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African Journal of Emergency Medicine (2015) 5, 127135

African Federation for Emergency Medicine

African Journal of Emergency Medicine


Sepsis, severe sepsis, and septic shock: A review of the literature

Septicemie, septicemie grave et choc septique: etude bibliographique

Keegan Tupchong a, Alex Koyfman b,*
, Mark Foran a

Department of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center, New York, NY, USA
Division of Emergency Medicine, UT Southwestern Medical Center/Parkland Memorial Hospital, Dallas, TX, USA

Received 25 November 2013; revised 14 April 2014; accepted 25 May 2014; available online 1 August 2014

Sepsis represents a continuum of illness due to systemic inammation caused by an infection that requires prompt recognition and treatment. While sepsis is a signif-
icant cause of death worldwide, its mortality is believed to be disproportionately high in low- and middle-income countries (LMICs). Since 1992, its denition has
become standardized, and beginning in 2002, an international collaboration has produced a set of consensus guidelines on the optimal management of septic patients.
Based on new evidence, signicant updates have been made since then. It is known that application of a bundled approach to patient care with the use of specic resus-
citation endpoints to guide therapy leads to signicant reductions in mortality from sepsis. However, it is also recognized that the implementation of such interventions
in LMICs is extremely challenging. Consequently, a body of literature on practical guidelines for sepsis in developing countries has emerged. This article provides a
review of the evidence for the best practice of sepsis management, with recommendations for resource-limited settings.

La septicemie represente un eventail de maladies dues a une inammation systemique provoquee par une infection qui necessite une identication et un traitement
rapide. Si la septicemie est une cause de deces importante dans le monde, la mortalite associee est consideree comme disproportionnellement elevee dans les pays a
faible et moyen revenus. Depuis 1992, sa denition sest standardisee, et a partir de 2002, une collaboration internationale a produit un ensemble de lignes directrices
consensuelles sur la prise en charge optimale des patients souffrant de septicemie. Sur la base de nouvelles donnees factuelles, des mises a jour denvergure y ont depuis
ete apportees. On sait que lapplication dune approche globale a la prise en charge des patients, combinee au recours a des criteres de reanimation visant a guider la
therapie, permet dobtenir une reduction signicative de la mortalite liee a la septicemie. Il est cependant egalement reconnu que la mise en uvre de telles interventions
dans les pays a faible et moyen revenu est extremement difcile. Par consequent, un certain nombre de publications sur les directives pratiques relatives a la prise en
charge de la septicemie dans les pays en voie de developpement sont apparues. Cet article propose un examen des elements probants sur une meilleure pratique de la
gestion de la septicemie, ainsi que des recommandations pour les milieux a ressources limitees.

African relevance Since then, additional terminology has emerged. Sepsis compli-
cated by organ dysfunction is referred to as severe sepsis,
 Sepsis has an especially high mortality in Africa. while sepsis complicated by hypotension refractory to ade-
 Rapid recognition of sepsis and a protocoled approach to quate volume resuscitation in the absence of an alternate cause
management save lives. has been termed septic shock.1 The clinical signicance of
 Tailored recommendations for resource-limited settings the sepsis spectrum of illness cannot be understated. In the
offer a practical approach to sepsis care. US alone, the incidence of severe sepsis is over 700,000 annu-
ally with an estimated 30% mortality.3 This is estimated to
represent over 450,000 emergency centre (EC) visits per year.
Introduction 4
While some research has been devoted to the study of sepsis
in developing countries, its epidemiology in these countries
In 1992, sepsis was formally dened as the presence of both remains poorly described.5,6 Despite this, the morbidity and
suspected infection and two of the four criteria of the systemic mortality of sepsis in low- and middle-income countries
inammatory response syndrome (SIRS) (Tables 1 and 2).1,2 (LMICs) are believed to be disproportionately high, given
environmental degradation, widespread malnutrition, and
* Correspondence to Alex Koyfman. higher rates of bacterial, parasitic, and HIV infection.6,7 In
Peer review under responsibility of African Federation for Emergency Medicine. an effort to reduce the risk of death from sepsis, the Surviving
Sepsis Campaign (SSC) was initiated in 2002 from the collab-
oration of the European Society of Intensive Care Medicine
(ESICM), the International Sepsis Forum (ISF), and the
Production and hosting by Elsevier Society of Critical Care Medicine (SSCM). In 2004, the SSC
2211-419X 2014 Production and hosting by Elsevier B.V. on behalf of African Federation for Emergency Medicine.
128 K. Tupchong et al.

SS, this article will primarily discuss SS/SS. A particular focus

Table 1 SIRS criteria.1
will be on providing care in resource-limited settings with
Presence of two or more of the following. tailored recommendations. Of note, this review pertains
1. Temperature  >38 C (100.4 F) or specically to adults and not to children. See Tables 1 and 2
 <36 C (96.8 F) for denitions.
2. Heart rate  >90/min
3. Respiratory rate  >20/min or Epidemiology
 PaCO2 < 32 mmHg
4. White blood cell count  >12,000/lL or
 <4000/lL Despite the documented impact of sepsis in developed coun-
tries, literature on its incidence, prevalence, and mortality in
developing countries is sparse.10 What is recognized, however,
is that the global burden of sepsis lies in LMICs. As a surro-
Table 2 Diagnostic criteria for sepsis.1 WBC, white blood gate marker for sepsis, over 90% of worldwide deaths due to
cell; SBP, systolic blood pressure; MAP, mean arterial pressure. pneumonia, meningitis, and other infections occur in less
Table adapted from Levy et al. (2003).1 developed nations.6,11 Globally, an estimated 70% of the 9
Infection (documented or suspected) and some of the following. million annual neonatal and infant deaths are attributable to
sepsis, and more than half of these occur in Asia and Sub-
Classication Variables
Saharan Africa.11,12
General Fever (>38.3 C)
Hypothermia (core temperature < 36 C)
Heart rate > 90/min or more than two SD
above the normal value for age
Tachypnea During infection, offending microbes interact with the host
Altered mental status immune system producing a downstream inammatory cas-
Signicant oedema or positive uid balance cade involving cytokines and other mediators, which in turn
Hyperglycaemia triggers a systemic response. The resultant effects include
Inammatory Leukocytosis vasodilation, increased vascular permeability, myocardial
Leukopenia depression, and impairment of the coagulation cascade,
Normal WBC count with greater than 10% resulting in global imbalance of systemic oxygen supply
bands and demand, and a procoagulant state. During the late stage
Plasma C-reactive protein > 2 SD above the of sepsis, immunosuppression predominates, leading to
normal value
multiorgan dysfunction and further clinical deterioration.13
Plasma procalcitonin > 2 SD above the
normal value
Clinical assessment
Hemodynamic Hypotension (SBP < 90 mmHg,
MAP < 70 mmHg, or an SBP
decrease > 40 mmHg in adults or < 2 SD During history taking, the focus should be on detecting risk
below normal for age) factors for infection (such as immunosuppression), the pres-
ence of infection, and if suspected, the most likely sources.
Organ dysfunction Creatinine increase
Caution should be advised in geriatric patients, as they may
Hypoxaemia not be able to communicate traditional symptoms (e.g., dys-
Ileus uria in occult urinary tract infections). The physical examina-
Oliguria tion should be used to identify possible foci of source control.
Thrombocytopenia A critical action at this point is the measurement, documenta-
Hyperbilirubinemia tion, and evaluation of vital signs, including temperature,
Tissue perfusion Hyperlactatemia
blood pressure (BP), heart rate (HR), respiratory rate (RR)
Decreased capillary rell or mottling and oxygen saturation (if below 90% then supplemental
oxygen should be immediately applied). Repeated recording
of these parameters will be used to gauge clinical improvement
produced the Surviving Sepsis Campaign guidelines for or deterioration and trigger specic interventions (see below).
management of severe sepsis and septic shock, one of the Consistently analysing the vital signs for the presence of SIRS
most recognized consensus statements regarding the treatment criteria in any possible patient with sepsis will aid in the early
of sepsis (most recently updated in 2012).8 In many countries, recognition of critical illness.
it is held to be the standard of care.7 As 50% of hospital Importantly, vital sign derangements may be absent early
admissions occur through the ED, there is a signicant oppor- on and in elderly patients.14,15 Specic physical exam ndings
tunity to improve outcomes.9 This review will discuss the that are predictive of sources of infection include indwelling
epidemiology, pathophysiology, and diagnostic and therapeu- devices (e.g., intravascular or urinary catheters), rales,
tic approach to patients with sepsis, severe sepsis, and septic abdominal tenderness, and evidence of CNS infection.16,17 A
shock in the ED and other acute care settings. It is important cardiovascular and volume status assessment, including
to note that as international guidelines focus on the evaluation auscultation, mucous membranes, skin colour and turgor,
and management of patients with severe sepsis and septic peripheral pulses, capillary rell and oedema should be
shock (SS/SS) as opposed to sepsis without evidence of SS/ undertaken at this stage as well.
Sepsis, severe sepsis, and septic shock 129

In the absence of automated devices to track vital signs, it is (provider-driven) care.23 It is critical to note, however, that
imperative to keep a written log and to have early recognition patients in the usual care group were aggressively resusci-
of SIRS. As more advanced and invasive equipment used to tated (in the rst 6 h of EC arrival: 4.4 L of intravenous uids,
gauge response to therapy (see below) may be absent in 58% had central venous catheters, 44% were placed on vaso-
LMICs, changes in BP, HR, RR and oxygen saturation to pressors, 22% underwent mechanical ventilation), and in the
interventions should be used as indicators of clinical status. absence of this high level of usual care, protocol-based
resuscitation may still be advocated.
Diagnostic studies Some of the markers of resuscitation and their usage (e.g.,
central venous pressure, CVP; mean arterial pressure, MAP;
Initial laboratory and radiographic testing is aimed at locating central venous oxygen saturation, ScvO2, serial lactate) will
a source of infection and identifying evidence of organ dys- be discussed below.
function. At the discretion of the examiner, common labora- Patients with hypotension despite uid resuscitation and
tory studies include a complete blood count (white blood cell those with evidence of end organ dysfunction (SS/SS) have
count including a differential of subtypes and measure of high mortalities and aggressive resuscitation or adherence to
bands, haemoglobin and haematocrit, platelets), chemistries protocoled, goal-oriented therapy may improve mortality.
(electrolytes, bicarbonate, creatinine, glucose), prothrombin Using as many of the available following techniques can alter
time (PT)/international normalized ratio (INR), liver transam- the course of illness. Upon recognition of SS/SS, a team of care
inases, bilirubin, and either arterial or venous blood gas anal- providers should be alerted and enlisted.
ysis with the inclusion of a serum lactate level. Urinalyses are
of high-yield, particularly in patients older than 65.18 Chest Initial resuscitation
radiography is often sought to identify sources of pulmonary
infection and causes of respiratory distress. Importantly, all The initial evaluation of patients with sepsis includes the rapid
patients with possible sepsis should have blood cultures drawn establishment of multiple points of intravenous (IV) access
as they may narrow antibiotic choices and uncover reasons for with anticipation for the need for uid resuscitation, antimi-
treatment failure.8 As the volume of blood is more important crobials, and possibly vasoactive medications (vasopressors).
for culture yield than the number of blood cultures, ideally, As patients are often hypovolaemic, frequently suffering large
20 mL of blood should be collected.19 In general, cultures uid decits, immediate administration of 30 mL/kg (typically
should be obtained from every possible source of infection 2 L) of crystalloid is recommended.8,24 The goal is to restore
(e.g., blood, urine, sputum, wounds, catheters, cerebrospinal tissue perfusion, and volume resuscitation leads to increases
uid) deemed likely in the clinical scenario. in cardiac output and systemic oxygen delivery.24 Patients with
If only select laboratory tests are available, preference hypotension (MAP < 65 mmHg) after a uid bolus, hyperlac-
should be given to those that may indicate a source of infec- tatemia (>4 mmol/L), signs of hypoperfusion or organ failure
tion, consequently identifying a target for therapy. Blood cul- are deemed to be in SS/SS. In such instances, transition to a
tures should be obtained whenever possible. goal-directed approach to therapy is recommended by consen-
sus guidelines with measurable endpoints at the 3- and 6-h
Treatment and management marks.8 It is important to note that patients meeting criteria
for sepsis but not SS/SS may benet from a similar approach
General approach to therapy. However, consensus guidelines advocating bundled
care pertain specically to SS/SS patients.8
Prompt recognition of the septic patient is critical, and early In resource limited settings, administer at least 30 mL/kg
localization along the sepsis spectrum of illness (sepsis, severe (typically 2 L) of crystalloid upon the recognition of sepsis,
sepsis, septic shock) helps to dene the early goals of manage- as many patients are hypovolaemic.
ment. A key distinction should be made between sepsis and
severe sepsis/septic shock (SS/SS), the latter of which are the Measures of intravascular volume
focus of the Surviving Sepsis Campaign guidelines. It is recom-
mended that patients with SS/SS undergo a protocol-driven The rst protocoled step in the care of patients with SS/SS is
approach to treatment using quantitative resuscitation.8 This uid resuscitation with the goal of restoring intravascular vol-
is the concept of using explicit, predened physiological or lab- ume (and presumptively, preload).8 There are several methods
oratory resuscitation endpoints to guide management.20 Its to estimate volume status that are gaining support, such as
international recognition was sparked by a landmark study ultrasound-guided assessment of the respirophasic variation
by Rivers in 2001, which utilized a goal-directed approach to of the inferior vena cava (IVC), and pulse-pressure variation
therapy of SS/SS patients (early goal-directed therapy, EGDT) (PPV).25 However, the efcacy of these monitoring techniques
and demonstrated a 16% absolute reduction in in-hospital in improving clinical outcomes is believed to require further
mortality (number needed to treat = 6.25).21 A 2008 meta- study.8 As such, consensus guidelines continue to recommend
analysis provided further support for the use of early and CVP measurement as a surrogate for preload despite a well-
quantitative resuscitation as it showed a survival benet in het- known systemic review demonstrating a very poor relationship
erogeneous populations with sepsis.22 Of note, however, the between CVP and uid responsiveness.8,26 Consequently, the
ProCESS trial, a recent multicenter randomized trial of over rst resuscitation endpoint in SS/SS according to the Surviving
1300 patients demonstrated no mortality benet with the use Sepsis Campaign guidelines is a target CVP of 812 cm
of protocol-based resuscitation (such as EGDT) over usual H2O. Values signicantly below this may be suggestive of
130 K. Tupchong et al.

hypovolaemia and the potential need for additional uid resus- using vasopressors, targeting a MAP P 65 mmHg is an
citation. It is worth highlighting here that utilizing CVP requires accepted clinical end point for most patients.8 An important
the placement of a central venous catheter above the diaphragm. caveat is that higher MAPs may be required in patients with
In the resource-limited setting, be aggressive in empirically chronic hypertension and lower MAPs may be tolerated in
uid loading patients as they may require more than 46 L of young patients.8 Ideally, uid resuscitation (CVP P 8 cm
crystalloid in the rst 6 h of care.21 This intervention alone has H2O) should occur prior to the use of vasopressors, however,
been shown to reduce mortality.27 As shown in the ProCESS patients in shock may require them to be started sooner.8
trial, aggressive uid resuscitation (an average of 4.4 L in the There are several options for choice of vasopressor agent.
rst 6 h in this study) should be the norm.23 In the absence In the Rivers study, dopamine and norepinephrine were
of advanced modalities to estimate uid responsiveness, check used.21 In a recent, multicenter trial comparing norepinephrine
jugular venous distension and listen for crackles as evidence of and dopamine, both were deemed equally efcacious at revers-
uid overload.28 ing hypotension and there was no signicant difference in mor-
tality, though there were more arrhythmias in the dopamine
Ongoing uid administration group.36 The authors concluded that norepinephrine is
superior in the setting of sepsis.36
In patients with refractory hypotension despite uid resus-
While highly variable by case, patients in the ProCESS trial
citation and norepinephrine administration, vasopressin may
usual care arm received an average of 4.3 3.9 L of intrave-
be added at low doses of 0.03 units per minute and has been
nous uid from hours 6 to 72 (after initial resuscitation).23
shown to have benecial hemodynamic and renal function
In resource-limited settings, use markers of hypoperfusion
effects.37 Epinephrine and phenylephrine are alternative addi-
such as hypotension, lactate clearance, and urine output (see
tions to norepinephrine.8
below) to guide the rate of uid administration following the
The newest consensus guidelines recommend norepineph-
initial resuscitation period. While variable, this may be in
rine as the rst-line vasopressor, while epinephrine and vaso-
excess of 8 L over the following 72 h.
pressin are possible additions. Dopamine is recommended
against being used except in highly select circumstances, such
Fluid selection as relative bradycardia.8
In resource-limited settings, vasopressors should be initi-
The results of numerous trials support the preferential use of ated once patients are believed to be adequately uid resusci-
crystalloid, the avoidance of hydroxyethyl starches (HES), tated. If available, norepinephrine is preferred, followed by
and the select use of albumin only after large quantities of crys- epinephrine and/or vasopressin. Dopamine and phenylephrine
talloid administration. Crystalloid has repeatedly shown to be may be used if no other agent is available.
cheaper, and has either no mortality difference or a lower mor-
tality in comparison HES, along with a decreased need for Blood products and inotropes
renal replacement therapy (RRT) and is strongly recom-
mended.8,29,30 Additionally, it is important to note that while The third resuscitation endpoint for the treatment of SS/SS is a
there are emerging data on the potential benets of using bal- SCVO2 of at least 70%, as a measure of the balance between
anced crystalloid solutions (e.g., Ringers lactate) as opposed tissue oxygen delivery and consumption. There are several
to chloride-rich uids (e.g., normal saline), the primary consid- causes of low central venous oxygen saturations (SCV-
eration in LMICs should be on ensuring adequate crystalloid O2 < 70%) in septic patients who have achieved adequate
volume resuscitation regardless of the type.31,32 It is important uid resuscitation and adequate blood pressure. This may be
to reiterate here that this review focuses on adult patients, as a due to metabolically active tissue, arterial hypoxaemia, low
study of over 3000 children in shock with febrile illnesses who oxygen carrying capacity, or decreased cardiac output. The
were randomized to uid boluses vs. no boluses demonstrated degree of oxygen delivery can be improved by the transfusion
an increased mortality in the uid bolus group.33 The applica- of packed red blood cells.21
bility of this trial to adult patients has yet to be established. Red blood cells should be transfused to a target haemoglo-
In resource-limited settings, use crystalloids liberally. The bin concentration of 79 g/dL.8 This differs from the Rivers
type of crystalloid infusion is not as important as the volume study, which used a threshold haematocrit of 30%.21 However,
given. while the optimal haemoglobin concentration in sepsis is not
specically known, results from the Transfusion Requirements
Vasopressors in Critical Care trial did not demonstrate increased mortality
when using a haemoglobin count of 79 g/dL compared to
The second resuscitation endpoint in SS/SS is the establish- 1012 g/dL.38 Routine administration of fresh frozen plasma
ment of a MAP of at least 65 mmHg. In SS/SS, there is an to correct a coagulopathy should be avoided unless there is
imbalance between vasodilation and vasoconstriction. Accord- active bleeding or a planned invasive procedure. Platelets
ingly, vasoactive medications are often required in septic should be transfused below 5000/mm3 even in the absence of
patients with hypotension (MAP < 65 mmHg). Their purpose bleeding, and may be considered between 5000 and 30,000/
is to restore adequate arterial pressures and blood ow to vital mm3 if there is a signicant risk of bleeding. If the platelet count
organs. Below MAPs of 60 mmHg, coronary, renal and CNS is 50,000/mm3 or above then transfusion should only take place
autoregulation are lost and organ blood ow has a linear rela- in the setting of planned surgery or invasive procedures.8
tionship with pressure.34 However, tissue perfusion can be If ScvO2 is less than 70% despite an appropriate haemoglo-
maintained at MAPs as low as 65 mmHg.35 As such, when bin level (above), inotropic agents may be administered to
Sepsis, severe sepsis, and septic shock 131

augment cardiac output. Dobutamine (2.5 mcg/kg/min to broad-spectrum antibiotics be given as soon as possible in sep-
maximum 20 mcg/kg/min) is the agent of choice.21 Exceeding sis, but always within the rst hour after recognition of SS/SS.8
this dose has not been shown to be effective. While the feasibility of this requires further study, and is not yet
In resource-limited settings, blood product transfusions the international standard of care, the importance of adminis-
should be used sparingly, as indicated above. Inotropic ther- tering correct antibiotics as soon as possible cannot be
apy can be initiated to augment cardiac output if evidence of overstated.39
shock persists despite liberal uid administration, vasopressor The choice of empirical antibacterial therapy varies signi-
initiation, and blood product transfusion (if indicated). cantly based on patient characteristics. Important consider-
As SCVO2 measurement requires a central venous catheter ations include (but are not limited to): the most likely
(CVC), other measures of shock such as lactate and urine source(s) of infection, recent antibiotics (last 3 months), recent
output (see below) can be used as surrogate indicators. healthcare exposure (e.g., hospitalization), underlying chronic
disease, local pathogens and drug resistance.8 Patients with
Lactate recent antibiotic exposure have an elevated incidence of
high-risk infections such as methicillin-resistant Staphylococ-
Lactate is an important marker of severe sepsis and elevated cus aureus and Pseudomonas aeruginosa, whereas those with
levels (P4 mmol/L) are associated with a high mortality rate.39 recent healthcare exposure have increased likelihood of being
A recent multicenter randomized trial by Jones compared lac- colonized with ESBL-producing bacteria.44 Importantly, the
tate clearance (P10%) with SCVO2 (P70%) as a quantitative most common pathogens in SS/SS among hospitalized patients
resuscitation endpoint and found it to be noninferior.40 This in the descending order are Gram-positive bacteria, Gram-neg-
suggests that measuring peripheral lactate levels instead of ative bacteria, and mixed bacterial microorganisms.8 In all
SCVO2 (which requires a CVC) may spark a noninvasive path- cases, antibacterial therapy should be guided by the most likely
way of quantitative resuscitation. However, this possibility has sources of infection along with local antibiograms.
yet to be included in consensus guidelines, which currently In addition to bacteria, fungi have emerged worldwide as
state a goal of lactate normalization.8 Importantly, SCVO2 growing causes of infection, particularly in the hospital setting,
and lactate need not be used to the exclusion of one another, and Candida is the fourth most common agent identied in
and when available, can be used concurrently. blood cultures of septic patients. Despite this, it is estimated
In the absence of CVCs, checking serial lactate levels for that fungi are responsible for only 5% of all cases of SS/SS,
clearance can be used to guide therapy (above) and therefore, the routine administration of antifungals is
not recommended. Rather, they should be reserved for select
Urine output patients with known Candida colonization at multiple sites,
impaired physiologic barriers (recurrent gastrointestinal perfo-
Regardless of whether SCVO2 or lactate levels are used to guide rations or anastomotic leakages, acute necrotizing pancreatitis,
therapy, resuscitation within the rst 6 h includes the mainte- chemotherapy-induced mucositis, vascular access devices)
nance of urine output P 0.5 mL/kg/h. This is a supplemental immunocompromised states (neutropenic cancer patients or
endpoint to other markers of tissue perfusion, and low levels transplant recipients), or failure to improve while receiving
suggest the need for more aggressive resuscitation.8 antibiotics.45 First-line agents are azoles or echinocandins.46
In resource-limited settings, urine output should be In resource-limited settings, rapid administration of appro-
measured for all patients. An indwelling urinary catheter can priate antibiotics is a cornerstone to sepsis care and has a time-
be used, or a urine collection container. The time and amount sensitive effect on mortality. Antibiotics should be started as
of each voiding episode should be recorded, similar to the vital soon as possible (ideally within the rst hour of the recognition
signs. of sepsis). Important patient characteristics include recent use
of antibiotics and healthcare exposure. Local or regional anti-
Antimicrobials biotic guidelines are preferred and should be used to choose
the most appropriate agent(s). Consider the addition of an
In the setting of SS/SS, it has been demonstrated that delayed antiviral agent in select cases.28
antibiotic administration is clearly associated with increased
mortality. Even prior to the onset of persistent or recurrent Malaria
hypotension, there is an 8% increase in mortality for each hour
of delay in antimicrobial administration.41 In another cohort In Sub-Saharan Africa, malaria co-infection with sepsis is
of patients undergoing EGDT, those who received appropriate common in children. In a study of over 3000 children in
antibiotics less than one hour after triage had a 14% lower Uganda, Kenya and Tanzania with febrile illnesses, 57% were
mortality than those who did not.42 While timing is essential, found to have malarial infection.33 In another study of chil-
antibiotic choice is similarly important. Targeting the offend- dren with malaria, 6% had concomitant invasive bacterial
ing pathogens has outcome implications as well. In a prospec- infection along with associated increased mortality.47 In
tive study, Gram-negative bacteraemia patients who adults, however, the co-infection rate is less clear, with a recent
empirically received appropriate (pathogen susceptible) study of septic adults in Uganda, a malaria-endemic area,
antibiotics had a signicantly lower mortality than those demonstrating a malarial prevalence of only 4%.48
who empirically received inappropriate (pathogen not suscep- As there are many forms of rapid diagnostic tests (RDTs)
tible) antibiotics (18% vs. 34%).43 Not surprisingly, patients for malarial antigens (e.g., histidine-rich protein 2, Plasmodium
who receive inadequate therapy have a 10% increase in lactate dehydrogenase) now in use in endemic areas, parasito-
hospital mortality.41 As such, it is recommended that logical conrmation has risen from 20% to 47% from 2005
132 K. Tupchong et al.

to 2011.49 Despite this, RDTs do not have high enough nega- a protocoled approach to insulin dosing begins only after
tive predictive values to support withholding treatment in the two blood glucose measurements > 180 mg/dL.8
presence of severe illness, and presumptive antimalarial treat- In resource-limited settings, check blood glucose levels on
ment for febrile illnesses has long been recommended.5054 all patients. In the presence of mild hyperglycaemia, without
In resource-limited settings, while there is insufcient close monitoring, be cautious about reducing glucose levels,
evidence to recommend empiric antimalarial treatment in all as precipitating hypoglycaemia may be more harmful.
adult patients with SS/SS, if there is clinical concern for
concomitant malarial infection, empiric treatment should be Intubation and mechanical ventilation
started and guided by local resistance patterns.
In septic patients, the development of shock in the rst 24 h is
Source control the best predictor of the need for mechanical ventilation, and
half of all patients with this severity of illnesses go on to
Removing the source of infection is important as well and is develop acute respiratory distress syndrome (ARDS).61
termed source control. It includes interventions such as uid Endotracheal intubation and mechanical ventilation can help
drainage, debridement of soft tissues, device removal, and by decreasing work of breathing and improving oxygen
other denitive measures to restore function. The physical delivery.8,21 When required, the decision should be made early
removal of an ongoing locus of infection should be identied on. There are several options for induction agents in rapid
or excluded as soon as possible as it can rapidly alter the sequence intubation (RSI) and there is debate as to which is
course of sepsis.8,55 Interventions should start with the least the most favoured.
invasive method (e.g., percutaneous as opposed to surgical) Etomidate is a commonly used induction agent in the Uni-
when possible. When vascular catheters are left indwelling, ted States. Its use in sepsis has become a focus of discussion,
blood cultures should be sent from them. Indwelling urinary particularly in recent years as the CORTICUS study showed
catheters should be replaced and a urine culture should be sent that patients receiving etomidate had a 17% increased rate
from the new catheter.17 of adrenal suppression and increased risk of death at 28 days
In resource-limited settings, remove the source of infection (4045% vs. 3032%).59 However, since that time, several pro-
whenever possible, particularly if it can be drained or spective and retrospective studies have not shown a statistically
debrided.11 signicant increase in mortality with the use of etomidate.6265
As such, there are no denitive data at this time preventing the
Corticosteroids use of etomidate in SS/SS. There are, however, advantages to
other agents such as ketamine, which has drawn attention due
SS/SS may be associated with a relative adrenal insufciency.56 to its sympathomimetic effects on heart rate, blood pressure,
As such, several studies have attempted to determine whether and cardiac output.66,67 Presently, the choice of induction
the routine administration of corticosteroids may aid the reso- agent is clinician-dependent.
lution of shock and improve overall mortality. As anti-inam- The inammatory response to sepsis can cause lung injury
matory agents, it is theorized that corticosteroids may reduce and the development of ARDS. In a landmark multicenter
the tissue damage caused by cytokines and neutrophils.13 Early randomized trial of lung-injured patients, those who under-
on, corticosteroids were not shown to be benecial in SS/SS went mechanical ventilation with lung-protective ventilation
and in fact, potentially worsened outcomes.57 However, a later (low tidal volumes of 6 mL/kg of predicted body weight and
study by Annane et al demonstrated that patients with vaso- low plateau pressures 6 30 cm H2O) had a 9% absolute reduc-
pressor-unresponsive septic shock developed shock reversal tion in mortality.68 As such, this is the preferred ventilation
and mortality reduction when treated with low-dose hydrocor- strategy. Following intubation, fractions of inspired oxygen
tisone and udrocortisone.58 A follow-up, large multicenter (FiO2) should be reduced as soon as possible to prevent oxygen
trial (CORTICUS), which included septic shock patients toxicity. Maintaining low levels of positive end-expiratory
who responded to vasopressors, did not show a survival benet pressure (PEEP) can prevent extensive alveolar collapse at
for patients receiving low-dose steroids.59 As such, consensus end-expiration.8,41,61 Additionally, the head of the bed should
guidelines recommend against the routine use of hydrocorti- be elevated 3045 as it has prospectively been shown to reduce
sone if IV uids and vasopressors can restore hemodynamic the rate of ventilator-associated pneumonia.69
stability. In the event of vasopressor-unresponsive shock, In resource-limited settings, use pulse oximetry routinely
hydrocortisone at a dose of 200 mg IV daily is suggested.8 and keep oxygen levels above 90% by administering supple-
In resource-limited settings, steroids, when available, mental oxygen.
should be reserved for persistent septic shock following ade-
quate uid resuscitation and administration of vasopressors. Summary

Glucose Consensus guidelines exist with specic recommendations for a

bundled approach to the treatment of septic patients, and in
While it was previously believed that tight glycaemic control particular, those with SS/SS. The concept of quantitative
(blood glucose 80110 mg/dL) was benecial, data from the resuscitation has gained support in recent years and has helped
NICE-SUGAR trial have demonstrated increased mortality standardize the approach to the care of sepsis. What is
with this approach compared to conventional glucose control included above is the inclusion of ideal practices. Key points
(blood glucose 6 180 mg/dL).60 It is now recommended that include:
Sepsis, severe sepsis, and septic shock 133

Table 3 Sepsis interventions in resource-limited settings.11 Table adapted from Dunser et al. (2012).11
Resource-limited interventions
Category Intervention
Circulation  Target adequate tissue perfusion as the primary endpoint of resuscitation. Additionally, aim for a blood
pressure > 90 mmHg
 When there is evidence of hypoperfusion, infuse crystalloid uids aggressively and continue liberal infusions for 24
48 h. Patients may require more than 4 L during the rst 24 h
 Preferentially use norepinephrine in patients with hypoperfusion despite liberal uid resuscitation. Monitor blood
pressure and heart rate frequently
 Reserve steroids for patients requiring escalating doses of vasopressors
Oxygenation  Apply oxygen with goal oxygen saturation > 90%. Administer empiric oxygen in patients with SS/SS in the absence of
a pulse oximeter
Antimicrobial therapy  Administer antimicrobials within 1 h of recognizing sepsis
 Choose antimicrobials with a high likelihood to be active against the suspected pathogens
Diagnosis  Gather a detailed patient history and perform a thorough examination, seeking to identify the source of infection
 Use imaging techniques when available
 Obtain cultures from every likely source of infection and test for antimicrobial sensitivities
Source control  Drain or debride the source of infection when possible
 Remove any foreign body or device that may be the source of infection

 Rapid screening using SIRS criteria and vigilant recogni- have been generated in their absence. They highlight the high
tion of the sepsis spectrum of illness. rate of HIV and other potentially contributing infectious dis-
 Continually repeated vital signs. eases (such as malaria and typhoid fever), regional variation
 Supplemental oxygen for oxygen saturation levels < 90%. in bacteriology, and emphasize the importance of rapid recog-
 Immediate intravenous access at multiple sites. nition of sepsis and the need for additional training and
 Fluid resuscitation using P 30 mL/kg of crystalloid fol- research.6,11,75 Table 3 is a summary of a systematic review of
lowed by intravascular volume assessment. best-practice interventions tailored to resource-limited settings.
 Maintenance of MAP P 65 mmHg and the use of vasopres-
sors (norepinephrine rst line) if necessary. Future directions
 The use of blood products (haemoglobin 79 g/dL) and/or
dobutamine to keep SCVO2 P 70% (when available). Much is needed in the way of research pertaining to the care of
 Measurement and normalization of lactate levels. septic patients in LMICs. Particular areas of focus include the
 Cultures obtained from every suspected source of infection.
epidemiology of sepsis, availability of resources in non-tertiary
 Administration of broad-spectrum antibiotics as quickly as care settings, efcacy of bundled care and the relative efcacy
possible (ideally within the rst hour). of specic targeted interventions, health care worker knowl-
 Early source control. edge and training programs, and cost-benet analysis of each
 Avoidance of corticosteroids except in vasopressor-unre-
of these components.
sponsive shock.
 Conventional glucose control 6 180 mg/dL.
Conicts of interest
 Ventilation with low tidal volumes (6 mL/kg).
 Continued reassessment of clinical status and revaluation of
treatment modalities. The authors declare no conict of interest.

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