SHOCK, Vol. 30, Supplement 1, pp.

53Y59, 2008

EXPERIMENTAL MODELS OF SEPSIS AND THEIR CLINICAL RELEVANCE

Luiz F. Poli-de-Figueiredo,*† Alejandra G. Garrido,*

Naomi Nakagawa,* and Paulina Sannomiya*
*Heart Institute, and † Department of Surgery, University of São Paulo School of Medicine, São Paulo, Brazil

Received 17 Dec 2007; first review completed 18 Feb 2008; accepted in final form 11 Mar 2008

ABSTRACT—Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ
dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed
to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data
obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may
have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed
to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of
endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis
models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite
several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock
because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that
cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation
of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals,
which often do not represent the human septic patient.
KEYWORDS—Animal models, bacteremia, endotoxin, shock, sepsis

INTRODUCTION sistant to endotoxin, have distinct hemodynamic profiles, and

limited blood volume in comparison with humans (10). En-
Sepsis remains a major cause of morbidity and mortality
dotoxemia and bacteremia represent models without an in-
worldwide despite developments in monitoring devices, diag-
fectious focus. They may reproduce many characteristics of
nostic tools, and new therapeutic options (1, 2). It is a clinical
sepsis and are highly controlled and standardized. However,
syndrome resulting from a complex interaction between host
they reflect a primarily systemic challenge without an in-
and infectious agents, characterized by a systemic activation
fectious focus and the sepsis-induced immune reaction that
of multiple inflammatory pathways, including cytokine net-
characterizes human sepsis. Therefore, experimental models
work and coagulation (3). The main cause of death is multiple
with an infectious focus are more clinically relevant (11).
organ failure, which is the final pathway for sepsis-induced
In human sepsis, gram-positive organisms and fungi have
systemic and regional hemodynamic changes, widespread
exceeded gram-negative organisms as a cause of sepsis, but
microcirculatory disturbances, and cellular alterations, lead-
they are very uncommon in animal studies (8), in contrary to
ing to an uncoupling between blood flow and metabolic
gram-negative bacteria. This does not reflect the diversity of
requirements (4, 5).
infectious agents, sites of infection, and progress of the in-
Extensive clinical and animal research, with substantial ex-
fection encountered clinically. There is an increasing concern
penses, have been undertaken to address the pathophysiology
about possible important differences in host inflammatory
and treatment of severe sepsis and septic shock (6, 7). In
responses to sepsis caused by gram-positive versus gram-
contrast to many preclinical studies, most clinical trials of
negative bacteria (8, 12). Experimental evidences suggest that
promising new treatment strategies for sepsis have failed to
the efficacy of mediator-specific anti-inflammatory agents in
demonstrate efficacy (8, 9). Although many reasons could
sepsis may be altered by the bacteria type of underlying
account for this discrepancy, the misinterpretation of preclin-
infection with significant differences between gram-negative
ical data obtained from experimental studies and especially
and gram-positive strains (8).
the use of animal models that do not adequately mimic human
I.v. bacteria infusion, caused by the relatively large inocula
sepsis may have been contributing factors.
that are required, probably constitutes a model of endotoxin
We reviewed the experimental models of sepsis, addressing
intoxication rather than evolving infection. Intraperitoneal
their limitations and benefits, to clarify the extent to which
challenges typically require 100- to 1,000-fold fewer bacteria
their findings are relevant to human sepsis.
(13). Thus, the models used most extensively do not precisely
replicate many important clinical parameters and do not du-
LIMITATIONS
plicate the dynamic interactions among investigational drugs,
The animal model most frequently used at the beginning of microbial pathogens, and host defenses that occur in patients
preclinical studies is rodents (6). However, they are quite re- with sepsis.
Although promising agents are studied later in larger
Address reprint requests to Luiz F. Poli-de-Figueiredo, Av Dr. Arnaldo, 455-4th animals, including primates, and attempts are made to mimic
floor Suite 4215, Sao PauloYSPYBrazil, ZIP 01246-903. E-mail: lpoli@uol.com.br.
DOI: 10.1097/SHK.0b013e318181a343 various aspects of human septic shock, the experimental
Copyright Ó 2008 by the Shock Society conditions encountered in human sepsis trials are more
53

Copyright @ 2008 by the Shock Society. Unauthorized reproduction of this article is prohibited.
54 SHOCK VOL. 30, SUPPLEMENT 1
complicated than simulated even in large-animal models.
Animals are carefully selected to have no preexisting dis-
eases and to have a similar genetic background, age, weight,
sex, and nutritional status. These animals are then chal-
lenged with a single well-defined precipitating event, where-
as patients with sepsis patients are heterogeneous with
respect to age, preexisting conditions, sources of infection,
types of infecting microorganism, and many of them have
experienced trauma or major surgery. Adequacy, rapidity
and quality of care, including antibiotics, and timing of
surgical intervention among others are critical for survival
in human sepsis (10).
The natural history of severe sepsis in laboratory animals
is generally distinct from human sepsis, with animals more
often having a rapid onset of hypodynamic circulatory col-
lapse and a more rapid resolution or decline to mortality. In
clinical sepsis, the mortality is most commonly caused by
the development of multiple organ failure days to weeks
after initial presentation. For this reason, animal models that
lead to significant mortality within the first 6 to 12 h may
not describe an outcome that is relevant to humans (6).
Agents under investigation are often administered to animals
before or immediately after the induction of sepsis, condi-
tions that can rarely be achieved in clinical trials.
EXPERIMENTAL MODELS
Signs and laboratory findings seen in human sepsis can be
observed in a variety of animal models including intravascular
infusion of endotoxin (9, 14Y17) or live bacteria (14, 18Y21),
bacterial peritonitis (8, 22Y25), cecal ligation and perforation
(26Y30), soft tissue infection (31), pneumonia model (32, 33),
and meningitis model (34). Different animal species have
been used including rats, mice, rabbits, dogs, pigs, sheep, and
nonhuman primates (26). Even though those models replicate
many of the features of sepsis, it is important to critically
evaluate the extent to which they mimic the septic picture.
ENDOTOXIN
Endotoxin is commonly used in animal models of sepsis.
However, there is controversy over its relevance to our un-
derstanding of human sepsis. When administered to human
subjects, endotoxin may mimic many of the features of
sepsis (26). In critically ill patients, increased concentra-
tions of serum endotoxin have been associated with the
development of sepsis, disease severity, and mortality (6, 26).
Detectable levels of endotoxin were identified in up to 75%
in intensive care unit (ICU) sepsis patients in intensive care
settings (35). Endotoxin levels often remain undetectable in
serum in more indolent forms of uncomplicated sepsis, with
the recorded levels being of no prognostic significance (6).
Occasionally, very high levels of endotoxin can be detected
in patients with meningococcemia and with the beginning
of the antibiotic therapy, killing bacteria (36). The hypothesis
that endotoxin plays a significant role in sepsis is supported
by many studies that show that antibiotic administration may
lead to a sudden release of massive amounts of endotoxin
Copyright @ 2008 by the Shock Society. Unauthorized reproduction of this article is prohibited.
POLI-DE-FIGUEIREDO ET AL.
from dead bacteria and an acute hemodynamic deterioration
(6, 12, 15, 29, 36).
Endotoxin or LPS, as the principal component of the gram-
negative bacterial cell wall, stimulates the release of inflam-
matory mediators from various cell types, responsible for
initiating the process of sepsis (26). LPS is a stable rela-
tively pure compound that can be stored in lyophilized form.
An accurate dose can be measured and may be administered
as a bolus or infusion (26). This has formed the basis for the
simplest sepsis model and many endotoxicosis models (35).
The sensitivity to endotoxin shows considerable differen-
ces between species. Rodents, cats, and dogs are relatively
endotoxin resistant, whereas humans, rabbits, sheep, and
nonhuman primates show an enhanced response (6, 10, 26).
In insensitive animals, presensitization with killed organism
or D-galactosamine reduces the dose of LPS needed to
produce an inflammatory response (35). Despite lower doses
being more physiological, most studies have continued to use
high endotoxin doses in nonsensitized animals. The duration
and route of administration have varied between studies
as well.
A large i.v. dose of LPS in rats results in a sudden car-
diovascular collapse and death (37), whereas a lower dose
promotes a hyperdynamic response, with an early increase in
cardiac output (38). Similarly, rabbits challenged with high
doses of LPS (5 mg/kg) show low cardiac output and high sys-
temic vascular resistance, but when challenged with a much
lower dose (1Y3 2g/kg), they manifest a hyperdynamic state
(26). A low dose of LPS (0.75 2g/kg) in sheep promotes a
biphasic response characterized by an early reduction and a
later increase in cardiac output, whereas a prolonged ex-
tremely low dose of LPS (9, 12, or 24 ng/kg per h for 24 h)
promotes a delayed hyperdynamic state, with high cardiac
output and vasodilatation (15). As in human sepsis, a higher
dosage of endotoxin in sheep has been associated with a
more profound myocardial depression (9). Endotoxin admin-
istration in dogs (2 mg/kg) provokes a severe hypodynamic
state with an abrupt decrease in arterial pressure, cardiac
output, hepatic blood flow, and an increase in systemic
vascular resistance and blood lactate levels (39). Most
nonhuman primate endotoxicosis models have used massive
i.v. doses, resulting in rapid circulatory collapse and early
death, whereas lower doses more closely resembled hu-
man sepsis with coagulopathy and progressive multiorgan
dysfunction (16).
Several authors argued that the endotoxin model is not a
suitable one to study sepsis (6, 26), despite the fact that endo-
toxin may play an important role in the pathogenesis of sepsis.
The use of high doses of endotoxin in animals that are resis-
tant to endotoxin has toxic effects that are not seen when
low doses are administered to endotoxin-sensitive species,
such as man (6). Although released by gram-negative sep-
sis, endotoxin is not released in gram-positive bacteria, but
mortality is similar (38). The use of corticosteroids and
antiYTNF-! has been effective in animal models of endotox-
emia, but has failed in clinical trials (6, 40). In addition, killed
Escherichia coli are more lethal than endotoxin. As the
endotoxin is only one component of gram-negative bacteria,
SHOCK OCTOBER 2008
it is suggested that the other cell wall components may
contribute to systemic inflammatory response (26).
Thus, caution must be exercised whenever assessing clin-
ical efficacy of novel therapeutic agents in animal models
of endotoxemia (6). There is general agreement among
researchers that LPS injection may serve as a model for
endotoxic shock but not for sepsis (26).
INTRAVASCULAR INFUSION OF LIVE BACTERIA
Because the rate of positive blood cultures is associated
with increasing sepsis severity, (sepsis [17%], severe sepsis
[25%], septic shock [69%]), it has been suggested that bacter-
emia plays an important role in the outcome of sepsis (26).
Different aerobic bacterial species have been investigated to
induce sepsis and septic shock (26). Escherichia coli is the
most common one. There is a wide variability in the dose of
and duration of infusion, as seen with endotoxicosis models.
In small animals, low doses of E. coli, administered over
several hours, have been associated with minimal early phys-
iological changes, whereas higher doses have often produced
a biphasic response, with an early rise and late fall in cardiac
output (35). In baboons, a bolus i.v. injection of LD100 dose of
E. coli induced an exaggerated TNF-! response with cardio-
vascular collapse and early death. In this model, pretreatment
with a TNF-! inhibitor showed hemodynamic improvement
and better survival, highlighting the role of TNF-! in car-
diovascular collapse and resultant organ dysfunction and
death (41). A severe disseminated intravascular coagulation
induced by both sublethal and lethal doses of live E. coli and
endotoxin has been described in baboons (14), resulting in a
complex inflammatory and hemostatic response that involves
the microvascular endothelium and its regulatory anticoagu-
lant networks, thereby contributing to the multiorgan dys-
function development (14).
FIG. 1. Experimental model of septic shock induced by lethal i.v. dose of live E. coli in dogs. Changes in MAP, cardiac index, portal vein blood flow
index, and PCO2 gastric mucosal-arterial gradient (PCO2 gap) during the experimental protocol (mean T SEM). BIYbacterial infusion (1.2  1010 colony-forming
units/kg over 30 min); FRYfluid resuscitation period; CTYcontrols, no fluid (n = 7); RLYRinger’s lactate solution 32 mL/kg over 30 min (n = 7). Modified from
Garrido (43).
Copyright @ 2008 by the Shock Society. Unauthorized reproduction of this article is prohibited.
EXPERIMENTAL MODELS OF SEPSIS 55
In a porcine model, in which both gram-positive and gram-
negative bacteria were used at a similar dose, the hemody-
namic and pulmonary changes depended on the bacterial
species used. Whereas Staphylococcus aureus induced mini-
mal changes, both E. coli and Pseudomonas aeruginosa re-
sulted in shock and acute respiratory failure (21).
In an ovine model, a nonlethal dose of E. coli promoted a
hyperdynamic cardiovascular response with hypotension, in-
creased output, tachycardia, fever, oliguria, tachypnea, and hy-
perlactatemia (4). In a porcine model, P. aeruginosa infused
over a week resulted in biphasic changes to the cardiac out-
put, with late systemic hypotension and pulmonary hyper-
tension (42).
In dogs, both sublethal and lethal i.v. dose of live E. coli
promoted early profound cardiovascular deterioration with
hypotension, very low cardiac output, splanchnic hypoperfu-
sion, and severe metabolic changes (18Y20, 43Y45). Animals
challenged by a lethal dose of E. coli (1.2  1010 colony-
forming units/kg) presented only partial and transient
improvements in systemic and regional blood flows during
fluid resuscitation, but the progressive cardiovascular col-
lapse was unavoidable (Fig. 1). In this model, the magnitude
of changes at the splanchnic region was greater than the
systemic ones. Moreover, the transient benefits after fluid
replacement were much less evident within the splanchnic
region, particularly at the microcirculatory level, as demon-
strated by the PCO2 gastric mucosal-arterial gradient (Fig. 1).
This discrepancy between systemic and regional parameters
has been well demonstrated in experimental and clinical
studies (18, 43Y47). The intense compromise of splanchnic
perfusion, particularly at the gut mucosa, has been implicated
in the genesis, amplification, and perpetuation of the sys-
temic inflammatory response and the progression of multiple
organ dysfunction (47). The pathophysiological basis that
has been used to explain this phenomenon is that the gut
56 SHOCK VOL. 30, SUPPLEMENT 1
FIG. 2. Histological examination of the lung (A and B) and liver (C and
D) in an experimental model of septic shock induced by lethal i.v. dose
of live E. coli in dogs. A, Two recent fibrin thrombi in pulmonary small
vessels. B, Intense inflammatory process in pulmonary parenchyma forming
a microabscess. C, Liver parenchyma and portal triad display an intense
mixed inflammatory infiltration. D, Microabscess in liver parenchyma. From
Garrido (43).
hypoxia and/or ischemia contribute to gastrointestinal tract
barrier dysfunction and translocation of cytokines, bacteria,
and their products (47).
At the time of autopsy, those animals receiving live E. coli
showed evidence of major inflammatory alterations and injury
in lungs and liver (43). An illustrative example of the impact
of this model of septic shock is presented in Figure 2. Tissue
inflammatory recruitment, presence of small-vessel thrombo-
sis, vascular congestion, focal hemorrhage, and microabscess
were observed in lung and liver. These alterations have been
described in experimental and clinical sepsis (48), and reflect
the complex host systemic response with activation of mul-
tiple inflammatory pathways and the coagulation system
contributing to widespread microcirculatory disturbances.
The acute i.v. live bacteria injection results in immediate
cardiovascular collapse and early death, behavior rarely seen
in human sepsis. However, within these limitations, this mod-
el may mimic extreme clinical sepsis such as seen in menin-
gococcemia, pneumococcal bacteremia in splenectomized
individuals, and gram-negative bacteremia in the setting of
profound granulocytopenia (26), which are increasingly seen
nowadays. This model also allows the study of the acute
effects of early interventions in short periods, such as fluid
replacement. Large animals allow the use of systemic and
regional monitoring similar to the ones used in ICUs, in
addition to regional blood flow measurements and blood
sampling only feasible in experimental studies.
As in other models, the hemodynamic response to the
challenge with live bacteria also depends on fluid resuscita-
tion and antibiotic treatment. The use of fluid resuscitation
has varied between studies, but in its absence, early death is
frequent. There is considerable evidence that antibiotic ther-
apy may, through the destruction of bacteria and release of
substantial amounts of cell wall components by gram-
negative, gram-positive, and fungi, promote an intense in-
flammatory response with excessively high levels of TNF-!,
Copyright @ 2008 by the Shock Society. Unauthorized reproduction of this article is prohibited.
POLI-DE-FIGUEIREDO ET AL.
causing hemodynamic deterioration, especially in the absence
of fluid resuscitation (12, 29, 36).
Not all models using an intravascular infusion of live bac-
teria are acute preparations characterized by abrupt cardiovas-
cular deterioration secondary to overwhelming bacteremia.
Shaw and Wolfe (49) described a chronically instrumented
unanesthetized canine model, wherein animals were infused
intra-arterially with viable E. coli and were studied 24 h later.
The animals were aggressively resuscitated at the time sepsis
was induced, the dose of bacteria being invariably lethal in
the absence of adequate restoration of intravascular volume.
However, with fluid resuscitation, 85% of the animals sur-
vived the protocol and, at the time of study, were hyper-
dynamic and hypermetabolic (49). In addition, many of the
hormonal alterations typical in humans with sepsis were
observed. Although not widely used, this model mimics many
of the features of clinical sepsis and avoids the confounding
effects of anesthesia and surgical preparations.
Because most patients are not challenged with a massive
bacterial load at any time, but rather harbor a septic focus
that is intermittently and persistently showering the body with
bacteria, several authors have questioned the relevance of
models using a bolus infusion of viable bacteria (26). In
addition, concerns over the use of an appropriate strain of an
infective organism extend also to studies of endotoxemia,
where the most commonly used strain of endotoxin is un-
commonly seen in human bacteremia. There are a number of
features of either the host or host-bacterium interactions that
are species specific (6). For example, Salmonella typhi does
not cause systemic infection in laboratory rodents but is
responsible for typhoid fever in humans. In mice, a rela-
ted bacterium, Salmonella typhimurium, causes a systemic
infection and it is commonly used as a model of human
typhoid infection, despite its low virulence in humans (6).
Individual bacteria may also cause a broad spectrum of
disease processes, depending on the expression of virulence
genes. These findings suggest that it may be difficult to make
conclusions regarding the efficacy of a therapy based on a
study looking at infection with a single bacterial strain, par-
FIG. 3. Aspect of the necrotic cecum after ligation and puncture for
the evaluation of leukocyte-endothelial interactions displayed in
Figure 5 (28).
SHOCK OCTOBER 2008 EXPERIMENTAL MODELS OF SEPSIS 57

FIG. 4. Intravital microscopy in rat mesentery, allowing the evaluation of leukocyte-endothelial interactions shown in Figure 5.

ticularly if it is a pathogen not commonly seen in critically ill sample size, whereas variability remains a problem in larger
patients (6). Despite these criticisms, numerous laboratories species. The gastrointestinal contents of animals, particularly
continue to use intravascular infusions of viable bacteria to herbivores, vary between species. Initial attempts to induce
induce sepsis in animals, and many of these models remain peritonitis by intraperitoneal implantation of feces were often
very useful, provided that certain inherent limitations are disappointing, with animals appearing tolerant to their own
recognized (26). fecal flora (35). To overcome those limitations, human feces
were used, or barium sulfate, bile salts, or autologous hemoglo-
PERITONITIS MODELS bin added to the fecal material (8).
Both CLP and fecal inoculation models deliver a variable
Peritonitis may be induced in animals in several ways. Bowel microbiological dose (8), so pure bacterial culture peritoni-
can be perforated, allowing contamination with gastrointestinal tis models have been developed. In 1980, Ahrenholz and
contents, or inocula of fecal material or pure bacterial cul- Simmons (50) showed that 24-h mortality was 100% when
tures can be instilled into the peritoneal cavity (35). In early viable E. coli suspended in saline was injected intraperito-
models, segments of intact bowel were isolated, and the de- neally in rats. However, when the same number of bacteria
velopment of peritonitis was expected (35). The disadvantage was implanted intraperitoneally in a bovine clot, early mor-
of this model was that the onset of peritonitis was uncon- tality was prevented, but the rats developed abscess, and the
trolled and depended on the timing of gastrointestinal per- 10-day mortality rate was 90% (50). Thus, fibrin delays the
foration. To overcome this limitation, the cecal ligation and systemic absorption of the entrapped bacteria and promotes
puncture (CLP) model was developed as a simple and repro- the development of chronic intraperitoneal abscess, a more
ducible model that has been used widely in sepsis research local septic focus (26). This highly reproducible model has
(24, 25). The cecum is ligated distal to the ileocecal valve and
perforated using two needle punctures (Fig. 3). Needle size
can be used to manipulate CLP to give a lethal and non-
lethal sepsis (8, 26).
The principal advantage of CLP models is their simplicity.
Because sepsis is induced by a straightforward surgical
procedure, there is no need to grow and quantify bacteria or
in other ways prepare the inoculum. Furthermore, these are
models of sepsis caused by peritoneal contamination with
mixed flora in the presence of devitalized tissue and thus
establish a clear resemblance to clinical problems such as a
perforated appendicitis or diverticulitis (35). This technique,
without fluid resuscitation, promotes rapid onset of shock.
After fluid resuscitation, mortality rate may be reduced with
pathophysiological responses resembling those noted in
human sepsis (29). The use of intravital microscopy in the
vascular mesentery (Fig. 4) allows in vivo observation of
altered mesenteric leukocyte-endothelial interactions after
cecal ligation/puncture and their modulation by different fluid
FIG. 5. Number of rolling leukocytes/10 min, adherent leukocytes/
regimens, and reversion after surgical sepsis source control 100 2m venule length, and migrated leukocytes/5,000 2m2 in rat
(Fig. 5) by removing the necrotic cecum (27, 28). mesenteric microcirculation. Rats were sham-operated (SHAM, n = 6),
However, it is difficult to control the magnitude of the septic submitted to CLP (n = 7), or to CLP + necrotic tissue resection/peritoneal
lavage (REL, n = 6). *P G 0.05 among CLP versus SHAM and CLP + REL
challenge in the CPL model. In studies using small animals, the groups. Removal of the necrotic tissue restored microcirculatory disturban-
problem of variability is easily overcome by increasing the ces induced by sepsis. From Nagakawa et al. (28).

Copyright @ 2008 by the Shock Society. Unauthorized reproduction of this article is prohibited.
58 SHOCK VOL. 30, SUPPLEMENT 1
been described in small and large mammals, and displays
many features of human sepsis including insidious onset,
hyperdynamic cardiovascular state (8, 25), reversible com-
promised myocardial performance (25), and a high mortality
rate (8, 26). Moreover, unlike other peritonitis models using
fecal implantation or cecal ligation/perforation, the fibrin clot
model allows control over the dose of bacteria and the type
of organism implanted (26). Mixed cultures more accurately
mimic the gastrointestinal flora than single-organism cultures
(23), which can fail to reproduce the synergy between aero-
bic and anaerobic organisms seen in human peritonitis. The
aerobic gram-negative organism seems to be responsible for
many of the acute physiological features of sepsis, whereas
anaerobes seem to contribute to the development of intra-
peritoneal abscess (35).
CONCLUSIONS
Many of the problems with the use of animal data in sepsis
drug development stem, not only from the animal models
per se, but from how those results have been adapted to clinical
trial designs. Animal models provide insights about specific
components of the septic process but cannot truly mimic the
full clinical complexity and intrinsic heterogeneity of patients
with sepsis. Despite these limitations, animal models will
remain essential in the development of all new therapies for
sepsis and septic shock because they provide fundamental
information about the pharmacokinetics, toxicity, and mecha-
nism of drug action that cannot be duplicated by other methods.
Nonetheless, there is much to be improved in animal ex-
periments. Examples are the need for long-term studies with
ICU-like conditions to simulate the often delayed onset of
organ dysfunction in the clinical setting, using sepsis or or-
gan dysfunction criteria to start treatment instead of a fixed
time schedule. New therapeutics agents should be studied in
infection models even after initiation of the septic process.
Furthermore, debility conditions need to be reproduced to
avoid using healthy animals, which often do not represent the
human sepsis patient.
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