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CE: Namrta; QCO/310610; Total nos of Pages: 6;

QCO 310610

REVIEW
URRENT
C
OPINION

Current management of Gram-negative
septic shock
Jean-Louis Vincent and Wasineenart Mongkolpun

Purpose of review
Sepsis is a common condition in critically ill patients and associated with high morbidity and mortality.
Sepsis is the result of infection by many potential pathogens, including Gram-negative bacteria. There are
no specific antisepsis therapies and management relies largely on infection control and organ support,
including hemodynamic stabilization. We discuss these key aspects and briefly mention potential
immunomodulatory strategies.
Recent findings
New aspects of sepsis management include the realization that early treatment is important and that fluids
and vasopressor agents should be administered simultaneously to insure rapid restoration of an adequate
perfusion pressure to limit development and worsening of organ dysfunction. New immunomodulatory
therapies, both suppressive and stimulatory, are being tested.
Summary
Early diagnosis enabling rapid treatment can optimize outcomes. The multiple components of adequate
sepsis management necessitate a team approach.
Keywords
fluid administration, immunomodulation, infection, organ dysfunction

INTRODUCTION
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. Patients with persisting hypotension
requiring vasopressors to maintain mean arterial
pressure more than 65 mmHg and a serum lactate
level more than 2 mmol/l (18 mg/dl) despite adequate volume resuscitation are said to have septic
shock [1]. Sepsis is largely caused by bacteria, but can
also be the result of infection with other microorganisms including fungi, viruses, and parasites.
Among the bacterial causes, Gram-negative and
Gram-positive bacteria occur with similar frequency
overall [2]. The most frequently isolated Gram-negative organisms in patients with sepsis are
Escherichia coli, Klebsiella spp., Enterobacter, and
Pseudomonas spp. [2].
The treatment of septic shock occurring as a
result of Gram-negative organisms is currently not
very different from the treatment of septic shock
because of other organisms. There are some differences in initial microorganism recognition and signaling by pathogen-recognition receptors according
to bacterial species and the precise patterns of mediator release and activation may vary depending on

the invading pathogen [3]. However, there is considerable crosstalk and receptor collaboration [4,5]
and these pathways ultimately converge leading to
the same effects on cellular and organ function [6,7].
In the past, attempts were made to separate the
hemodynamic presentation of sepsis (‘warm’ or
‘cold’ shock states) according to the type of microorganism [8], but with improved understanding of
the similar pathophysiological events regardless of
causative microorganism, this approach has now
been abandoned. Several studies have shown no
differences in mortality rates according to bacterial
class [9]. Indeed, outcomes are influenced by multiple other factors including appropriateness of initial
antibiotics, antimicrobial sensitivity and virulence,

Department of Intensive Care, Erasme Hospital, Universite´ Libre de
Bruxelles, Brussels, Belgium
Correspondence to Jean-Louis Vincent, Department of Intensive Care,
Erasme University Hospital, Route De Lennik 808, 1070 Brussels,
Belgium. Tel: +32 2 555 3380; fax: +32 2 555 4555;
e-mail: jlvincent@intensive.org
Curr Opin Infect Dis 2018, 31:000–000
DOI:10.1097/QCO.0000000000000492

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QCO 310610

Gram-negative infections

KEY POINTS
In terms of management, there is no clear distinction
between Gram negative and other causes of sepsis.
Early and appropriate antibiotics are key, as well as
effective source control.
All patients need fluid, and evaluation of the presence
or degree of edema provides no useful information
regarding fluid requirements.
In terms of vasoactive agents, norepinephrine is the
vasopressor of choice. Routine use of vasopressin may
be dangerous and the place of angiotensin II is not yet
clear. Dobutamine possibly has a place to increase
cardiac output.
Moderate doses of hydrocortisone should be considered
in severe forms.

source of infection, severity of illness, and patient
age and comorbidities [10–12].
The management of septic shock includes three
major components, as shown in Fig. 1. Importantly,
infection control and hemodynamic support need
to be performed promptly and together. In a classical experimental study in a model of peritonitis,
Natanson et al. [13] showed that no animals survived with no treatment, 13% survived when treated
with antibiotics or with cardiovascular stabilization,
and when antibiotics and cardiovascular stabilization were combined, survival reached 43%.

INFECTION CONTROL
Antibiotic therapy must be both appropriate, in
terms of effectiveness against the causative microorganism(s), and adequate, in terms of dose and

duration. Results from microbiological cultures,
which should be taken prior to starting antibiotics
whenever possible, without delaying antibiotic
administration, still take several days to become
available. Broad-spectrum empiric therapy is thus
indicated in the majority of patients to insure that
all likely microorganisms are covered. When deciding which empiric antibiotic(s) to use, various factors should be taken into account, including the
most likely focus of infection, knowledge of local
microbiological flora and resistance patterns, any
recent or ongoing antimicrobial therapy, the
immune status and the origin of the patient (nursing home, other hospital, home), and disease severity. Specific antimicrobial choices, dosing, and
duration of treatment for Gram-negative sepsis have
been covered in other manuscripts in this issue.
The need for early antibiotic administration is
particularly important in septic shock. This logical
statement is supported by epidemiological data. For
example, in a large series of 18 000 patients included
in the Surviving Sepsis Campaign database [14], mortality increased from about 25% when antibiotics
were administered within 1 h to about 33% when
they were administered more than 6 h after recognition of the sepsis syndrome. Admittedly, this may not
seem to be a large difference and other factors, including difficulty recognizing sepsis in some patients with
atypical presentation and/or comorbidities, may
complicate the picture, but the effect is clinically
relevant and appropriate antibiotics should be
administered as soon as possible after diagnosis.
Source control, when necessary, must also be
accomplished rapidly. Source control is a heterogeneous problem because it can range from relatively
simple catheter removal to more complex percutaneous drainage for an intra-abdominal abscess. It is,
therefore, difficult to specify a time limit that could

FIGURE 1. The three components of sepsis management.
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Gram-negative septic shock Vincent and Mongkolpun

apply to every patient and situation, but care needs
to be taken to insure that time is not lost waiting for
source control interventions; for example, if surgery
is needed for an acute abdomen, the procedure
should be performed without delay. Importantly,
although trying to find a source of infection is of
paramount importance because it can influence
management, one should recognize that in roughly
20–25% of cases, no source will be identified.

HEMODYNAMIC SUPPORT
Resuscitation for patients with septic shock requires
both fluid and vasopressor agents. The overall resuscitation period will follow four phases that can be
summarized by the letters SOSD [15]:
(1) Salvage – this is a short phase during which
fluids and vasopressor agents are administered
with little monitoring, the aim being to keep the
patient alive and minimize deterioration in
organ function. It is difficult to give fluids by
formula, because individual requirements vary
substantially from one patient to the other.
Therefore, monitoring equipment should be
placed as soon as possible.
(2) Optimization – during this phase, fluid administration rates are adjusted according to the
results obtained from various monitoring techniques and clinical evaluation.
(3) Stabilization – fluid administration rates are
maintained to insure patient stability, but fluid
boluses are no longer necessary and doses of
vasoactive agents kept constant.
(4) De-escalation – fluid administration is limited
to allow for elimination of edema fluid and
vasopressor agents are decreased.
The duration of each of the four phases can vary
substantially from one case to another, but recognizing these phases can help to identify the priorities in patient management.

Fluids
Fluids are always required, not only to correct true
hypovolemia because of poor intake and increased
internal (edema) and external losses, but also to
compensate for the vasodilation associated with
the sepsis process and help to achieve the hyperkinetic (high cardiac output) state required in sepsis.
Hence, the fundamental reason for fluid administration is to improve tissue perfusion by increasing
cardiac output, and the risk is that excess fluids will
increase cardiac filling pressures, with increased
edema formation.

Physicians must consider these two aspects
when prescribing fluids and arrange for the two
components, that is, cardiac output or an index of
tissue perfusion and a cardiac filling pressure, usually the central venous pressure, to be monitored.
When the benefit/risk ratio becomes too low, that is,
when cardiac output increases proportionately less
than filling pressures, fluid administration should
be stopped. The fluid challenge technique should
include only small amounts of fluids given over a
10-min period, to avoid the risks of fluid overload
[16]. Similarly, fluid administration should be
stopped when the immediate risk of poor tissue
perfusion seems to be substantially attenuated. This
strategy is also applied in children and neonates
[17]. One should avoid giving large amounts of
fluids over a relatively long period of time because
if the patient does not respond, too much fluid will
have been given with the associated risks of fluid
overload and no benefit.
During the optimization phase, attempts to
assess likely fluid responsiveness can be tried before
any fluid administration is given. One option is the
assessment of pulse pressure variation or stroke
volume variation in patients who do not stimulate
the respirator, but this is a relatively rare condition,
limiting the usefulness of this approach. A passive
leg raising maneuver can also be considered, but this
technique is more complex than it appears, as it
requires careful and continuous assessment of stroke
volume during the test. Hence, the fluid challenge is
still the preferred method to assess ongoing fluid
needs and enable the benefits of fluid infusion to be
maximized (increase cardiac output) while minimizing the risks (edema formation). Unfortunately, just
assessing the degree of edema does not help evaluate
fluid requirements and the term ‘fluid overload’ can
be misleading [18].
Crystalloids are considered as the initial fluid of
choice, although albumin can have a place early in
patients who are already edematous in a context of
hypoalbuminemia (patients with decompensated
cirrhosis represent a typical example), and later if
the patient has already received large amounts of
crystalloids. Saline solution can be selected initially
in the absence of severe acidosis, but chloride levels
must be monitored [19] because hyperchloremia
can have deleterious effects, most notably on the
kidneys. Otherwise, balanced solutions (Ringer’s
lactate or Plasmalyte R) represent the best option.

Vasoactive agents
Norepinephrine is the vasopressor of choice; dopamine should no longer be used in this setting [20].
Epinephrine is also best avoided because it is more

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Gram-negative infections

likely to induce arrhythmias, can reduce splanchnic
blood flow, and may increase blood lactate levels as
a result of increased cellular metabolism. The place
of angiotensin II is not yet well defined, but it may
be of value in patients with renal failure [21 ] or in
acute respiratory distress syndrome (in which angiotensin II levels may decrease and become inadequate) [22].
In patients who poorly tolerate fluids, administration of dobutamine may be considered to
increase cardiac output; small doses are usually sufficient. A low central venous oxygen saturation
value can be a useful trigger for administration of
dobutamine or for a blood transfusion if the hemoglobin concentration is decreased.

recent clinical trial suggested a benefit of an IgMenriched mixture in patients with severe community-acquired pneumonia who had low IgM levels
and significant inflammatory response [25 ].
&

&

MODULATION OF THE HOST RESPONSE
As experimental studies first began to elucidate the
mechanisms underlying the inflammatory response
to infection, multiple molecules involved in initiating or propagating the response have become potential targets for therapeutic intervention. Yet,
although many agents have reached clinical trials,
none has so far been persistently shown to have
beneficial effects on patient outcomes.

Glucocorticoids
Recent results have shed new light on the ongoing
debate regarding corticosteroid use in sepsis. In the
presence of severe septic shock, administration of
moderate doses of hydrocortisone (200 mg/day)
should be considered [23 ] until shock is resolved,
because relative adrenal insufficiency may develop.
&&

Vasopressin
Vasopressin should not be considered as just another
vasopressor agent, but as a form of hormonal support,
because vasopressin stores may be decreased in septic
shock. However, the exact place for vasopressin
administration in patients with sepsis is hard to
define. Vasopressin derivatives may perhaps decrease
edema formation [24] but carry the risk of inducing
severe vasoconstriction and decreasing blood flow to
the cutaneous, splanchnic, and coronary regions. If
vasopressin is used, it should be administered in small
doses of about 0.03 U/min without titration, and only
in hyperkinetic states demonstrated by the presence
of high cardiac output.

Gamma globulins
Although there is no place for routine administration of gamma globulins in patients with sepsis, a
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Extracorporeal removal of toxins
One cannot discard the role of endotoxin in the
pathophysiology of Gram-negative sepsis, but antiendotoxin strategies have not been particularly
effective. Moreover, endotoxin is not released only
in Gram-negative infections; indeed, measuring
endotoxin levels is not very helpful to distinguish
Gram-negative from Gram-positive infections [26].
Nevertheless, given the role of endotoxin and other
mediators in sepsis pathophysiology, there is a
sound rationale behind a potential beneficial effect
of extracorporeal techniques to remove these compounds, including hemofiltration, hemoadsorption, and coupled plasma filtration adsorption.
However, although appealing, the effectiveness of
this approach is difficult to demonstrate. Many
studies have reported some hemodynamic improvement, but questions remain regarding the optimal
device, timing, duration, and frequency of treatment [27], as well as how to insure that only excess
harmful compounds are removed. The use of polymyxin-based hemoperfusion to remove endotoxin
has not been shown to be successful and is not
currently recommended [28 ].
&

Immunostimulation
Although attempts to modulate the immune
response in sepsis have largely focused on immunosuppressive therapies, more recently the potential
importance of immunostimulatory approaches has
been increasingly raised, with the recognition that
patients with sepsis also develop immunosuppression. Importantly, the immune status of patients
with sepsis varies among patients and in the same
patient during the course of their disease. Some
promising immunostimulatory strategies include
interferon-gamma, granulocyte–macrophage colony stimulating factor, interleukin-7, and anti-programmed cell death protein 1 antibodies [29].

Pharmaconutrition
The use of pharmaconutrition – the supplementation of feeds with various macronutrients (e.g., glutamine, arginine, and fish oil) and micronutrients
(e.g., selenium, vitamin C, vitamin E) – to improve
outcomes has generated considerable interest in
patients with sepsis. However, clinical trials have
failed to consistently demonstrate any positive
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Gram-negative septic shock Vincent and Mongkolpun

effects of the different supplements on outcomes
and there is no evidence to support the routine use
of macronutrient supplements in patients with sepsis [30,31]. Supplementation with vitamins or selenium should not be provided except in certain cases
of malnutrition resulting in deficient levels. In
patients with septic shock, nutrition can be withheld completely [32].

CONCLUSION
The management of septic shock is challenging, but
good and appropriate treatment can make a clear
difference in complication rates and survival. The
likely outcome can be influenced by many factors
including the pathogenicity of the infecting bacteria, the speed of diagnosis, and various host factors,
including immune status and comorbidities. Hence,
treatment should be individualized and guided by
repeated clinical and laboratory review. Importantly, septic shock is always associated with
increased blood lactate levels, and blood lactate
levels should be measured serially (typically every
hour) to be sure they are decreasing with time,
which indicates that the resuscitation process is
effective. If lactate levels do not decrease then the
diagnosis and/or ongoing treatment should be reexamined. As the treatment of septic shock involves
multiple diverse interventions all of which need to
be performed rapidly without delay, a team
approach should be used, not only during working
hours but 24 h a day.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
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Gram-negative infections
29. Vincent JL, Grimaldi D. Novel Interventions: what’s new and the future. Crit
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