficiency’, meaning that levels of vasopressin are noradrenaline to adrenaline, as data show similar improvements
lower than expected for a shock state.44 Thus, the addition of in cardiac output with the use of single-agent adrenaline
low-dose vasopressin or analogues can be effective treatments compared to dobutamine paired with noradrenaline.14,50
for refractory shock. Furthermore, the addition of vasopressin
has been noted to have a dose-sparing effect on norepinephrine
Diagnostic techniques
requirements, potentially decreasing the risk of tachyar-
rhythmia45,46 and other catecholamine-associated side-effects.47 Microbiological cultures
In addition, vasopressin has been proposed to have a neph- Positive blood cultures are demonstrable evidence of systemic
roprotective effect in septic shock, but this effect was not seen infection. If sepsis is suspected, current guidelines recommend
when assessed as the primary outcome of the large VANISH drawing two sets of blood cultures, both aerobic and anaerobic.
RCT.48,49 However, blood culture yield is variable and is dependent upon
Though previously recommended as an alternative to vaso- sampling technique. Care must be taken to adequately prepare
pressin as a second-line vasopressor for septic shock, 2021 SSC the skin with antiseptic agent and to inoculate each bottle with a
guidelines recommend adrenaline (epinephrine) as a third-line minimum of 10 ml of blood. Ideally, cultures should be obtained
agent, particularly for patients with cardiac dysfunction.10 prior to the administration of antibiotics to improve yield. Cul-
Notably, given its stability at room temperature, adrenaline re- tures of other bodily fluids should also be obtained as clinically
mains a frequently used first-line agent for septic shock in indicated (e.g. sputum, urine, cerebrospinal fluid, etc.).60
resource-limited settings. In low doses, adrenaline is an inotrope,
but at higher doses it can manifest vasoconstrictive properties. Lactate
Head-to-head comparisons of adrenaline to noradrenaline or to As mentioned above, the use of lactate as an endpoint of resus-
noradrenaline and dobutamine in septic shock showed no dif- citation in sepsis has been recently questioned. Undeniably, an
ference in mortality but increased adverse events with adrenaline elevated serum lactate level is a marker of disease severity in
versus noradrenaline alone.46,50 Notably, adrenaline infusions, sepsis. Likewise, the normalization of lactate with resuscitation
via the metabolic effects of b-2 receptor stimulation, almost in early sepsis is predictive of a good outcome.61 However, the
invariably cause hyperlactatemia, and, though adrenaline- aetiology of the rise in lactate is multifactorial, potentially
induced lactic acidosis has been associated with reduced mor- including anaerobic metabolism resulting from inadequate oxy-
tality,51 this effect nonetheless limits the usefulness of lactate gen delivery but also including a variety of metabolic perturba-
clearance as an indicator of response to therapy in adrenaline- tions unrelated to fluid status. Prior RCT data suggested that
treated patients. lactate-guided resuscitation in patients with septic shock
Previously considered the first-line vasopressor for septic reduced mortality, though this finding has not been consistently
shock, dopamine has fallen out of favour since the 2010 SOAP II reproduced. Despite this controversy, the 2021 SSC guidelines
RCT.52 A subsequent 2015 meta-analysis found decreased all- continued to suggest the use of lactate clearance as a resuscita-
cause mortality with norepinephrine compared to dopamine in tion goal (albeit a weak recommendation based on low-quality
septic shock.53 Dopamine should be reserved for select patients evidence) and elevated lactate levels are part of the current
(e.g. septic patients with bradycardia).54 criteria for the diagnosis of septic shock.4,40,62,63

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Biomarkers Adjunctive therapies

Numerous novel biomarkers (e.g. suPAR, presepsin, cell-free
Steroids
plasma DNA) are under study with the aim of improving diag-
Despite dozens of trials, the role of corticosteroids in sepsis re-
nostic precision and prognostication and ultimately predicting
mains controversial. The 2021 SSC guidelines recommended
treatment response. However, most have not shown the sensi-
200 mg per day of IV hydrocortisone either given 50 mg IV every
tivity, specificity, or cost-efficacy needed to justify their use in
6 hours or as a continuous infusion for patients who have
clinical practice.64
persistent circulatory failure despite adequate fluid resuscitation
Procalcitonin (PCT) is the most studied sepsis biomarker.65 A
and vasopressor therapy defined as a dose of noradrenaline
precursor to the hormone calcitonin, levels are routinely elevated

0.25 micrograms/kg/minute at least 4 hours after initiation.
in the setting of systemic infection. Thus far, studies show pro-
This recommendation is largely based on two recent major
calcitonin to be useful in decreasing the duration of antibiotic
corticosteroid trials with somewhat discordant results. The AD-
treatment, healthcare costs, the length of hospitalization, and
RENAL trial randomized septic shock patients to receive hydro-
adverse events.66,67 That said, elevations of PCT can also be seen
cortisone versus placebo, and while no difference in mortality
in uninfected patients. For example, modest elevations in PCT
was noted, there was a significant improvement in reversal of
are common in patients with renal disease, requiring adjusted
shock, ICU length of stay, ventilator-free days, and need for
interpretation. Based upon available data, the SSC suggests using
blood transfusions.75 On the other hand, another multi-centre
procalcitonin only to limit or discontinue antibiotic therapy. It
RCT administering hydrocortisone plus fludrocortisone versus
should be emphasized that elevated or normal procalcitonin
placebo to patients in septic shock did find a reduction in all-
levels alone are insufficient to justify the initiation (or not) of
cause mortality in the treatment group, along with shorter du-
antibiotics.43
rations of shock, ICU length of stay, and organ support.76 Much
like the evidence, the critical care community remains divided on
Molecular techniques
the use of steroids in septic shock.
Identifying and treating an offending organism in a timely
manner is often a challenge. Conventional blood cultures can Vitamin C (thiamine)
take up to 72 hours to provide a definitive result, while recently The use of vitamin C in patients with sepsis and septic shock is
developed molecular techniques can detect pathogens far more no longer recommended in the latest SSC guidelines.10 Since a
quickly. Ongoing evaluations of pathogen identification tech- heavily publicized observational study in 2017 that claimed
niques using multiplex polymerase chain reaction (PCR), PCR- a reduction in mortality, multiple subsequent RCTs have fai-
electrospray ionized mass spectroscopy (ESI-MS), and function- led to show benefit, and, in some cases, have demonstrated
alized nanoparticles coupled with magnetic resonance have harm.77e79
demonstrated the capability of identifying organisms in under 6
hours with reasonable sensitivity and specificity. Further studies Blood purification techniques
and cost analyses will determine whether these techniques are Endotoxin is circulating in 50% of patients in septic shock and is
incorporated into general clinical practice, but in the near future associated with poor outcomes.80 The EUPHRATES trial attemp-
these techniques may very well obviate the need for conven- ted to neutralize endotoxin via haemoperfusion with a polymyxin
tional blood cultures.68 fibre device.81 EUPHRATES was the largest RCT to study this
technology but was terminated early due to a failure to achieve
Molecular phenotyping and treatment enrichment the primary mortality endpoint. However, while it did fail to show
strategies a mortality benefit in the overall trial population, a post-hoc
Recent research has shown that sepsis may be far more hetero- analysis found that polymyxin B haemoperfusion decreased
geneous than once thought. In 2017, Scicluna et al. analysed a mortality in a subset of patients with moderate endotoxin activity
cohort of patients with sepsis and found markedly different (EA) as opposed to extreme EA.82 Based on these findings, the
genomic endotypes associated with a spectrum of hyper- TIGRIS trial is currently enrolling patients to evaluate haemo-
inflammatory or hypoinflammatory responses to infection.69 perfusion in patients with moderate-EA septic shock.83 Other
They demonstrated that the subjects on either extreme had techniques, such as extracorporeal plasma filtration to remove
higher mortality rates than those that exhibited a more measured pro- and anti-inflammatory mediators from the bloodstream are
or balanced response, leading to the suggestion that sepsis under evaluation.84,85 While the concept remains appealing, at
treatments tailored to an individual’s inflammatory phenotype or this time data are lacking to support the routine adoption of any
endotype may improve outcomes. blood purification technologies for sepsis.
Subsequent research has further classified sepsis into distinct
phenotypes that present with a myriad of clinical presentations, Glycaemic control
laboratory abnormalities, and patterns of organ dysfunction.70,71 Glycaemic control in sepsis is a much-debated topic. On one
Furthermore, these genetic subgroups have been shown to be hand, hyperglycaemia can exert an immunosuppressive effect,
associated with different responses to pro- and anti-inflammatory diminishing the body’s ability to mount a competent immune
modulators, leading to the potential for tailored treatment based response. On the other, the anti-inflammatory effects of insulin
on phenotypic or endotypic classification.70 Currently, large trials may inhibit cellular autophagy and negatively impact a patient’s
are in process exploring tailored treatments for specific sepsis capacity to clear infection.86
subgroups and biomarker enriched (selected) sepsis sub-pop- Evidence shows that severe hyperglycaemia in patients with
ulations.72e74 sepsis is associated with increased 30-day mortality.87 On the

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