doi:10.1111/imj.

14199

CLINICAL PERSPECTIVES

Sepsis and septic shock: current approaches to management

Kelly Thompson,1,2 Balasubramanian Venkatesh1,2,3,4 and Simon Finfer 1,2,5,6

1
The George Institute for Global Health, 2University of New South Wales, 5Sydney Medical School, University of Sydney, and 6Malcolm Fisher
Department of Intensive Care Medicine, Royal North Shore Hospital, Sydney, New South Wales, and 3The Princess Alexandra Hospital, University of
Queensland, and 4The Wesley Hospital, Brisbane, Queensland, Australia

Key words Abstract

sepsis, septic shock, critical care, intensive care
unit, infection.
Correspondence
Simon Finfer, Division of Critical Care and
Trauma, The George Institute for Global Health,
Level 5, 1 King Street, Newtown, NSW 2042,
Australia.
Email: sfinfer@georgeinstitute.org.au
Received 3 August 2018; accepted
28 September 2018.
Sepsis, defined as life-threatening organ dysfunction due to a dysregulated host
response to infection, is recognised by the World Health Organization as a global
health priority. Each year, 5000 of the 18 000 adults with sepsis treated in Australian
intensive care units die, with survivors suffering long-term physical, cognitive and
psychological dysfunction, which is poorly recognised and frequently untreated.
There are currently no effective pharmacological treatments for sepsis, making early
recognition, resuscitation and immediate treatment with appropriate antibiotics the
key to reducing the burden of resulting disease. The majority of sepsis, around
70–80%, is community acquired making emergency departments and primary care
key targets to improve recognition and early management. Case fatality rates for sep-
sis are decreasing in many countries with the reduction attributed to national or
regional screening and quality improvement programmes focused on early identifica-
tion and immediate treatment. The optimum approach to treating established sepsis
has been informed by high-quality, multicentre investigator initiated randomised tri-
als with much of the valuable data coming from National Health and Medical
Research Council-funded trials run from Australia. While early recognition and
improved management of the acute episode are important steps in reducing death
and disability from sepsis, a substantial reduction in the burden of sepsis-related dis-
ease requires action across the entire healthcare system. In this narrative review, we
provide a summary of current knowledge on epidemiology of sepsis and septic shock
and recommendations on the optimum approach to the management of these condi-
tions in adults.

Introduction and Torres Strait Islander Australians are fourfold

higher.4,5
Sepsis, now defined as life-threatening organ dysfunc-
Survivors of acute sepsis episodes are at an increased
tion due to a dysregulated host response to infection,1
risk of death in the year following hospital discharge,6
was recently recognised by the World Health Organiza-
and over half of all survivors report reduced health-
tion as a global health priority.2 Sepsis causes or contrib-
related quality-of-life with physical and cognitive impair-
utes to up to half of all in-hospital deaths in the USA.3
ment impacting their ability to perform usual activities of
Globally, the population incidence of hospital-treated
daily living.7,8
sepsis in adults is estimated as 270 per 100 000, with
In May 2017, the World Health Assembly adopted a
overall mortality estimated at 26%. Without counting
resolution co-sponsored by Australia to improve the pre-
sepsis in children or occurring outside hospital, this
vention, diagnosis and management of sepsis worldwide.
equates to 19.4 million cases and 5.3 million deaths glob-
The resolution urges all United Nations member states to
ally each year.4 The most recent population-based esti-
adopt a national action plan for sepsis and to include the
mate of sepsis in Australia is 188 per 100 000 with
prevention, diagnosis and treatment of sepsis in national
hospital mortality at 17.1%. Case rates for Aboriginal
health system strengthening efforts.
In this narrative review, we provide a summary of
Funding: None. current approaches to the management of sepsis and
Conflict of interest: None. septic shock focusing on adults.

160 Internal Medicine Journal 49 (2019) 160–170

© 2019 Royal Australasian College of Physicians

Risk factors and diagnosis
Sepsis results from the host response to infection, conse-
quently the populations at highest risk are those at greatest
risk of contracting severe infections, these include the very
young and the very old, and those with underlying non-
communicable diseases, such as diabetes, cancer and peo-
ple with disease or treatment-related immunosuppression.9
The definitions of sepsis and septic shock were
updated in January 2016 with the goal of identifying
patients at higher risk of adverse outcomes, specifically
those needing treatment in an intensive care unit (ICU)
or with a high risk of death.1,10 Previously, a diagnosis of
sepsis required the presence of infection accompanied by
two or more systemic inflammatory response syndrome
(SIRS) criteria, and when accompanied by organ dys-
function this was designated ‘severe sepsis’ (Box 1).11
The updated definition no longer considers the presence
of infection and SIRS to indicate sepsis, and instead the
diagnosis of sepsis requires an infection plus organ dys-
function indicated by an acute change in Sequential
Organ Failure Assessment (SOFA)12 of two points or
more (Supporting Information Table S1). Thus, the old
‘severe sepsis’ becomes ‘sepsis’ with the new definition
providing specific criteria to identify qualifying organ
dysfunction for the first time. The most severe form of
Box 1 Sepsis and septic shock
1992 definitions of sepsis and septic shock
Sepsis
• Suspected or confirmed infections AND
• Two or more systemic inflammatory response syndrome cri-
teria of:
 Core temperature >38 C or <36 C
 Heart rate >90 beats per min
 Respiratory rate > 20 breaths per min or a PaCO2 <
32 mmHg or mechanical ventilation for an acute process
 White blood cell (WBC) count of >12 × 109/L or < 4 × 109/L,
or > 10% immature neutrophils
Septic shock
Sepsis with hypotension, despite adequate fluid resuscitation,
along with the presence of perfusion abnormalities that may
include lactic acidosis, oliguria, or an acute alteration in men-
tal state
2016 consensus definitions of sepsis and septic shock
(sepsis-3)
Sepsis
• Suspected infection AND
• An acute change in SOFA score of ≥2 points consequent to
infection(see Table S1)
Septic shock
• Sepsis
• Hypotension requiring vasopressor therapy to maintain a
mean arterial blood pressure of 65 mmHg or greater
• Serum lactate level greater than 2 mmol/L after adequate
fluid resuscitation
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© 2019 Royal Australasian College of Physicians
Sepsis and septic shock
Table 1 Common sites of infection and causative microorganisms†
Common infection Common microorganisms
sites
Pulmonary‡ Pneumococcus, staphylococcus, atypical
infections, such as mycoplasma and legionella,
viruses and Gram negatives
Abdominal§ Gram negatives such as Escherichia coli,
Klebsiella, anaerobic organisms, Enterococcus,
Candida
Skin/soft tissue Streptococcus, methicillin-sensitive
Staphylococcus aureus, Gram negatives
Urinary Gram-negative bacilli, Enterococcus
Intravascular MRSA, Coagulase negative staphylococcus,
catheters Gram negatives
Central nervous Neisseria, pneumococcus, Gram positives
system
Endocarditis MSSA, coagulase negative staphylococcus
†Only one-third of patients with septic shock have positive blood cul-
tures. ‡In patients admitted with septic shock from the medical wards
or the emergency department, the sepsis is predominantly of pulmo-
nary origin. §In patients, admitted with septic shock from the operating
room, the sepsis is predominantly of abdominal origin. In immunocom-
promised patients, in addition to the above, opportunistic infections
from fungi, pneumocystis must be considered. MRSA, methicillin-resis-
tant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus
aureus.
sepsis is septic shock, a state of circulatory failure that
occurs in a subset of patients with sepsis in whom circu-
latory, cellular and metabolic abnormalities are associ-
ated with an increased risk of death.10 The diagnosis of
septic shock requires the presence of sepsis and hypoten-
sion requiring vasopressor therapy to maintain mean
arterial pressure (MAP) 65 mmHg or greater and a
serum lactate of greater than 2 mmol/L despite adequate
fluid resuscitation. In settings where lactate measure-
ment is not available, other indices of tissue hypoperfu-
sion, such as oliguria, altered mental status (Glasgow
Coma Scale of 13 or less) and delayed capillary refill,
may be used instead.10 While hyperlactaemia is not a
specific sign of sepsis and is not part of the definition of
sepsis, it is a valuable marker of disease severity and
remains an important component of many effective
screening programmes and treatment algorithms.13–15
Common sites of infection and common microorgan-
isms are documented in Table 1.
The importance of screening, early
recognition and early treatment
There are currently no licensed pharmacological treat-
ments for sepsis, but early recognition and treatment,
particularly early administration of effective antibiotics,
are associated with decreased mortality.16,17 While there
has never been, and likely never will be, a prospective
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Thompson et al.

randomised trial of early versus late antibiotics for sepsis, triage from 29.3 to 52.2% and was associated with a
observational data support their immediate administra- decrease in mortality from 19.3 to 14.1%, there was also
tion. The original influential data came from Kumar’s a significant reduction in the time patients spent in an
group in Canada16 and have recently been confirmed by ICU.13 Similar programmes are now being implemented
a study of the New York State Department of Health in Queensland and Victoria.13,19,20 Achieving similar
Database.17 In the New York study, risk-adjusted in- improvements for the 20% of patients who develop sep-
hospital mortality was 28% in patients in who antibiotic sis in hospital is challenging as it requires the education
treatment was delayed 12 h compared with 23% in of the entire clinical workforce, an enormous and ongo-
patients who received antibiotics within 1 h, represent- ing, but not impossible commitment. The feasibility and
ing a 22% increase in relative risk of death. Taken results of this approach have been documented at the
together, these studies suggest that the relative risk of Peter MacCallum Cancer Centre where a whole of hos-
death from sepsis or septic shock may increase by pital nurse-led sepsis pathway produced significant
between 4 and 8% for each hour of delay in administer- improvement in time to diagnosis and treatment of sep-
ing effective antibiotics. sis associated with reduced rates of ICU admission,
The majority, approximately 80%, of hospital-treated reduced post-sepsis length of stay and reduced sepsis-
sepsis arises in the community and presents to emer- related mortality.21 Improvements are more likely if sep-
gency departments, with the remaining 20% occurring sis education can be incorporated into systems designed
in patients already hospitalised for another reason.18 This to recognise and respond to deteriorating patients as
makes routine screening targeting early recognition and mandated by the Australian Commission on Safety and
treatment in emergency departments an attractive strat- Quality in Health Care’s National Safety and Quality
egy to reduce the number of deaths and such pro- Health Service Standard.22 This approach entails training
grammes have proven effective in Australia and in other members of rapid response teams to recognise sepsis and
countries.13,17 The New South Wales ‘Sepsis Kills’ pro- to treat it as a time critical medical emergency. Such rec-
gramme focused on recognition of risk factors, signs and ognition is widespread in some national healthcare sys-
symptoms of sepsis, resuscitation with rapid administra- tems, notably in the UK, but not yet across Australia.
tion of fluids and antibiotics and referral to senior clini- Systematic screening is recommended by the Surviv-
cians and teams. Using the slogan RECOGNISE, ing Sepsis Campaign: International Guidelines for Man-
RESUSCITATE, REFER, the programme increased the agement of Sepsis and Septic Shock,15 and by the UK
proportion of patients receiving antibiotics within 1 h of National Confidential Enquiry into Patient Outcome and

Principles: If suspected infection, screen for sepsis. If hypotensive, shocked or increased lactate, commence fluid and vasopressor resuscitation

Priority
Immediate Monitor haemodynamic and
organ function
Ongoing Screen for Sepsis using Assess organ function - Heart rate
local screening tool: - Heart rate - Blood pressure
- qSOFA/SOFA - Blood pressure - Arterial oxygen saturation Other supportive therapies as required
- NEWS - Arterial oxygen saturation - Respiratory rate
- SEPSIS KILLS - Respiratory rate - Mental status
Recognise Suspected or confirmed infection
- Mental status - Temperature
- Serum lactate Mechanical Ventilation
- Urine output
- Serum Lactate - Lung protective ventilation strategy (see text)

Renal Replacement Therapy

- If indicated for fluid overload or metabolic
1st 2nd derangement, (severe uraemia, hyperkalemia,
Obtain blood cultures Administer antibiotics Measure Lactate acidosis) (see text)
- All patients - All patients - To determine illness
- Prior to first dose - Broad spectrum severity / diagnose
antibiotic - Follow local guidelines septic shock Nutrition
- Two sets, aerobic for empiric therapy - Commence enteral feeding early (see Table 2)
and anaerobic
Resuscitate Glucose control
All within 1 hour
(if haemodynamic Administer intravenous crystalloids Commence Vasopressors - Maintain blood glucose < 10 mmol/L (see Table 2)
instability or - Normal saline or buffered salt solution - MAP target 65 mmHg
increased lactate) - Up to 30 ml/kg over 3 hours - Noradrenaline, first line
- Albumin, if failure to respond to crystalloid - Vasopressin/epinephrine Venous Thromboembolism Prophylaxis
- (NEVER administer hydroxyethyl starch) if needed - unfractioned heparin or low-molecular-weight
heparin (see Table 2)

Blood Transfusion
- If Hb<70 g/L (see Table 2)
Administer intravenous corticosteroids
- Consider 200 mg hydrocortisone per day if Minimise sedation
If shock persists hypotension / shock persists > 4 hours despite
Early mobilisation when stabilised
fluid resuscitation and vasopressor support

Figure 1 Flow diagram for the management of a patient with suspected sepsis.

162 Internal Medicine Journal 49 (2019) 160–170

© 2019 Royal Australasian College of Physicians

Death. A variety of screening tools are used around the
world, for example, the National Early Warning Score in
the UK,22 the Sepsis Kills pathway in NSW13,22 and tools
based on the SIRS criteria and markers of organ dysfunc-
tion in other countries. The recent working group on
sepsis definitions suggested a new screening tool, the
quick SOFA score.1 The quick SOFA assigns one point
for each of hypotension (systolic blood pressure ≤
100 mmHg), tachypnoea (respiratory rate of ≥22 per
minute) and altered mental status (Glasgow Coma Scale
score of 13 or less) and is suggested as a simple way to
identify patients with suspected infection who are likely
to have a prolonged stay in intensive care or to die in
hospital. Regardless of the screening system used,
improved outcomes will only result if sepsis is identified
and treated with minimum delay.
Figure 1 outlines initial screening and management
priorities for patients with sepsis and septic shock.
Management of patients with
established sepsis
Haemodynamic management
Treatment and resuscitation of patients with sepsis and sep-
tic shock should commence immediately and immediate
priorities are the identification and control of the source
infection, and its treatment with appropriate antibiotics.
Infections for which urgent source control is indicated
include abscesses amenable to percutaneous or surgical
drainage, ischaemic bowel, gastrointestinal perforation,
some infections of the biliary or urinary systems, necrotis-
ing soft tissue infection and infected implanted devices.
Haemodynamic management of sepsis related hypo-
tension should commence immediately. The 2018
update of the Surviving Sepsis Campaign guidelines
introduced the ‘Hour-1 Bundle’ which recommends
treatment with intravenous fluids, measurement of
serum lactate concentration as a marker of illness sever-
ity, administration of vasopressors, obtaining blood cul-
tures and administering broad-spectrum antibiotics, all
within the first hour.14 Ideally, such treatment will be
carried out or supervised by senior or experienced clini-
cians recognising that even with optimal treatment septic
shock carries a high risk of death.
Septic shock is now defined as sepsis accompanied by
hypotension requiring vasopressor therapy to maintain a
MAP of 65 mmHg or greater and a serum lactate of
greater than 2 mmol/L despite adequate fluid resuscita-
tion. Sepsis-induced hypotension results from different
pathological processes that require different treatments.
Hypovolaemia from intravascular volume loss due to
increased vascular permeability requires fluid
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© 2019 Royal Australasian College of Physicians
Sepsis and septic shock
resuscitation, vasodilatation affecting both the venous
capacitance vessels and the arterial resistance vessels is
treated with vasopressor agents, and sepsis-related myo-
cardial dysfunction may require specific inotropic
agents.23
Protocols and algorithms for the management of
sepsis-related hypotension are the focus of ongoing
research. A landmark trial published in 2001 suggested
that ‘Early Goal Directed Therapy’ (EGDT), a protocol
based around using central venous oxygen saturation as
a resuscitation target during the first 6 h of treatment,
would significantly reduce mortality.24 Patients ran-
domly assigned to EGDT received more intravenous
fluid, blood transfusions and inotropes in the first 6 h of
treatment than those assigned to ‘usual care’. Mortality
was 46.5% with usual care and 30.5% with EGDT. As
the study was conducted in a single hospital in the USA
and open label it was considered at high risk of bias, and
subsequently the protocol was tested in three large
multi-centre trials in the USA, the UK and in Australia
and New Zealand, and all three reported no benefit from
EGDT.25–28
Not all commentators agree with the Surviving Sepsis
Campaign Guideline recommendation to commence
intravenous fluid resuscitation of sepsis-induced hypo-
perfusion at a rate of 30 mL/kg over 3 h,15 and currently
the bundle is under review because of concerns that its
uncritical application may be harmful.29 In response to
the EGDT trials, more restrictive approaches to fluid
resuscitation are currently being evaluated in rando-
mised controlled trials (RCT).30 While it is not possible to
make firm evidence-based recommendations on indivi-
dualising fluid therapy, it is common sense and good
practice to review repeatedly individual patients and pre-
scribe fluid resuscitation based on repeated assessment of
ongoing need. There is widespread agreement that fluid
resuscitation should commence with a crystalloid solu-
tion, either normal saline or a buffered salt solution,
such as Hartmann’s solution or PlasmaLyte. For patients
who fail to respond to crystalloid resuscitation albumin
can be added, although the evidence of its benefit
remains equivocal.31,32 Hydroxyethyl starch should not
be used as it increases the risk of acute kidney injury and
death.33 A restrictive approach to blood transfusion is
safe and transfusing when haemoglobin concentration
falls below 70 or 90 g/L results in equivalent mortality
and morbidity.34
Initial MAP target for patients with septic shock who
require treatment with vasopressors should be 65 mmHg.
In a trial comparing target MAP of 65–70 mmHg and
80–85 mmHg mortality outcomes were the same while
those assigned the higher target received more vasopres-
sors and had a higher risk of atrial fibrillation. In the
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study, randomisation was stratified by presence or
absence of chronic arterial hypertension, and in their
electronic supplement, the authors report a reduction in
use of renal replacement therapy in patients with
chronic arterial hypertension assigned to the high MAP
group. This raises the possibility that individualising
treatment by targeting a MAP of 80–85 mmHg in such
patients may improve some outcomes though a recent
systematic review of vasopressor blood pressure targets
in critically ill adults with hypotension did not support a
higher MAP target.35–37
Patients requiring vasopressors or ongoing fluid resus-
citation should be treated in an ICU and undergo inva-
sive vascular monitoring. Noradrenaline is the most
commonly used vasopressor in Australian critical care
practice and RCT support its use. In patients with sepsis,
noradrenaline with dobutamine produced equivalent
outcomes to adrenaline used alone. Adrenaline use
results in a transient treatment-related lactic acidosis
which, although not harmful, interferes with assessment
of response to resuscitation. Historically, dopamine was a
popular inotrope and vasopressor, but its use is associ-
ated with a nonsignificant increase in mortality and sig-
nificantly greater risk of cardiac arrhythmias. Owing to a
recent noradrenaline shortage, some hospitals in the
USA were forced to use other vasopressor agents, most
commonly phenylephrine patients with septic shock
admitted to these hospitals at the time of the noradrena-
line shortage had higher in-hospital mortality,38 provid-
ing further support for the use of noradrenaline as the
first line agent.
Vasopressin can be added to norepinephrine if
required to achieve the target MAP although in two RCT
its use did not reduce mortality.39,40 Selepressin, a selec-
tive vasopressin 1a receptor agonist,41 and synthetic
human angiotensin II,42 are both effective vasopressors
but do not have proven advantages compared to nor-
adrenaline. Adding levosimendan, a calcium-sensitising
inotropic agent with other properties, to standard care
did not reduce organ dysfunction or mortality but was
associated with more adverse effects.
Corticosteroids
There is an established biological rationale for the
administration of adjunctive corticosteroids in the man-
agement of patients with septic shock. Corticosteroids act
through two mechanisms: immune modulation and car-
diovascular modulation. Evidence from RCT in the late
1980s demonstrated that high-dose methylprednisolone
(30 mg/kg), although effective in reversing shock, did
not reduce mortality in sepsis and that treatment with
high dose corticosteroids was associated with increased
164
mortality from superinfection.43,44 Studies in the late
1990s consistently demonstrated that treatment with
lower doses of corticosteroids, typically hydrocortisone
in a dose of 200 mg per 24 h, results in more rapid rever-
sal of shock.45 Concomitant with these findings was the
observation that patients with a reduced cortisol
response to an exogenous corticotropin stimulation test
with adrenocorticotrophic hormone (ACTH) (‘nonre-
sponders, also termed ‘relative adrenal insufficiency’)
had a higher mortality in severe sepsis. Two RCT pro-
duced divergent results on the efficacy of corticosteroids
in reducing mortality, although both lacked the statistical
power to demonstrate a clinically significant reduction in
mortality.46,47
Recently, two large-scale RCT have added substantial
new data to inform opinion regarding the role of cortico-
steroids in the treatment of septic shock.48,49 The
Australia-based ADRENAL trial investigated the role of a
continuous infusion of 200 mg/day of hydrocortisone
compared with placebo in critically ill patients with septic
shock; it reported no difference between groups with
respect to short or longer term mortality, but patients
assigned to hydrocortisone had earlier shock reversal, lib-
eration from mechanical ventilation, reduced frequency
of blood transfusion and earlier discharge from intensive
care.48,50 The APROCCHS trial (n = 1241) examined the
effect of 200 mg per day of hydrocortisone given as four
50 mg doses, combined with oral fludrocortisone com-
pared to placebo and reported improved mortality in the
steroid group, coupled with earlier shock reversal and
earlier liberation from mechanical ventilation.49 Meta-
analyses, including the results of these two trials, have
concluded that low dose corticosteroids produce either
no or a very small reduction in short term mortality, but
use is associated with more rapid resolution of shock,
and shorter ICU stay.51,52 Currently, the Surviving Sepsis
Campaign guidelines recommend against the use of low-
dose corticosteroids if fluid resuscitation and vasopressor
therapy are adequate in restoring hemodynamic stability.
If hemodynamic instability persists despite adequate fluid
resuscitation and vasopressor therapy, intravenous
hydrocortisone can be added at a dose of 200 mg per day.
The results from these recent RCT are likely to reinforce
the role of steroids in septic shock and change the recom-
mendation in future clinical practice guidelines.
Adjunctive therapies
Anti-inflammatory and immune stimulation
strategies
The original rationale for treating sepsis with corticoste-
roids was that sepsis was an uncontrolled inflammatory
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 Sepsis and septic shock

response to infection and the anti-inflammatory effects
of corticosteroids would improve outcomes. This same
rationale spawned a multitude of clinical trials targeting
the pathways and mediators of sepsis, including endo-
toxin, toll-like receptors, tumour necrosis factor α, inter-
leukins, prostaglandins and leukotrienes, platelet
activating factor, proteases, nitric oxide and others. None
of these trials has resulted in a licensed and effective
pharmaceutical for the treatment of sepsis, probably in
part because some of the agents tested are ineffective,
but also probably because of flaws in patient selection
and trial design.53
In developed healthcare systems, relatively few patients
die rapidly of fulminant sepsis that is unresponsive to
efforts at resuscitation, most deaths result from multiple
organ failure and occur days or weeks after the onset of
sepsis. In addition, patients who survive sepsis are at
increased risk of being readmitted to hospital and suffer-
ing further episodes of infection and sepsis.6,54,55 These
observations and basic science research suggest that
immunosuppression contributes significantly to delayed
sepsis mortality,56 and agents that stimulate immunity,
such as Interleukin-7 and checkpoint inhibitors, may be
beneficial in reducing sepsis mortality and morbidity.57,58
Renal replacement therapy and cytokine
removal
Septic shock is the most common cause of acute kidney
injury in the ICU accounting for approximately half of all
acute kidney injuries and is associated with the highest
mortality.59 Renal replacement therapy may be indicated
for the treatment of uraemia, fluid overload and the met-
abolic derangement, such as severe hyperkalemia, that
accompanies acute kidney injury. Renal replacement
therapy, given almost exclusively as continuous veno-
venous haemodiafiltration in Australian ICU, lowers
temperature and often lowers vasopressor requirements.
Early use of renal replacement therapy is theoretically
attractive as it may limit organ injury and fluid overload
and remove inflammatory mediators responsible for the
clinical manifestations of sepsis.59 To date, there are no
compelling data that strategies to remove cytokines, or to
use more intensive renal replacement therapy,60–63
improve outcomes for patients with septic shock.
Other management recommendations for patients
with sepsis and septic shock are closely aligned with the
general management of critically ill patients and are
documented in Table 2.

Table 2 General management of the critically ill patient with sepsis and septic shock

Mechanical ventilation
Venous thromboembolism
prophylaxis
Nutrition
Glucose control
Sedation and analgesia
Positioning and early
mobilisation
Agreement on treatment
goals
Target tidal volumes of 6 mL/kg ideal bodyweight. If sepsis-related acute respiratory distress syndrome (ARDS) target
tidal volumes of 6 mL/kg ideal bodyweight and plateau airway pressure of 30 cm H2O. In intensive care units (ICU)
experienced in the practice, ventilate patients with severe ARDS in the prone position for 16 h each day.
Extracorporeal membrane oxygenation (ECMO) may reduce mortality in patients with very severe ARDS, such
patients should be referred to an ECMO retrieval service.
Pharmacologic prophylaxis using unfractionated heparin or low-molecular-weight heparin is recommended in the
absence of contraindications to the use of these agents. Non-pharmacological prophylaxis recommendations
include; anti-embolism stockings and consideration of passive and early mobilisation, where appropriate.
Early initiation of enteral feeding using trophic/hypocaloric or full enteral feeding is recommended in patients who can
tolerate enteral feeding. Early feeding should be commenced within 48 h and feeding goals met ideally within 72 h of
admission to the ICU. If enteral feeding is not fully established within a week, parenteral supplementation should be
considered.
Blood glucose should be managed using a protocolised approach with commencement after two consecutive levels
are >10 mmol/L. The target of blood glucose level is 6–10 mmol/L. Measurement should be conducted every 1–2 h
until values and insulin infusion rates stabilise, then every 4 h thereafter in patients receiving insulin infusions.
Continuous or intermittent sedation should be minimised in mechanically ventilated patients. Common approaches
include implementation of nurse-directed protocols, administration of intermittent sedation, and daily sedation
interruption. Short-acting sedatives including propofol and dexmedetomidine may result in improved outcomes.
Other pain, agitation and delirium guidelines provide additional detail on implementation of sedation management
for mechanically ventilated patients with sepsis and septic shock.
Elevate bed head between 30 and 45 for mechanically ventilated patients. Regular pressure area care as per unit
specific guidelines. Active and early mobilisation should commence as soon as the patient is stable enough to
participate. While, to date, no studies have found improvements in short- and long-term mortality active early
mobilisation may improve mobility status and muscle strength, with several larger multicentre trials underway.
Sepsis is common in elderly patients and in patients with serious underlying medical conditions and unlimited
interventions will not be appropriate for all patients. Limitations to treatment may include both withholding and
withdrawing life sustaining treatments when these will no longer produce an outcome acceptable to the individual
patient. Agreement on treatment goals should whenever possible be informed by the patient’s pre-stated wishes
either to family or close friends or in legal documents such as advance directives or living wills.

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Thompson et al.

Table 3 Major investigator-initiated trials and consensus statements informing the management of sepsis and septic shock

Trial name or Population Design or description Interpretation and implications for clinical practice
first author

Kumar 2006 Patients with septic shock (N = Multicentre retrospective cohort Risk of death increased by 8% for each hours delay in
2731) study administration of antibiotics. Antibiotics should be
administered within 1 h of diagnosis or strong suspicion of
sepsis.
Seymour 2017 Patients with sepsis at Multicentre retrospective cohort Completion of mandated - hour sepsis ‘bundle’ associated
149 hospitals in New York state study with reduction in risk adjusted mortality with reduction
(N = 49 331) attributable to earlier administration of antibiotics
Burrell 2016 Emergency department patients Multicentre retrospective cohort Introduction of the Sepsis Kills programme was associated
included in the New south Wales study with significant increase in proportion of patients receiving
‘Sepsis Kills’ database (N = antibiotics and commencing 2nd litre of intravenous within
13 567) first hour of diagnosis of sepsis. These practice changes
were associated with significant reduction in mortality.
Finfer 2011 Patients treated in mixed medical Multicentre blinded RCT of 4% Overall albumin and saline both appropriate fluids but
and surgical and specialty ICU in albumin versus saline for fluid albumin may result in lower mortality in patients with sepsis
Australia and New Zealand – resuscitation in ICU and septic shock
subgroup of patients with sepsis
and septic shock (N = 6997)
ALBIOS trial 2014 Patients with severe sepsis in Multicentre blinded RCT Administering albumin to maintain serum albumin
100 ICU in Italy (N = 1818) crystalloid plus 20% albumin to concentration does not reduce mortality in patient with
maintain serum albumin ≥30 g/L sepsis, reduced mortality in septic shock subgroup
versus no albumin
6S Trial 2012 Patients with severe sepsis in ICU Multicentre blinded RCT 6% Hydroxyethyl starch should not be given to patients with
in Scandinavia (Denmark, hydroxyethyl starch (130/0.42) sepsis – increased risk of death, use of renal replacement
Norway, Finland, Iceland) (N = vs ringer’s acetate for fluid therapy and renal failure
804) resuscitation in ICU
Rochwerg 2018 Patients with sepsis/septic shock Systematic reviews and Corticosteroids possibly result in a small reduction in
and randomly assigned to meta-analyses mortality, reduce duration of shock and duration of
Rygård 2018 corticosteroids or not (N = treatment in ICU. Might increase neuromuscular
10 194 sepsis; N = 7297 septic complications.
shock)
Holst 2014 Patients with septic shock Multicentre RCT of two No difference in outcomes – safe to use conservative
(N = 1005) transfusion thresholds approach to transfusion in patients with septic shock
comparing <70 versus <90 g/L
Iwashyna 2010 Survivors of severe sepsis from Prospective long-term cohort Sepsis survivors had 10% increase in prevalence of moderate
the US Health and Retirement study to severe cognitive impairment, and significantly more new
Study (N = 516) physical impairment than survivors of non-sepsis
hospitalisations
ADRENAL 2018 Patients with septic shock Multicentre RCT of continuous No difference in 90-day all-cause mortality. Patients in the
(N = 3800) 200 mg/day hydrocortisone or hydrocortisone group had faster resolution of shock,
placebo infusion for 7 days shorter duration of the initial episode of mechanical
while in ICU ventilation and were less likely to receive blood
transfusions.
APPROCHS 2018 Patients with septic shock Multicentre RCT of 90-day all-cause mortality was lower among those who
(N = 1241) hydrocortisone (50 mg IV bolus received hydrocortisone plus fludrocortisone than among
every 6 h) and fludrocortisone those who received placebo
(50 μg tablet daily via NG tube)
for 7 days compared with
matched placebo
Rhodes 2016† Patients with sepsis and septic Consensus evidence-based Comprehensive evidence review focused mainly on initial
shock guidelines for the management resuscitation and care in the ICU
of sepsis and septic shock in
adults

†Rhodes 2016 provides comprehensive evidence-based guidelines (Surviving Sepsis Campaign Guidelines) for managing patients with sepsis and sep-
tic shock. While this is not a major investigated initiated trial, it is included as it is a valuable resource for clinicians and researchers. ICU, intensive care
unit; RCT, randomised controlled trial.

166 Internal Medicine Journal 49 (2019) 160–170

© 2019 Royal Australasian College of Physicians

Table 3 provides a list of important research that has
informed the current clinical management of sepsis and
septic shock.
General intensive care management
Patients with respiratory failure requiring positive pres-
sure mechanical ventilation should have target tidal vol-
umes of 6 mL/kg ideal bodyweight. For adult patients
with sepsis-related acute respiratory distress syndrome
(ARDS), a ventilation strategy targeting a tidal volumes
of 6 mL/kg ideal bodyweight and a plateau airway pres-
sure of 30 cm H2O results in lower mortality than allow-
ing larger tidal volumes and a higher plateau pressure.64
A restrictive approach to fluid administration is also ben-
eficial.65 In ICU experienced in the practice, ventilating
patients with severe ARDS in the prone position for 16 h
each day significantly reduced mortality.66 A recent trial
lends further support to the contention that extracorpo-
real membrane oxygenation (ECMO) reduces mortality
in patients with very severe ARDS,67 such patients
should be referred to specialist ECMO centres who offer
an ECMO retrieval service as safe transport requires
ECMO to be established at the referring hospital.
Personalised medicine
Clinicians treating patients with sepsis recognise marked
inter-patient variability in response to treatment, and it
is clear that genetic factors play an important role in sus-
ceptibility to sepsis and response to treatment. A land-
mark study of Danish adoption records reported that
adopted children whose biological parent had died
before the age of 50 from an infective cause had a five-
fold increase in the relative risk of death from infection.
There was no corresponding increase in risk of death
from sepsis if it was the adoptive parent who died from
the same cause.68 Since then, many studies have sought
to understand the genetic basis of sepsis.69
The development of sepsis-specific biomarkers and
molecular diagnostics for the assessment of the host
response and for pathogen detection is the subject of
ongoing research and success would likely result in
improved patient outcomes. Around 180 distinct mole-
cules have been proposed as potential biomarkers of sep-
sis, given its biological complexity a panel of multiple
biomarkers may be the best risk stratification tool.70,71
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Internal Medicine Journal 49 (2019) 160–170
© 2019 Royal Australasian College of Physicians
Sepsis and septic shock
Pharmacogenomics is a rapidly evolving field in the
area of sepsis with the ultimate goal of identifying which
patients are likely to benefit from or be harmed by partic-
ular drug treatments; as yet this research has produced no
tangible clinical benefits for the management of sepsis.
Longer term morbidity and increased
healthcare resource use of sepsis survivors
Although mortality from sepsis and septic shock remains
unacceptably high, it is decreasing around the world
making the long-term effects suffered by the increasing
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among the many specialists and general practitioners to
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Conclusion
While acute case fatality rates of sepsis are decreasing,
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