m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 8 0 ( 2 0 2 4 ) 4 e9

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j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m j a fi

Review Article

Organ support in sepsis: A panoramic view from

infection to death

Vikas Srivastava a,*, Shalendra Singh b

a
Brig AFMS (P&T), O/o DGAFMS, New Delhi, India
b
Senior Advisor (Anaesthesia) & Neuroanaesthesiologist, Command Hospital (Northern Commmand), Udhampur,
India

article info abstract

Article history: Despite significant advancements in medical research, sepsis persists as a leading cause of
Received 28 September 2023 mortality in intensive care units (ICUs). Sepsis intricately contributes to organ failure,
Accepted 10 November 2023 amplifying both morbidity and mortality. In these instances, a comprehensive compre-
Available online 26 December 2023 hension of the physiology of each organ is imperative for accurate diagnosis and effective
management. Within the context of an ICU clinical scenario, a meticulous evaluation and
Keywords: monitoring of six pivotal organ systems cardiovascular, renal, respiratory, neurological,
Organ support hematological, and hepatic are essential. The primary objective in managing sepsis-induced
Sepsis organ failure is the early detection and intervention, encompassing timely administration of
Intensive care units antibiotics, identification and control of the infection source, and implementation of sup-
Infection portive therapy. Despite the extensive body of medical literature, there is a conspicuous
absence of evidence-based multi-organ management strategies for such patients. The
intricate interplay between organs, commonly referred to as organ crosstalk, presents a
formidable challenge in navigating the complexities of sepsis management.
© 2023 Director General, Armed Forces Medical Services. Published by Elsevier, a division of
RELX India Pvt. Ltd. All rights reserved.

morbidity and mortality rate. This intricate and multifaceted

Introduction
Sepsis manifests as a systemic inflammatory response to
infection, marked by an uncontrolled immune reaction.
Alarming statistics reveal its devastating toll, claiming the
lives of 47 to 50 million people annually, translating to a
staggering rate of one death every 2.8 seconds. The fatality
rate ranges from 15% to 50%, underscoring the urgency of
addressing this global health concern.1e4 Sepsis often culmi-
nates in organ failure, characterized by a notably high
condition involves a combination of processes, including
immunological dysregulation, endothelial dysfunction, and
metabolic alterations, all contributing to the development of
sepsis-induced organ failure. In the intensive care unit (ICU)
clinical setting, a comprehensive assessment and continuous
monitoring of six vital organ systems cardiovascular, renal,
respiratory, neurological, hematological, and hepatic are
paramount.5 The primary objective in managing sepsis-
induced organ failure, referred to as sepsis-induced organ

* Corresponding author.
E-mail address: vikas.icu@gmail.com (V. Srivastava).
https://doi.org/10.1016/j.mjafi.2023.10.010
0377-1237/© 2023 Director General, Armed Forces Medical Services. Published by Elsevier, a division of RELX India Pvt. Ltd. All rights
reserved.
 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 8 0 ( 2 0 2 4 ) 4 e9
degeneration (SIOD), is early detection and intervention. This
encompasses prompt administration of antibiotics, meticu-
lous source control, and the implementation of supportive
therapy. Addressing SIOD at its onset is crucial for improving
patient outcomes and mitigating the severe consequences
associated with sepsis.
Newer adjuvants
Numerous adjuvant therapies have undergone exploration,
encompassing immunomodulatory medications, blood purifi-
cation techniques, and metabolic interventions.6 Immuno-
modulatory drugs play a pivotal role in modifying the immune
response and reinstating immunological homeostasis. Among
these therapeutic options are corticosteroids, intravenous
immunoglobulin, and monoclonal antibodies designed to
target specific inflammatory mediators.7 Blood purification
methods, such as hemodialysis, hemofiltration, and adsorp-
tion, have been investigated for their capacity to eliminate
inflammatory mediators and pollutants from the blood-
stream.8,9 These approaches offer potential avenues for miti-
gating the systemic impact of sepsis. Metabolic therapies have
also emerged, aiming to optimize cellular energy metabolism
and thwart cellular malfunction. Strategies include meticulous
glucose control, thiamine supplementation, and providing
mitochondrial support.10 These interventions contribute to
addressing the metabolic dysregulation associated with
sepsis-induced organ failure (SIOD). Effectively treating SIOD
necessitates a comprehensive, multidisciplinary strategy.
Tailoring care to the individual patient based on the underlying
pathophysiology of organ dysfunction is essential for maxi-
mizing therapeutic outcomes and enhancing the overall
management of sepsis.
Organ dysfunctions associated with sepsis
A systemic inflammatory response triggered by infection can
lead to the malfunction of one or more organs in the body,
resulting in sepsis-induced organ dysfunction (SIOD). The
severity and extent of organ dysfunction are influenced by
factors such as the nature of the infection, the characteristics
of the patient, and the timeliness of treatment initiation.
Recognizable symptoms of SIOD encompass respiratory
distress, confusion, jaundice, decreased urine output, low
blood pressure, and impaired heart function. Swift identifi-
cation and immediate treatment of SIOD are imperative for
optimizing outcomes and reducing mortality. Early interven-
tion plays a crucial role in addressing the underlying inflam-
matory response, restoring organ function, and preventing
further deterioration. Timely and targeted management is key
to improving the prognosis and enhancing the overall survival
rate in cases of sepsis-induced organ dysfunction.
Sepsis-induced brain dysfunction
Sepsis-induced encephalopathy (SIE) arises when the central
nervous system (CNS) malfunctions, leading to cognitive
5
dysfunction. Typically observed in the early stages of the
disease, SIE affects up to 70 % of sepsis patients.11 Long-term
consequences may manifest as cognitive-behavioral disor-
ders. Inflammatory mediators like leukotrienes, interferon,
and adapter proteins contribute to breaching the bloodebrain
barrier, resulting in inflammation and proptosis in brain cells
and subsequent dysfunction.12 Patients with SIE may experi-
ence seizures, focal neurological deficits, cognitive dysfunc-
tion, mood swings, agitation, and depression. Additionally, a
CNS infection can be a causative factor for sepsis. Prognosis
tends to be poor for patients without identifiable brain imag-
ing foci, often presenting with altered behavior or conscious-
ness changes. Before administering any sedative medication a
thorough, a neurological examination is essential. Diagnosis
involves ruling out symptoms caused by medications or
metabolic factors, and an electroencephalogram aids in
excluding CNS-related causes. Elevated levels of C-reactive
protein and procalcitonin in the blood indicate a prolonged
acute brain insult, while a high peak concentration of C-type
natriuretic peptide (NT-proCNP) in early sepsis stages sug-
gests SIE.13 Management is primarily symptomatic, focusing
on early control of sepsis foci, prompt oxygen delivery, and
resuscitation to maintain hemodynamics. Recent advance-
ments include specific therapies like vagus nerve stimulation,
which has shown efficacy in reducing proinflammatory cyto-
kines in the CNS.14 Steroids have also emerged as a valuable
treatment for SIE patients.15 Supportive treatments targeting
neuroinflammation regulation, neuroendocrine function, and
neuroimmune disorders have demonstrated beneficial effects
in managing SIE.
Sepsis-induced heart dysfunction
The heart is frequently compromised in cases of sepsis, with
sepsis-associated cardiomyopathy (SAC) representing a
reversible form of myocardial depression. The incidence of
SAC varies between 18% and 65% in sepsis patients, often
presenting with a diminished ejection fraction and a dilated
left ventricle.16 Thankfully, recovery typically occurs after
the resolution of sepsis within a few days. Extensive research
in recent decades has identified numerous mediators or
pathways contributing to global myocardial injury in sepsis.
While circulating leukotrienes, inflammatory markers, dys-
regulated coagulation pathways, and endothelial activation
factors in the bloodstream are suspected causes, clear evi-
dence is still awaited. Left ventricular dysfunction, charac-
terized by poor contractility and systemic vasodilation, is a
common consequence. Over time, right ventricular dysfunc-
tion can also manifest due to increased pulmonary artery
pressure. Excessive nitric oxide, among other inflammatory
mediators, hampers calcium flux, leading to myocardial
depression and the loss of compensatory reflexes, resulting in
hemodynamic instability.
In managing SAC, specific guidelines are currently lack-
ing. During fluid resuscitation, patients are prone to devel-
oping pulmonary infiltrates. Gradually escalating doses of
inotropes and vasopressor therapy are recommended if fluid
treatment fails to maintain perfusion pressure in the end
organs. Norepinephrine is the preferred vasopressor in the
6 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 8 0 ( 2 0 2 4 ) 4 e9
absence of fluid resuscitation, with dobutamine as the
first-line inotrope.17 Levosimendan, a calcium sensitizer,
has demonstrated mortality reduction by establishing
early hemodynamics.17 In cases of refractory shock, dobut-
amine may be administered. Crucially, amid ongoing he-
modynamic management, early and optimal antibiotic
administration and surgical infection evacuation take pre-
cedence. Invasive blood pressure monitoring and central
venous access facilitate close monitoring, contributing to
improved perfusion and associated with a more favorable
mortality rate.
Sepsis-induced liver dysfunction
A substantial proportion of sepsis patients, up to 46%,
concurrently experience sepsis-induced liver dysfunction
(SILD), which has been correlated with an elevated 28-day
mortality rate.18,19 SILD is characterized by an increase in
bilirubin concentration >2 mg/dL and coagulation abnor-
malities with INR >1.5, as outlined in the Surviving Sepsis
Campaign Guidelines.20,21 Clinical manifestations of SILD
include hypoxic hepatitis, sepsis-induced cholestasis, and
protein synthesis dysfunction leading to coagulopathies.
SILD results in the compromised ability of the liver to
detoxify, leading to elevated serum ammonia levels and
such as unconsciousness, confusion, irritation, and hepatic
encephalopathy. Liver cells release acute-phase proteins
(APPs) into the systemic circulation in response to proin-
flammatory cytokines, exerting both proinflammatory and
anti-inflammatory effects.22 Hypoxic hepatitis and sepsis-
induced cholestasis are key processes explaining liver
injury and subsequent sepsis risk. In clinical scenarios,
hypoxic hepatitis is typically identified by reduced oxygen
delivery or utilization by the liver, elevated serum amino-
transferase levels exceeding 20 times the upper limit of
normal, and the absence of other likely liver-damaging fac-
tors.23 Sepsis induces severe hemodynamic changes,
microthrombi formation, sinusoidal obstruction, and endo-
thelial dysfunction, impairing liver perfusion and causing
damage and hypoxic hepatitis.
“Sepsis-induced cholestasis” refers to abnormal bile flow
and reduced bile production due to a nonobstructive intra-
hepatic insult, with total blood bilirubin levels surpassing
2 mg/dL and aminotransferase levels more than double the
accepted upper limit. Ursodeoxycholic acid, with cytopro-
tective and immunomodulatory properties, could be consid-
ered for treating sepsis-induced cholestasis.
Extreme caution is necessary when using hepatotoxic
medications, and rigorous glucose monitoring is crucial due to
the susceptibility of these patients to hypoglycemic episodes.
Early enteral nutrition has demonstrated benefits in
enhancing recovery and reducing complications. Early goal-
directed resuscitation involves promptly initiating antibiotics,
neutralizing the source of infection, and maintaining hemo-
dynamics with fluid and ionotropic agents.24 The judicious
use of steroids, particularly in cholestasis patients with sepsis,
appears to aid in immunomodulation, as evidenced by the
early recovery of liver failure in the CORTICUS study despite
the lack of conclusive evidence.19,25
Sepsis-induced lung dysfunction
The lungs are the predominant site of disease leading to sepsis
in 64% of cases. A study indicates that mortality rates are 35%
in mild acute respiratory distress syndrome (ARDS), 40% in
moderate ARDS, and 46 % in severe ARDS.26 Over the past
decade, the incidence has decreased, attributed to reduced
use of blood products and the adoption of lung-protective
ventilation strategies. Despite an unknown cause, studies
suggest that acute inflammation of the alveolar-capillary
membrane, the lung's gas exchange surface, increases mem-
brane permeability, attracting neutrophils and other inflam-
matory mediators leading to high-permeability pulmonary
edema. This process inactivates surfactant, causing collapse
and consolidation.
The LASARUS trial has influenced ventilation strategies,
advocating for tidal volumes below 6 ml/kg ideal body weight
and plateau pressures below 30 cm of H2O.27
The CESAR trial recommends extracorporeal membrane
oxygenation (ECMO) as a viable option for severe respiratory
failure but does not establish its superiority over conventional
ventilation.28 Due to insufficient data, consensus on the ideal
end-tidal carbon dioxide level is yet to be reached. In ARDS
patients, liberal and conservative fluid therapy shows no sig-
nificant difference, and conventional therapy lacks robust
evidence, with potential risks of renal failure and cognitive
dysfunction. For moderate-to-severe ARDS cases, prone
positioning for up to 12 hours daily is strongly advised. Evi-
dence supporting the long-term efficacy of nitric oxide, high
positive end-expiratory pressure, muscle relaxants, and
inhalation agents in ARDS patients is insufficient. Regarding
steroids, most trials were conducted before the recognition of
ARDS, leading to low-quality evidence for their use.
Hematological manifestation in sepsis
Patients with sepsis often exhibit a spectrum of hematological
abnormalities, including neutrophilia, neutropenia, throm-
bocytopenia and in severe cases, disseminated intravascular
coagulation (DIC). DIC serves as a complex manifestation of
the intricate interplay between inflammatory and coagulation
pathways, leading to the consumption and depletion of
platelets and coagulation factors, resulting in bleeding and
hemorrhage into tissues.
The primary focus of treatment lies in addressing the un-
derlying infection with antibiotics, halting the activated he-
mostasis system, and replenishing the depleted coagulation
components. Heparin plays a role in managing clots, and
platelet transfusions may be necessary for certain patients. In
cases without bleeding or suspected thrombosis, the pro-
thrombin time (PT) and activated partial thromboplastin time
(aPTT) tests are recommended initially, followed by fibrinogen
and D-dimer tests if PT and aPTT are prolonged. Fibrinogen
levels are typically low, especially in acute DIC, while D-dimer
levels are elevated in both acute and chronic DIC. As long as
the platelet count remains above 10,000/microL, prophylactic
platelet and coagulation factor administration is not routinely
recommended for patients not bleeding or at high risk of
 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 8 0 ( 2 0 2 4 ) 4 e9
bleeding. However, in cases of significant PT or aPTT prolon-
gation with severe hemorrhage or a fibrinogen level below 50
mg/dL in bleeding patients, coagulation factor replacement is
warranted. Cryoprecipitate can be administered to raise
plasma fibrinogen levels if they are below 100 mg/dL. Indi-
vidualized management based on specific hematological pa-
rameters is crucial for effectively addressing the diverse
hematological challenges presented by sepsis.
Sepsis-induced renal dysfunction
Research indicates that approximately 40% to 50% of ICU pa-
tients with acute kidney injury (AKI) have sepsis. In a study
involving 198 ICUs across 24 European countries, AKI occurred
in 51% of sepsis patients, with an ICU death rate of 41%.29
Sepsis-induced AKI (S-AKI) was identified in 47.1% of sepsis
cases in a retrospective study encompassing 146,148 patients
in China.30 Risk factors for developing AKI include age, chronic
renal disease, and cardiovascular disease, with many patients
already having kidney damage before hospital admission. The
detection of early kidney injury remains a challenge, but new
prognostic biomarkers have recently been validated. The
multifactorial pathophysiology of AKI involves hemodynamic
variations, inflammation of the renal parenchyma, endothelial
dysfunction, and tubule blockage with necrotic cells and
debris. Mitigating the risks of AKI includes prompt volume
rejuvenation, maintaining hemodynamics, and avoiding
nephrotoxic agents like intravenous contrast. Once AKI is
identified, proper medication dosages, avoidance of fluid
excess with diuretics, and close monitoring of electrolyte levels
are essential. Early initiation of renal replacement therapy
(RRT) offers benefits for patients requiring this intervention.
The diagnosis of S-AKI involves a decrease in urine output
and an increase in serum creatinine concentration. Oliguria,
while relevant in sepsis, may not be a sensitive predictor of
kidney damage, and a correlation between oliguria and AKI
persists even after several hours. Monitoring urine output
closely is associated with improved patient survival when S-
AKI develops. Patients at the maximal AKI stage are more
likely to require in-hospital RRT, experience longer ICU and
hospital stays, and face a higher risk of death, according to
serum creatinine and urine output criteria. However, these
markers have limitations in diagnosing AKI, and the dilu-
tionary effects of vigorous fluid resuscitation in septic shock
may lead to undetected AKI.
Traditional methods like urine microscopy have been used
to detect kidney disease, but the use of diuretics may
constrain the applicability of oliguria and other urine in-
dicators for AKI diagnosis. The complex nature of AKI un-
derscores the importance of ongoing research and the
development of advanced diagnostic tools for early detection
and intervention.
Prevention and resuscitation of S-AKI
The primary pillars of sepsis treatment continue to be source
control and prompt, appropriate antibiotic administration, as
they play a crucial role in preventing additional kidney
7
damage. Delayed administration of antibiotics has been
linked to early development of acute kidney injury (AKI) in
septic shock. The Kidney Disease Improving Global Outcomes
(KDIGO) guidelines caution against the use of certain neph-
rotoxic drugs to prevent kidney damage. Examples include
aminoglycosides, vancomycin (especially when combined
with piperacillin-tazobactam), amphotericin B, and diagnostic
agents like intravenous radiocontrast media.
In managing shock, intravenous fluid infusion is founda-
tional. Vasopressor medications can be initiated promptly if
necessary. However, significant clinical trials such as Aus-
tralasian Resuscitation in Sepsis Evaluation (ARISE), Proto-
colized Care for Early Septic Shock (ProCESS), and Protocolized
Management in Sepsis (ProMISe) have consistently found no
mortality or renal replacement therapy (RRT) benefits with
protocol-based management in septic shock patients.31e33
The ProCESS study specifically demonstrated that early goal-
directed treatment, alternative protocolized resuscitation, or
standard care had no impact on the development of new AKI,
severity of AKI, fluid overload, the need for RRT, or renal
recovery.32
Isotonic crystalloids are recommended for patients at risk
of AKI, and norepinephrine is the preferred agent for treating
septic shock. Dopamine, with higher adverse effects, is not
advised for kidney protection. The emphasis on timely and
appropriate interventions, along with judicious use of fluids
and careful consideration of nephrotoxic medications, un-
derscores the importance of a nuanced and individualized
approach to sepsis management to mitigate the risk of kidney
complications.
Inter-organ crosstalk
Indeed, the concept of organ dysfunction and the potential for
a cascade of effects leading to multiple organ dysfunction
syndrome (MODS) exemplifies the intricate interplay known
as organ crosstalk. This phenomenon involves the cross-in-
fluence and mutual impact of dysfunction in one organ on the
function of others, creating a complex and often vicious cycle.
In addition to the six critical organs discussed in the context of
sepsis-induced organ failure (cardiovascular, renal, respira-
tory, neurological, hematological, and hepatic), organ cross-
talk can affect all organs, including the end organs. The
interdependence of various physiological systems highlights
the systemic nature of diseases like sepsis, where dysfunction
in one organ can trigger responses and complications in
others. Understanding and managing organ crosstalk is
crucial in providing comprehensive care to patients experi-
encing severe conditions, preventing the progression of
dysfunction, and improving overall outcomes.
Crosstalk with AKI
When a patient is diagnosed with sepsis-induced acute kidney
injury (S-AKI), the repercussions of oliguria, anuria, or fluid
overload caused by the condition can extend to impact other
vital organs, particularly the lungs and heart. The primary
mechanism of the kidneys, responsible for excreting toxic
8 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 8 0 ( 2 0 2 4 ) 4 e9
metabolites from the body, is compromised, leading to
harmful effects on other organ systems (Fig. 1). Animal studies
indicate that S-AKI induces lung inflammation and impairs
lung function by elevating IL6 levels in the blood. Bilateral
nephrectomy in animal studies has shown to cause lung, in-
testinal, and sepsis-induced liver dysfunction (SILD) due to
increased IL6 levels.34 S-AKI has been associated with
heightened inflammatory mediators in rats, leading to brain
oedema due to the disruption of the blood-brain barrier.
Additionally, the inability of S-AKI patients to efficiently
remove drug metabolites from their bodies may harm other
organs and contribute to ototoxicity when using amino-
glycosides. Therefore, it is crucial to adhere to renal doses
according to the recommended chart when administering
medications to S-AKI patients.
Furthermore, the challenges of managing S-AKI in patients
undergoing continuous renal replacement therapy (CRRT) are
compounded by the extracorporeal circuit, which can lead to
pharmacokinetic changes affecting the volume of distribution
and clearance. These changes induced by sepsis can impact
healthy organs and make antimicrobial dose optimization
exceptionally challenging. The dynamic alterations in the
clearance of hydrophilic antimicrobials in S-AKI CRRT pa-
tients may result in difficulties determining the appropriate
medication dosage, further emphasizing the complexities of
managing sepsis-induced complications.
Crosstalk with lung
Renal dysfunction can arise from hypoxemia induced by res-
piratory dysfunction, as depicted in (Fig. 1). Patients under-
going invasive ventilation are at an increased risk of
experiencing renal dysfunction, likely attributed to the release
of inflammatory mediators triggered by mechanical ventila-
tion. Additionally, the associated hemodynamic changes,
such as elevated intrathoracic pressures, can lead to reduced
cardiac output and oxygen delivery, potentially impeding
right ventricular function, as illustrated in (Fig. 1).
Fig. 1 e Showing cross talk between different organs in
sepsis. AKI-sepsis induced acute kidney injury, DIC-
disseminated intravascular coagulation, IL-interleukin,
TNF-tissue necrosis factor.
Abdominal compartment syndrome represents another
potential contributor to impaired renal function. This condi-
tion is characterized by elevated intra-abdominal pressure,
which can compromise renal perfusion and lead to renal
dysfunction. The interplay of these factors underscores the
complex relationship between respiratory, cardiovascular,
and renal systems, highlighting the importance of a compre-
hensive understanding and management approach in clinical
scenarios involving critically ill patients.
Crosstalk with gut
Certainly, abdominal compartment syndrome, characterized
by an elevation in intra-abdominal pressure, can indeed have
a significant impact on renal function, as illustrated in (Fig. 1).
The heightened intra-abdominal pressure associated with
this syndrome has the potential to alter renal perfusion,
leading to further complications and contributing to a decline
in renal function. The intricate interplay between abdominal
compartment syndrome and renal dysfunction underscores
the importance of recognizing and addressing multiple factors
that can affect organ systems in critically ill patients. A ho-
listic approach to patient care is crucial in managing complex
conditions involving the abdominal and renal systems.
Gut-liver crosstalk
The liver plays a crucial role in controlling the immunological
defense system, contributing to toxin clearance, protein and
cytokine production, and the body's adaptation to the in-
flammatory response triggered by sepsis. Sepsis-induced liver
dysfunction (SILD) exacerbates the situation by leading to the
accumulation of toxic metabolites and dysbiosis of the gut
microbiota, ultimately causing endothelial damage to the gut
barrier, as depicted in (Fig. 1). This disruption in the gut barrier
allows bacteria to migrate from the gut into the systemic cir-
culation, initiating an interaction between the liver and the
gut that intensifies the body's inflammatory response. This, in
turn, contributes to organ dysfunction and an elevated risk of
mortality.
In simpler terms, sepsis originating from the gut endo-
thelium results in gut barrier dysfunction, facilitating the
translocation of microorganisms and toxins from the gut into
the bloodstream. This process amplifies the inflammatory
response in various organs, leading to dysfunction. A
comprehensive understanding of the gut-liver crosstalk in
sepsis is essential for the development of therapeutic in-
terventions or preventive strategies. Recognizing the intricate
relationship between these vital organs is crucial in formu-
lating effective approaches to manage sepsis-induced com-
plications and enhance patient outcomes.
Disclosure of competing interest
All authors have none to declare.
 m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 8 0 ( 2 0 2 4 ) 4 e9 9

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