Revolution in Sepsis

Dobson et al.
Journal of Biomedical Science (2024) 31:57

https://doi.org/10.1186/s12929-024-01043-4
REVIEW Open Access
Revolution in sepsis: a symptoms‑based

to a systems‑based approach?
Geoffrey P. Dobson1*, Hayley L. Letson1 and Jodie L. Morris1
Abstract
Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunc-
tion, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear
to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect
the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital
organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target
approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand
how the body responds to an infection, identify new markers to detect its progression and discover new system-
acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a sys-
tems’ perspective and future opportunities. We argue that targeting the body’s early immune-driven CNS-response
may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple
CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing
a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis
and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic
dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy,
and maintains tissue O 2 supply. Future research will investigate the potential translation to humans.
Keywords Sepsis, Intra-abdominal, Infection, Inflammation, Coagulopathy, ALM
Introduction: a global perspective and ages [26]. It is the most common cause of admission
and death in the Intensive Care Unit (ICU) [91]. Each
At the present time there is no magic bullet or phar- year, ~ 49 million are afflicted and 11 million patients
macological therapy for controlling the bioburden of die, with the majority occurring in low- and middle-
propagating inflammation from intra-abdominal income countries [142]. Nearly half, ~ 20 million cases,
sepsis. occur in children under 5 years of age, with ~ 2.9 million
Coccolini and colleagues (2023) [26] deaths [91, 142]. These global mortality numbers trans-
late to ~ 1200 deaths per hour or one death every 3 s. The
Sepsis is recognised by the World Health Organization most common causes are infections of the respiratory
(WHO) as a global health priority across all countries tract (up to 50%), followed by the abdomen, bloodstream,
renal system, skin and central nervous system (CNS)
*Correspondence:
[177]. Males appear to have a higher risk of mortality
Geoffrey P. Dobson than females [122], which may be due to females having
geoffrey.dobson@jcu.edu.au
1
a more robust cell-mediated immune response [144].
Heart, Sepsis and Trauma Research Laboratory, College of Medicine
and Dentistry, James Cook University, 1 James Cook Drive, Townsville,
Sepsis continues to pose a significant threat to the senior
QLD 4811, Australia population with their lower physiological reserves and
multiple comorbidities [80].
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Dobson et al. Journal of Biomedical Science (2024) 31:57 Page 2 of 18
Sepsis is a clinical syndrome that develops from a dys- the mid-1800s when knowledge and practice became more
regulated host response to infection [68, 91]. It is char- evidence-based [40, 60, 158]. Louis Pasteur’s and Robert
acterized by a systemic inflammatory response syndrome Koch’s germ theory of diseases, Rudolf Virchow’s medi-
(SIRS) comprising hyperinflammation, immunosuppres- cine and cellular pathology and Claude Bernard’s unifying
sion, immune paralysis and multiple organ dysfunction concept of the internal milieu all formed the basis of the
syndrome (MODS) [91, 177]. Septic shock is a further modern era [60] (Fig. 1). During the latter half of the 19th
complication that leads to persistent hypotension, wide- century, emergent surgery for intra-abdominal peritonitis
spread tissue hypoperfusion, SIRS, MODS and an altered with drain tubes was advocated by Johann von Mikulicz;
mental state [4, 22, 56, 91]. Modern core definitions of Robert Tait practiced aseptic techniques and lavage of the
sepsis emphasize a more systemic pathobiology with peritoneal cavity; Joseph Lister made great strides in perio-
underlying sub-phenotypes, each potentially requiring perative infection-control, and John Murphy incorporated
different management strategies [148]. These new sub- most in his surgical practice (quote above), including the
phenotypes were recently identified by Seymour and use of 0.9% saline infusions to avoid dehydration (Fig. 1).
colleagues, who used artificial intelligence and machine Despite these advances, sepsis mortality remained high
learning clustering techniques of multiple data sets from (> 70%) [60, 127, 158].
over 20,000 patients [148]. The different phenotypes This clinical landscape changed in 1928, when Alexander
appear to reflect different patient responses to infec- Fleming discovered Penicillium, which launched the mod-
tion that may be associated with varying degrees of CNS ern antimicrobial era [127] (Fig. 1). Advances in bacteriol-
hyperactivation, inflammation, immune dysregulation, ogy and antibiotic use in the 1940s and 1950s resulted in
cardiac depression, endothelial-glycocalyx activation, a slight mortality reduction from sepsis and septic shock
coagulopathy and organ supply–demand imbalances. [60, 158]. In the 1960s, the molecular revolution led to an
Today, diagnosing and treating sepsis begins with iden- increased understanding of the underlying pathology of
tifying the type of infection, measuring the host response infection and clinical trials targeted blunting the immune
using biomarkers, such as C-reactive protein, procalci- and inflammatory responses [60]. In the 1980s, animal
tonin and lactate, predicting the likelihood of organ dys- models of sepsis were introduced into basic research.
function, fluid therapy and possible drainage/surgery for Today, despite new molecular-based technologies, nano-
source control [91, 142]. After providing a brief history technology diagnostics, thousands of research papers and
of sepsis, we will discuss its pathophysiology from a sys- hundreds of clinical trials, unacceptably high mortality
tems’ perspective, and the challenges and opportunities rates still remain [27, 155]. A new revolution is required to
for the twenty-first century. better understand how the body responds to an infection,
identify new markers to detect its progression and discover
new system-acting drugs to treat it.
Brief history
Pathophysiology from a system’s perspective
The medical profession will make early diagno- We begin our systems analysis of sepsis with the central
sis, will insist on early intervention, will limit its nervous system (CNS) as it is the hierarchical controller
surgical procedures to the least possible handling of whole-body homeostasis through the multiple feed-
and trauma consistent with closure of the opening back circuits (or axes) linking the O
2 we breathe to mito-
and relief of pus tension, will limit the duration of chondrial ATP production. The term ‘systems’ refers to the
anaesthesia and the amount of the anaesthetic, will whole body’s response to an infection, which includes its
shorten the actual time of operation, will insure the activation, progression and outcome [51–53]. A systems-
continued absence of pus tension, will eliminate the acting drug is defined as one that treats the pathophysio-
sepsis already in the blood, restore the blood pres- logical response from a systems’ perspective (see later).
sure and will inhibit absorption by position.
John Murphy (1908) [120] p872 CNS sympathetic hyperactivity: major controller
Pioneer surgeon John Murphy (1857–1916) wrote of pathophysiology
this description on how to treat a patient with perfora-
tive peritonitis over 100 years ago. When we study the Sepsis-associated encephalopathy is a diffuse brain
history of medicine, one is humbled by how far we have dysfunction that occurs secondary to infection in the
come in advancing knowledge, on one hand, and appreci- body without overt CNS infection.
ate the long road ahead to improve current practices, on Gofton and Young (2011) [62]
the other (Fig. 1). Despite flares of brilliance from ancient
times to the renaissance, major strides did not occur until
Fig. 1 Brief history of infection and sepsis from the Renaissance to the present. Note the advances in the 19th century when asepsis, surgical
practice and research were rapidly being developed for major diseases and trauma. The timeline provides a perspective of the changing ideas,
practices, and outcomes from which the current thinking and treatments have developed (See text). CNS, central nervous system; M gSO4,
magnesium sulfate
During an infectious challenge, immune cells and their In addition to increased sympathetic discharge, sepsis
inflammatory products modulate the hypothalamic– affects brain function through neural afferents, hormones
pituitary–adrenal (HPA) axis and activate sympathetic and signals from systemic immune cells and tissues (see
stress response via the nucleus tractus solitarius (NTS) below), which can enter the brain via a leaky blood–brain
[42, 49, 54, 153]. In sepsis, the CNS balance switches to barrier (BBB) (Fig. 2) [124, 146]. This creates a hostile
sympathetic dominance with suppression of parasym- CNS environment of inflammation, oxidative stress and
pathetic outflows [7, 96]. This promotes a systemic pro- redox imbalance, which can activate glial cells, con-
inflammatory state because the parasympathetic system strict the microcirculation and cause ischemia, hypoxia
normally keeps inflammation at bay via activation of and structural nerve damage [104, 183]. In severe cases,
vagal cholinergic neurons and splanchnic/splenic nerves, the bombardment of injury signals can cause a condi-
known as the inflammatory reflex [78, 132, 170]). This tion known as sepsis-associated encephalopathy (SAE),
shift in CNS balance also impacts on multiple brain-axes defined as diffuse brain dysfunction secondary to sep-
including the lung, heart and vasculature, gut microbi- sis with manifestations ranging from delirium to coma
ome, liver, spleen, kidney, lung and muscle (Fig. 2). Ani- [62, 146, 183]. SAE occurs in up to 70% of septic shock
mal studies, for example, have shown that blockade of the patients, especially in the elderly, neonates, and patients
brain renin–angiotensin–aldosterone system appears to with chronic illness [62]. Furthermore, SAE is a common
prevent sympathetic hyperactivity and markedly attenu- cause of long-term neurological damage, such as anxi-
ates LV dysfunction during sepsis [36]. Targeting the ety, memory impairment, and consciousness disorders
CNS to reduce its sympathetic discharge offers a poten- following severe sepsis [62]. Potential therapeutics could
tial target for future system-based therapies [96]. target the maintenance of BBB integrity to reduce the
Fig. 2 Schematic of CNS-control linked complications following a major infection and sepsis. Excessive inflammation and tissue damage can
lead to CNS dysfunction, pulmonary injury, cardiovascular uncoupling, endothelial activation, tissue ischemia, microbiome composition changes,
mitochondrial dysfunction, multiple organ failure, and ultimately death. Mortality rates are from Skei and colleagues [155]. Hyperinflammation,
immune dysfunction, endotheliopathy, coagulopathy and multiple organ dysfunction are all under the control of the CNS. CNS, central nervous
system; BBB, blood–brain barrier; NTS, nucleus tractus solitarius; HPA, hypothalamic-pituitary axis; LV, left ventricle; DAMPs, damage-associated
molecular patterns; PAMPs, pathogen-associated molecular patterns
entry of immune cells and their products, and possibly [32, 45, 101, 113, 117, 166]. More studies are urgently
reduce neuroinflammation and the incidence of SAE. required to examine the gut-brain axis and microbiome
Increased CNS-sympathetic outflows may also compositional changes during sepsis, which may offer
reduce mesenteric blood flow to the gut [37, 177]. potential targets for future therapeutics [25].
This is particularly relevant in sepsis because if the gut
becomes ischemic, it can become leaky and bacteria or Host response to infection: immune cell activation
their active metabolic products (lipopolysaccharides, and inflammation
cytokines, neuropeptides, and protein messengers) can
enter the mesenteric lymph or bloodstream and exacer- Except on few occasions, the patient appears to die
bate the infectious load, increase immune dysfunction, from the body’s response to infection rather than
heighten inflammation, worsen coagulopathy, and trig- from it.
ger immunosuppression and MODS [25, 37, 75, 156, Sir William Osler (1904) [128]
177]. The sepsis-induced derangements in microbial
William Osler’s statement over 100 years ago remains
balance can themselves have a profound influence on
the cornerstone of our thinking today. It is the body’s
immune function and cause harm to the host (Fig. 3)
response to infection that is the main determinant of out-
[89, 157]. Change in the host’s gut microbiome is bidi-
come, not the bacterial challenge per se. This helps to
rectionally linked to the CNS through vagal afferents,
explain why a sepsis patient, despite successful removal
immune, and HPA axis modulation, and the CNS in
of infectious foci, often fails to respond to ongoing
turn can modulate the gut and enteric nervous system
Fig. 3 A schematic of the source of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)
in response to an infection, sepsis or the trauma of surgery. The immune-driven inflammatory response is determined by the mix of cytokines
and other neural and inflammatory mediators that determine the selection, activation, recruitment and fate of immune effector cells. Secondary
injury is defined as a progressive process that begins with a pathogen or injury and leads to CNS dysfunction, excessive inflammation, immune
dysfunction, coagulopathy, oxidative stress and mitochondrial energy deficit. Sepsis progresses in the setting of hyperinflammation, immune
dysfunction, oxidative stress and redox imbalance. TLR, toll-like receptor; NLR, NOD-like receptor; RAGE, receptor for advanced glycation end
products; CLR, C-type lectin-like receptor; RLR, RIG-I-like receptor; NK cell, natural killer cell; ILC, innate lymphoid cell; ARDS, acute respiratory distress
syndrome; PIICS, Persistent Inflammation, Immunosuppression, and Catabolism Syndrome; MODS, multiple organ dysfunction syndrome
treatments [27]. The early systemic response to an infec- the vital organs of the body, including the brain, result-
tion involves recruitment of inflammatory leukocytes to ing in collateral tissue damage from cytokines, immune
phagocytose the invading bacteria and associated cellular modulators, complement, oxidants, proteases, and toxic
debris. Initially, neutrophils, which reside in large num- extracellular traps (Fig. 2) [84]. The cytokine ‘storm’
bers in the circulation, are recruited and quickly followed that ensues comprises a profound excess of proinflam-
by bone marrow-derived monocytes and macrophages matory over anti-inflammatory cytokines release into
to resolve the threat and restore homeostasis [42, 139]. the circulation (Fig. 2). Key mediators include interleu-
Other immune cells are also recruited, such as dendritic kin (IL-1β), tumor necrosis factor (TNF)-α, IL-6, IL-4,
cells, natural killer (NK) cells, B-cells, T-cells and innate IL-8, IL-17, IL-18, and IL-10, [152], as well as platelet-
lymphoid cells (ILC) [6, 22], however, their involve- activating factor, complement factors and reactants of
ment in sepsis is beyond the scope of the present review coagulopathy and fibrinolysis [179]. If concomitant anti-
(Fig. 2). inflammatory processes are not activated sufficiently,
If an infection, like sepsis, overwhelms the body’s the cytokine storm is often followed by persistent lym-
defences, innate immune cells continue to infiltrate phopenia and immunosuppression or paralysis, which
involves metabolic reprogramming of many different cell [85], which if overexpressed can lead to the death of the
types, immune cell depletion, cellular apoptosis and T patient [181]. Importantly, PAMPs and DAMPs are not
cell exhaustion [49, 54, 110, 177]. A number of potential mutually exclusive, and immune cells may express co-
targets for resolution of inflammation are underway [138, receptors and accessory molecules that form ‘partner-
186]). Razazi and colleagues, for example, have identified ships’ to coordinate an immune response [134]. The extra
in septic shock patients that activation of the IL-17/inter- barrage of DAMPs from an emergent laparotomy, if
feron (IFN) pathway and vascular endothelial growth required, in a sepsis patient is an additional burden rarely
factor (VEGF) strongly correlates with i) early sepsis res- mentioned as a potential target to improve outcomes
olution (reduced lactate) and ii) improved ICU survival [168] (see later). Identifying the different PAMPs and
[138]. Another target area that appears to show promise DAMPs in the blood of sepsis patients may offer a new
is metabolic reprogramming of immune cell populations early diagnostic treatment window for personalized care
for switching the host’s injury phenotype to a healing one before the cytokine storm develops or tissue blood flow
[92, 102, 103]. and O2 becomes limiting [15, 165, 174].
Source of pathogen‑ and injury‑generated signals

Endothelial‑glycocalyx: a sensor and effector of immune
The two main sources of molecular signals in sepsis that
activation
activate early immune cell recruitment and drive inflam-
mation are: 1) pathogen-associated molecular patterns
In acute inflammation, we find, as a general rule,
(PAMPs) from the invading infectious microbes, and 2)
vascular dilatation accompanied by an active con-
damage-associated molecular patterns (DAMPs) from
dition of the endothelium of the vessel-walls and
tissue injury [42, 177] (Fig. 3). PAMPs and DAMPs are
an exudation with diapedesis, that is to say, three
evolutionary conserved motifs that make foreign patho-
events which concur in producing a considerable
gens or tissue damage recognizable by the host [42, 82,
afflux of leucocytes towards the injured spot.
112]. PAMPs include bacterial lipopolysaccharide (LPS),
E. Metchnikoff (1893) [116] p171
flagellin and lipoteichoic acid, viral RNA and DNA, sur-
face glycoproteins, lipoproteins, and other membrane During sepsis, immune cells and their inflammatory
components [10, 82, 177]. DAMPs from damaged cells products activate the endothelium that result in shedding
and tissues caused by the infection include fibrinogen, of its ‘fuzz-like’ glycocalyx, indicated by serum elevations
annexins, platelet components, fibronectin, S100 pro- in syndecan-1 and soluble-thrombomodulin [81, 83,
teins, syndecan-1, F-actin, adenosine triphosphate (ATP), 179]. This is called sepsis-induced endotheliopathy [83].
histones, deoxyribonucleic acid (DNA), mitochondrial The glycocalyx is negatively charged and anchored to
transcription factor A (TFAM), mitochondrial reactive the single layer of endothelial cells that forms the nexus
oxgen species (mitoROS), cytochrome C, IL-1α, high between the vasculature and the tissues [88, 176]. It cov-
mobility group box protein 1 (HMGB1), heparan sul- ers a vast surface area of over 55,000 m2 [49, 54]. During
fate, tenascin C, defensins, amyloid-β, and many others sepsis, the activated endothelium becomes more adhesive,
[141]. Another source of PAMPs and DAMPs are derived leaky, pro-apoptotic, pro-inflammatory, pro-thrombotic
from extracellular vesicles (EVs) released by pathogens, and vasoactive (Fig. 3) [81, 83, 105, 123]. Glycocalyx
immune or endothelial cells, platelets and damaged host shedding is facilitated by stress-activated membrane-
cells [15, 165, 174]. bound enzymes, called sheddases, in response to pro-
How do host immune cells sense danger? PAMPs and inflammatory cytokines (e.g. TNF-α and IL1-β), reactive
DAMPs are detected by the host’s pattern recognition oxygen species (ROS) (e.g. superoxide, hydroxyl radical),
receptors (PRRs) located on the surface or in the cyto- and by aggressive fluid resuscitation [171]. Of clinical sig-
plasm of immune cells [160, 177]. PRRs are the body’s nificance, it appears that glycocalyx shedding can repair
“sensors” of a threat and communicate it to the host via itself quickly [185]. Luft states that “these cells usually are
immune cell activation. These sensors include toll-like able to replace their missing coats in a matter of minutes”
receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like [106]. However, very little is known about the loss and
receptors (NLRs), C-type lectin-like receptors (CLRs), recovery of the glycocalyx during an infection or sepsis
receptors for advanced glycation end products (RAGE) [171].
and cytosolic DNA sensors (Fig. 3) [1, 86, 173]. Another In critically ill patients, sepsis-induced endotheliopa-
important PRR that senses a wide range of PAMPs and thy is sometimes associated with vascular microthrom-
DAMPs is the NLR family pyrin domain containing 3 bosis mediated by platelet activation and the endothelial
(NLRP3) protein that activates a cytoplasmic multipro- release of von Willebrand factor (vWF) multimers, which
tein platform assembly known as the inflammasome in turn impairs O2 delivery to mitochondria. Excessive
production of vWF multimers become anchored to fibrin deposition was not evaluated at autopsy to assess
endothelial cells as elongated strings and form platelet- DIC. In 2023, Bui-Thi and colleagues undertook another
vWF complexes known as “microthrombi” [23, 81]. If the prospective, observational, single-center study and
pathology becomes more diffuse and systemic, it can lead reported 73% of 161 patients had sepsis/septic shock
to a lethal condition known as disseminated intravascular [14]. ROTEM showed 26% were hypercoagulable, 55%
coagulopathy (DIC) (see below). Reducing the early acti- were hypocoagulable, 14% had mixed hypo-hypercoagu-
vation of the endothelial glycocalyx or facilitating rapid lation patterns, and 19% were hyperfibrinolytic [14].
recovery after shedding may be potential targets for new The different coagulopathies appear to reflect differ-
therapeutics. ent timings and severity of infection and sepsis. An early
common phenotype in septic patients appears to be a
hypercoagulable subtype characterized by prolonged
Sepsis‑induced coagulopathy: a dynamic entity initial clot time with increased maximum clot firmness
that evolves over time (MCF) and high fibrinogen levels (Fig. 4). Bui-Thi and
colleagues further showed that progression from sepsis to
Reconstituted systems are as realistic as our insight severe sepsis was accompanied by a shift from hyper- to
into the clotting mechanism allows: extrapolation hypo-coagulability with fibrinolysis [14]. The thrombel-
to physiology should therefore be regarded with due astography (TEG) study of Luo and colleagues confirmed
suspicion. a hypocoagulopathy in severe sepsis patients which, if
Hemker and colleagues [76], p171 present at hospital admission, was an independent risk
factor for 30-day mortality [107]. Possible mechanisms
CNS dysfunction, inflammation, endotheliopathy and responsible for the switch from a hyper- to hypo-coagu-
coagulopathy are all functionally linked through common lopathy are summarized in Fig. 4 [47, 48].
pathways involved in the regulation of tissue factor (TF) A common mistake in the literature is to equate hypo-
[23, 47, 48, 100, 178, 179]. The common pathways include coagulopathy and fibrinolysis (a bleeding phenotype)
the TF inhibition pathway, platelet inhibition pathway, with disseminated intravascular coagulopathy (DIC) [47,
the heparin-antithrombin III system, thrombomodulin/ 48, 100, 125]. DIC is a rare and specific phenotype with
protein C system and fibrinolytic pathways (Fig. 4) [47, diffuse anatomopathologic fibrin deposition in small and
48, 123, 126]. Inflammasome-activated pyroptotic mac- mid-size vessels (Fig. 4) [46, 74, 99, 163]. Clinically, DIC
rophages [181], microbial agents, cytokines and comple- continues to be diagnosed using a scoring system involv-
ment factors can further increase TF levels, which can ing PT, platelet count, fibrinogen, and D-dimer levels [13,
activate the endothelial-glycocalyx and aggravate coagu- 167, 172]. However, without evidence of intravascular
lopathy [177–179]. Wu and colleagues further showed in fibrin deposition, diagnosis may not be DIC and impact
their mouse sepsis model that inhibition of TF abolishes on optimal patient treatment. We propose the concept of
inflammasome-mediated blood clotting and protects DIC should be confined to a phenotype with confirmed
against death [172, 181]. microvascular fibrin deposits.
Diagnosing sepsis-induced coagulopathy, like trauma- Understanding coagulopathy during sepsis is in its
induced coagulopathy (TIC), has undergone major devel- infancy. More research in clinically-relevant animal mod-
opments in the last 10 years as whole blood viscoelastic els and high quality prospective randomized human tri-
methods have replaced the older unreliable plasmatic als are urgently required to characterize the different
methods of prothrombin time (PT), activated partial early and late phenotypes, and their progression to sepsis
thromboplastin time (aPTT) and international normal- and septic shock, as well as sex differences. With more
ized ratio (INR) [14, 46–48]. Sepsis-induced coagulopa- high-quality studies, there is a strong potential that the
thy is not a static state but a dynamic one with multiple information can lead to more effective personalized and
phenotypes that can change over time (Fig. 4) [14, 47, 48, goal-directed treatments.
100]. In the rotational thromboelastometry (ROTEM)
study of Davies and colleagues, they examined 100 ICU Multiple organ dysfunction syndrome (MODS): not a single
patients (50 with sepsis, 20 with severe sepsis and 30 with event but a systems failure
septic shock) and found increased sepsis severity was
associated with shift from a hypercoagulable to hypoco-
Of those who die, most are from multiple organ fail-
agulable state, with no change in maximum clot firmness
ure which is a still poorly understood consequence
[35]. In septic shock, fibrinolysis was markedly impaired
rather than the immediate effect of infection.
towards a bleeding phase, and was significantly associ-
Coccolini and colleagues (2023) [27]
ated with 28-day mortality [35]. Anatomopathologic
Fig. 4 Coagulopathy is a systemic pathological condition in which the blood’s ability to clot is impaired with varying degrees of fibrinolysis. The
schematic illustrates the different sepsis-induced phenotypes around the Thrombomodulin (TM)-thrombin switch (1) [47, 48]. The TM-thrombin
“switch” regulates coagulation and fibrinolysis in both directions depending on different activators and inhibitors at the thrombin-TM active
sites (EFF-like domains) [47, 48]. During an early infection, patients appear to have a procoagulable phenotype which may form from activation
of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) (2), which decreases plasmin levels (3) and increases fibrinogen to form a stronger a stronger
clot. As infection progresses the phenotype may change to a more hypocoagulable state where fibrinogen is decreased, D-dimers increase
(fibrinolysis), and in extreme cases progresses to a specific hypocoagulation dominated by hyperfibrinolysis with microvascular fibrin deposits
(DIC). The phenotypic change from a hyper- to hypo-coagulable state to disseminated intravascular coagulopathy (DIC) appears to be associated
with a transition from a TF-dominated inflammatory microenvironment, favoring EGF-like Domain 3–6), to a non-TF dominated environment,
favoring EGF-like Domain 4–6, with high mortality. This hypothesis requires knowledge of cytokines, immune cells, tPA, PAI-1, α2-antiplasmin,
fibrinogen, TAFI levels and remains to be tested. Drugs to modulate the thrombin-TM “switch” following infection and sepsis are urgently required.
TPA: tissue plasminogen activator; PAI-1: plasminogen activator inhibitor-1; WVF: Von Willebrand factor; S100A10: S100 calcium binding protein A10;
FVIII: Factor VIII; EPCR: endothelial protein C receptor; FDP: FDP: fibrin degradation product
To highlight the lethality of MODS during sepsis, the progressive and potentially reversible physiologic dys-
2023 guidelines redefined sepsis as “life-threatening function in two or more organs or organ systems [19, 95].
organ dysfunction resulting from a dysregulated host Organ dysfunction syndromes include encephalopathy,
response to infection” [143]. In 1975, Arthur Bauer acute respiratory distress, myocardial infarction, hepato-
introduced the term MODS as multiple physiologi- renal syndrome, acute necrotizing pancreatitis, acute
cal derangements [8]. Today, MODS is considered a adrenal insufficiency, rhabdomyolysis, and muscle wast-
clinical syndrome characterized by the development of ing syndrome (catabolic response) [19, 95].
At the cellular level, MODS develops from persistent initially went through an early hyperdynamic phase (high
tissue hypoperfusion and loss of mitochondrial integrity cardiac output, CO) and either recovered or deteriorated
[49, 54]. ATP is no longer fully replenished leading to into cardiovascular collapse (low CO) [137]. In 1965,
ischemia, hypoxia, organ dysfunction, and possible fail- Wilson and colleagues challenged this view by report-
ure. Mitochondrial dysfunction includes decreased pro- ing that septic shock patients had normal or elevated CO
ton pumping across the inner mitochondrial membrane, with low systemic vascular resistance (SVR), and very
collapsed membrane potential, opening of the mitochon- rarely had a low CO [180]. This was highly controversial
drial permeability transition pore, C a2+ loading, loss of and contrary to hemorrhagic/cardiogenic shock, which
cytochrome C, release of apoptotic-cascade inducing fac- is characterized by a low CO and high SVR [137]. Using
tors, and increased DAMPs and ROS, which exacerbates nuclear imaging techniques and thermodilution meth-
immune dysfunction, inflammation and coagulopathy ods, Joseph Parrillo’s group confirmed Wilson’s findings
[49, 54, 73, 79]. Sepsis also impairs mitochondrial biogen- and showed that septic shock patients maintained high
esis and mitophagy, resulting in insufficient renewal of CO and low SVR [28, 60, 130]. The group also reported
mitochondria, which further impacts cellular respiratory that 75% of patients had a depressed left ventricular ejec-
capacity and organ dysfunction. Fever, a manifestation of tion fraction (LVEF) in the first few days after the onset
sepsis, is a result of uncoupling of muscle mitochondria of septic shock [130]. Sepsis-induced myocardial depres-
which leads to generation of heat, not energy, and helps sion appears to have all the hallmarks of myocardial stun-
to explain muscle wasting despite a high caloric intake ning after coronary artery bypass surgery [43, 175].
[79]. Targeting mitochondrial dysfunction in muscle, and Today, sepsis-induced cardiomyopathy is an acute
other organs, may offer novel and valuable targets for syndrome of myocardial depression that occurs early
sepsis. after the onset of septic shock and normally resolves in
Mitochondria are not only the cell’s powerhouses. 7–10 days [77]. It occurs in ~ 50% of septic patients and
In immune cells, mitochondrial activity regulates their characterized by LV dilatation and depressed LVEF with
activation, differentiation and survival [94, 102, 103, maintained coronary blood flow [77, 184]. Myocar-
114]. Expression of key mediators involved in regula- dial depression in sepsis patients is also associated with
tion of mitochondrial function (Sirt1/3, Ampk, Pgc1, higher aortic conduit stiffness [64, 87], which may be
Nrf1, Tfam, Mtco3, Nr3c1), for example, are significantly responsible for reduced venticulo-arterial (VA) coupling
reduced in leukocytes from septic patients [20, 102, 103]. and reduced blood flow and O2 to the tissues [135]. VA
Sepsis-induced mitochondrial dysfunction leads to meta- coupling is defined as the ratio of arterial elastance (Ea)
bolic reprogramming and altered functional capacity of to left-ventricular elastance (Ees), and can be derived
immune cells, heightened inflammation and immuno- from routine echocardiography [67]. The advantage of
suppression [94, 102, 103]. Therapies that target recovery VA coupling over LVEF or CO is that it provides arterial
of mitochondrial function may offer a novel approach to load properties in addition to LV function [24, 67]. New
reverse leukocyte dysfunction in sepsis [3, 114]. therapeutics are required to target VA coupling in septic
patients, which may prevent myocardial depression and
Cardiovascular dysfunction after sepsis: the puzzle impairment of vascular reactivity [151].
of myocardial depression There are at least five main hypotheses of myocardial
depression (Table 1). While all five are plausible, they are
There has been a tendency to equate shock, regard- not mutually exclusive and appear to involve alterations
less of its origin, with a low cardiac output (CO) and in Ca2+ handling, ATP replenishment and myofilament
high total peripheral resistance (SVR). While our function [9, 17, 64, 70, 77, 93, 115, 131, 138, 145, 159, 161,
experience suggests that this is true of hypovolemic 182]. The future challenge is finding which one or more
and cardiac shock, the same cannot be said of the of these mechanisms contribute to the decline in myocar-
septic form. dial depression and VA uncoupling seen clinically.
Wilson and colleagues (1965) [180]
Fluid resuscitation: doing more harm than good?
Cardiovascular collapse is a major reason for mortality
in septic shock patients (Fig. 3) [77]. In the early 1960s,
Recently, the safety of intravenous fluids in patients
two distinct hypotensive phases of septic shock were
with sepsis has been called into question with both
characterized; the first was a warm dry skin, tachycardic
prospective and observational data suggesting
condition (“warm” shock), and the second phase was a
improved outcomes with less fluid or no fluid.
cold clammy skin with a thready pulse with hypotension
Byrne and Van Haren (2017) [16]
(“cold” shock) [109]. Using this classification, septic shock
Table 1 Five hypotheses for sepsis-induced myocardial depression in the setting of inflammation and immune dysfunction. All five
are not mutually exclusive
Hypothesis Mechanism(s) References
1 Circulating myocardial depressant(s) Serum from septic shock patients depressed myocyte contractility in vitro. [120–122, 54,
Candidates include bacterial toxins, TNF-α, IL-1β, and interleukin-1 recep- 123–125, 105]
tor-like 1 (sST2), which may decrease myofilaments’ sensitivity to Ca2+
via the induction of excess NO synthesis (blocked by L-NAME). Possible
sources of TNF-α and IL-1β are activated monocytes and macrophages.
2 Overexpression of cardiac mitochondrial NOS Excess NO synthesis (and reactive oxygen species), which may partially open [126, 114]
the mitochondrial pore, depolarize the inner membrane, and reduce ATP
production for contraction.
3 Myofilament Ca2+ responsiveness Decrease cardio-myofilament Ca2+ sensitivity, reduces cross-bridge cycling [127, 128]
responsiveness to reduce contractile activation and force development.
4 Cardiac β-adrenergic desensitization Cardiac response to sympathetic hyperactivation and ↑catecholamines. [129]
Receptor switching from Gs to Gi, which signals β-2 adrenergic receptors
to produce a negative inotropic response, presumably by ↓Ca2+ availability.
5 Downregulation of master genes encoding Reduce cross-bridge cycling and ATP availability generated by oxidative [105]
for sarcomeric and mitochondrial proteins phosphorylation.
TNF-α tumor necrosis factor-alpha, IL-1β interleukin-1beta, NO nitric oxide, L-NAME NG-nitro-L-arginine methyl ester, ATP adenosine triphosphate
Current supportive strategies for severe sepsis patients necessitating an initial 500 mL crystalloid bolus [80].
may include an early and goal-directed fluid resuscitation Prior to 2001, use of fluid resuscitation was largely based
bundle, mechanical ventilation, inotropic and vasopres- on historical experience without empirical support from
sor therapies, blood cell transfusions, anti-fibrinolytics either animal studies or clinical trials [16]. The first sup-
and mechanical ventilation, and possible renal support portive evidence for fluid therapy came from the human
[91, 177]. The primary goal of fluid therapy is to reduce study of Rivers and colleagues that showed a 16% mor-
dehydration, restore circulating blood volume, optimize tality reduction in septic shock patients [140]. Unfortu-
cardiovascular function and improve tissue O2 (Fig. 5) nately, the survival benefit was not supported in larger
[16]. Dehydration is common in older adults, often
Fig. 5 Schematic of 2016–2021 Surviving Sepsis Campaign guidelines that suggest initial resuscitation of at least 30 mL/kg of isotonic crystalloid
fluid within the first 3 h of sepsis identification to restore circulating fluid volume and optimize stroke volume. However, there is a paucity
of high-quality data to support this clinical practice. The significant heterogeneity of sepsis and the reports that ~ 50% are non-responders makes
the recommendation highly problematic. Current evidence indicates that administration of large fluid volumes to the critically ill may cause harm
by exacerbating secondary injury (see text). IV, intravenous; CNS, central nervous system; ADP, adenosine triphosphate; ATP, adenosine triphosphate
independent trials, including the ProCESS, PROMISE Trauma of surgery: a forgotten confounder of poor patient
and ARISE trials [108]. outcomes
Despite the lack of clinical evidence, the 2016–2021
Surviving Sepsis Campaign guidelines continued to pro- It should be remembered always that the patient
mote fluid therapy for septic shock patients (Fig. 5) [58]. who has been in shock and resuscitated, and then
The guidelines proposed an initial resuscitation of at least operated upon, is in a precarious state. His nervous
30 mL/kg of isotonic crystalloid fluid during the first 3 h system has been disturbed not only by the original
to restore circulating fluid volume and optimize stroke trauma, but also by the low nutrient flow of blood,
volume [108]. Administering an IV fluid volume up to and by the surgical procedures incidental to opera-
60% of the normal blood volume to a 100 kg septic patient tion (our italics).
over 3 h has little or no clinical support and may be asso- Walter B. Cannon (1923) Quoted from Traumatic
ciated with higher mortality [58]. The Surviving Sepsis Shock [18] p192
campaign has now downgraded this recommendation
Patients with severe abdominal sepsis often require an
from strong to weak, although the practice appears to
emergency laparotomy, which is associated with higher
continue in many hospitals worldwide [58].
mortality and morbidity compared to less invasive pro-
Today, fluid resuscitation may cause harm to some
cedures (Fig. 2) [12, 59, 69, 90, 136, 154, 162]. Possible
patients. Contrary to its name, normal saline is not nor-
reasons for poorer outcomes include the trauma of sur-
mal, and the volumes and timings are not effective in
gery itself amplifying immune cell activation, increasing
critically ill patients [11, 16, 108, 121, 149, 150]. Large
inflammation, coagulopathy and MODS [39, 41]. The
aggressive fluid volumes create dilutional coagulopa-
extra barrage of DAMPs comes from tissue damage from
thy, fluid overload, and pathogenic pulmonary and tis-
the first incision, organ manipulation, and surgical cor-
sue edema, acute kidney injury, prolonged ICU stays
rection and drain (Fig. 2) [2]. Torp and colleagues have
and higher mortality [55, 108, 149, 150]. If normal saline
recently discussed how tissue injury from surgery trig-
was evaluated today by the European, USA and Austral-
gers a generalized inflammatory response and the role
ian regulatory bodies, there is a high chance it was not be
mitochondrial DAMPs (mDAMPs) play in worsening its
approved for human use. The harmful effects of normal
pathophysiology [168]. In addition, surgical site infec-
saline solutions were recognized over 100 years ago by
tions occur in up to 35% of patients, which further com-
George Evans when he wrote in 1911: “One cannot fail
plicates recovery [2]. Another aspect of the trauma of
to be impressed with the danger of such procedure, if one
surgery that is rarely discussed is that the anesthetized
observes the utter recklessness with which salt solution
brain is still “awake” to the circulating DAMPs from the
is frequently prescribed, particularly in the postopera-
surgery itself [30, 41], which may pass through the leaky
tive period, without previous knowledge of the condition
BBB and activate CNS dysfunction and lead to altered
of blood pressure, the ability of the heart to handle large
mental states [4, 56, 91]. The trauma of surgery aggra-
amounts of fluid successfully, or the functional capac-
vates an already precarious state, which is magnified fur-
ity of the kidneys to excrete the large amount of chloride
ther in older patients with multiple comorbidities [41].
thus formed on them” [5, 57]. More recently, vasopressor
This is an area that requires new therapies to reduce the
agents that increase cardiac contractility or vasoconstric-
host’s stress response of surgery [31, 38, 41, 61, 71, 133,
tion have also come under clinical scrutiny that include
164].
increased cardiac workload, arrhythmias and vasocon-
striction-related tissue ischemia [149, 150].
Future consideration for drug development:
Another vexing problem with the ongoing use of fluid
from symptoms to system
therapies is that up to 50% of patients are non-responders
(Fig. 5), meaning they fail to increase preload and stroke
Clinical study of antiinflammation strategies to
volume with IV fluid infusions, and therefore fails to
treat sepsis has been characterized by a predictable
improve tissue O2 supply [72, 111]. Unfortunately, there
cycle of abundant clinical failures punctuated by an
have been few high-quality clinical trials comparing non-
intermittent positive result.
responders and responders [55]. Some studies recom-
Shapiro and colleagues (2023) [149, 150]
mend the use of a lung ultrasound, echocardiographic
assessment, urine output, and other measures, to pre- Notwithstanding the ongoing challenges in treat-
vent fluid overload in the ICU in an attempt to improve ing sepsis, great strides are being made in personalized
patient stratification and optimize treaetment [55]. care based on blood biomarkers [143]. Individualized
treatments have also progressed in the chronic, immu-
nosuppressive stage of sepsis responsible for later-stage
morbidity and mortality [143]. Notwithstanding these stress response, maintain BBB integrity, promote CNS-
advances, there remains few safe and effective drugs for cardiovascular coupling, prevent myocardial depres-
the early treatment of sepsis [92, 102, 103, 149, 149, 150, sion, protect the endothelial-glycocalyx, reduce excessive
150]. For example, there are only a handful of drugs to inflammation, reduce immune dysfunction, correct coag-
reduce excessive inflammation and immune dysfunc- ulopathy, and deliver sufficient O 2 to tissue mitochondria
tion. Non-steroidal anti-inflammatory drugs (NSAIDs), [49, 50, 54]. The drug might also involve reprogramming
COX-2 inhibitors and TNF-α inhibitors do not appear immune cell metabolism and placing a ‘brake’ on the
to be pro-resolving, and may in fact exacerbate the pro- hyperinflammatory response and permitting anti-inflam-
inflammatory process [129]. A relative new area of drug matory processes to resolve the host’s responses to sep-
design is targeting metabolic reprogramming of immune sis. No such systems-acting drug exists.
cells responsible for hyperinflammation and immuno- We have been developing an adenosine, lidocaine and
suppression [102, 103]. The future challenge is to safely magnesium (ALM) fluid therapy for hemorrhagic shock,
and effectively translate these immunometabolism-alter- traumatic brain injury (TBI) [44, 50–53], burns [34,
ing drugs to improve patient outcomes in the hospital 51–53], orthopedic trauma [118, 119] and the trauma
setting. of surgery [33]. We have shown the drug shifts sympa-
Why have there been so few advances in pre-clinical thetic hyperactivity to parasympathetic dominance in the
drug development for sepsis and translation to humans? rat model of non-compressible hemorrhagic shock [96],
Three possible reasons include: 1) the widespread use of restores cardiac output [97], protects against endothelial
specific-pathogen free (SPF) animal models with their glycocalyx shedding with 97% rapid restoration [169], and
altered microbiomes and immature immune systems that reduces the incidence of MODS [50, 98]. During resus-
do not represent the human condition [45, 47, 48, 51– citation, we have shown the ALM therapy is neuropro-
53], Conventionally bred and housed animals should be tective at hypotensive pressures (MAPs 47–50 mmHg),
used if human translation is the end-game [51–53], 2) the which has important implications for sepsis [50–53,
flawed practice of the treat-as-you go mindset and single 97, 98]. This data has been use to formulate a Systems
nodal drug targeting, which ignores the complexity of Hypothesis of Trauma (SHOT), which may be applicable
the system [49–54], and 3) poor clinical trial design that for sepsis and septic shock [49, 50, 54].
does not represent the heterogeneity of patient responses Our proof-of-concept studies in a rat polymicrobial
to sepsis [21, 143]. With respect to single-nodal targets, sepsis model [65, 66] and pig lipopolysaccharide (LPS)-
we will give one example. It is well established that the endotoxin model [63] have been encouraging. In the pig
IL-1 receptor is a key amplifier of inflammation [149, LPS model, ALM therapy induced a profound and revers-
150], and its inhibition may resolve the cytokine storm. ible hypotensive state (MAP 47 mmHg) by maintaining
A drug that inhibits the IL-1-receptor, anakinra, has an CO and lowering SVR with little or no change in tis-
excellent safety record in humans, however, it has failed sue O2 delivery [63]. CO was maintained by preserving
to show a survival benefit after sepsis or COVID-19 [149, preload recruitable stroke work and improving VA cou-
150]. The ‘single-step’ drug target approach can be traced pling [63]. Importantly, systemic hypotension is not delete-
back to the molecular revolution of the 20th century, rious if CO, VA coupling and O2 delivery to the tissues are
which began in around 1953 after the discovery of DNA maintained by lowering SVR [51–53]. This ALM-induced
[51–53]. Nobel Laureate Sir Francis Crick embodied this hypotensive state involves re-setting the CNS-control of
highly mechanistic mindset when he wrote “the ultimate O2 delivery to tissue mitochondria, that may be beneficial
aim of the modern movement in biology is to explain all to sepsis patients [50]. Similarly, ALM therapy induced a
biology in terms of physics and chemistry” [29]. From a reversible hypotensive state in a rat model of polymicro-
molecular standpoint Crick was correct, however, its rel- bial sepsis with reduced pulmonary edema and correc-
evance to the workings of the whole body has not kept tion of coagulopathy [65]. ALM led to 88% survival after
pace [51–53]. The advent of the “Omic” technologies to six days, without antibiotics, whereas saline controls died
drill deeper into molecular mechanisms has occurred at early from inflammatory/immune dysfunction and mul-
the expense of systems analysis. Reductionism is impor- tiple organ failure [66]. Importantly, the combination of
tant in breaking a complex system into its simpler parts, ALM is key to whole body protection whereas the indi-
but it does not do away with the system. New systems- vidual actives, A, L or M are not [50]. While appreciat-
based therapies are urgently required to treat sepsis. ing the success rate of translating new drugs to humans
What would a systems-based drug look like? Ideally, a is less than 5% [147], further ALM preclinical sepsis stud-
systems-based drug would blunt the CNS-linked feed- ies are required to facilitate translation to human safety
back circuits (or axes) that drive secondary injury and trials.
poor patient outcomes. The drug would reduce the CNS
Conclusions 4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med.
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The clinical management of sepsis appears to be at a 5. Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr.
crossroads and requires a new revolution to better under- 2008;27:179–88.
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More than just fever and leukocytosis-a narrative review. Crit Care.
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a signalling pathway has not been successful because 7. Barman SM. 2019 ludwig lecture: Rhythms in sympathetic nerve
activity are a key to understanding neural control of the car-
it ignores the complexity of the system. We argue if the diovascular system. Am J Physiol Regul Integr Comp Physiol.
immune-driven, CNS-sympathetic hyperactivation can 2020;318:R191–205.
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Surg. 1975;110:779–81.
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Availability of data and materials children: a single-center study. Mediterr J Hematol Infect Dis.
The datasets during and/or analysed during the current review can be made 2023;15(1):e2023004. https://doi.org/10.4084/MJHID.2023.004. Avail-
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