European Journal of Internal Medicine xxx (xxxx) xxx

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review Article

Non-conventional immunomodulation in the management of sepsis

M.A. Slim a, b, †, *, O. Turgman a, †, L.A. van Vught a, b, T. van der Poll a, c, W.J. Wiersinga a, c
a
Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam Institute for Infection
and Immunity, Amsterdam, the Netherlands
b
Department of Intensive Care, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity,
Amsterdam, the Netherlands
c
Department of Medicine, Division of Infectious Diseases, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, the Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Sepsis remains a critical global health issue, demanding novel therapeutic strategies. Traditional immunomo­
Sepsis dulation treatments such as corticosteroids, specific modifiers of cytokines, complement or coagulation, growth
Immunomodulation factors or immunoglobulins, have so far fallen short. Meanwhile the number of studies investigating non-
Herbal medicine
conventional immunomodulatory strategies is expanding. This review provides an overview of adjunctive
Traditional Chinese medicine
Immunonutrition
treatments with herbal-based medicine, immunonutrition, vasopressors, sedative treatments and targeted tem­
perature management, used to modulate the immune response in patients with sepsis.
Herbal-based medicine, notably within traditional Chinese medicine, shows promise. Xuebijing injection and
Shenfu injection exhibit anti-inflammatory and immune-modulatory effects, and the potential to lower 28-day
mortality in sepsis. Selenium supplementation has been reported to reduce the occurrence of ventilator-
associated pneumonia among sepsis patients, but study results are conflicting. Likewise, the immune-
suppressive effects of omega-3 fatty acids have been associated with improved clinical outcomes in sepsis.
The immunomodulating properties of supportive treatments also gain interest. Vasopressors like norepinephrine
exhibit dual dosage-dependent roles, potentially promoting both pro- and anti-inflammatory effects. Dexmede­
tomidine, a sedative, demonstrates anti-inflammatory properties, reducing sepsis mortality rates in some studies.
Temperature management, particularly maintaining higher body temperature, has also been associated with
improved outcomes in small scale human trials.
In conclusion, emerging non-conventional immunomodulatory approaches, including herbal medicine,
immunonutrition, and targeted supportive therapies, hold potential for sepsis treatment, but their possible
implementation into everyday clinical practice necessitates further research and stringent clinical validation in
different settings.

1. Introduction 5]. Regulating the immune response to infection holds potential as a

viable treatment approach for sepsis. As a result dozens of compounds
Sepsis is defined as a life-threatening organ dysfunction caused by a targeting the innate immune response, the complement system, coagu­
dysregulated host response to an infection [1,2]. Despite significant lation as well as immunostimulatory cytokines and growth factors, im­
progress in our understanding of the pathophysiology of sepsis sup­ munoglobulins, mesenchymal stem cells, and immune-checkpoint
portive care and the eradication of infection, through appropriate an­ inhibitors have been investigated in patients with sepsis [6]. Nonethe­
tibiotics and source control, remain the cornerstones of sepsis less, despite the involvement of hundreds of clinical trials exploring the
management [3]. The host response in sepsis involves excessive impact of these so called classical immunomodulatory agents on out­
inflammation, activation of the complement system, coagulation, comes, a consistent beneficial effect of any immunotherapy has yet to be
endothelium and immune suppression, along with epigenetic and established [4,7,8]. It is unlikely that one immune modulator will be
metabolic changes that maintain the imbalanced immune response [4, able to successfully treat all sepsis patients, with different infection

* Corresponding author.
E-mail address: m.a.slim@amsterdamumc.nl (M.A. Slim).
†
Both authors contributed equally.

https://doi.org/10.1016/j.ejim.2023.10.032
Received 17 October 2023; Accepted 24 October 2023
Available online 31 October 2023
0953-6205/© 2023 The Author(s). Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: M.A. Slim et al., European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2023.10.032
M.A. Slim et al. European Journal of Internal Medicine xxx (xxxx) xxx

sources and individual immune responses. At the moment, intravenous strengthen the host immune response by increasing bactericidal activity,
corticosteroid therapy for adults with septic shock and an ongoing stimulating leukocytes, and neutralizing bacterial endotoxins [26–28].
requirement for vasopressor therapy is the only immunomodulatory The evidence however to use IVIG in the treatment of sepsis is still weak
therapy that is recommended by the Surviving Sepsis Campaign guide­ and not generally recommended [3]. Since the 1990s, the observed
lines (weak recommendation; moderate quality of evidence) [3]. disproportionate production of proinflammatory cytokines such as
Since the aforementioned conventional immunomodulatory ap­ interleukin (IL)− 1 and tumor necrosis factor (TNF) in sepsis, in concert
proaches have not yielded significant breakthroughs in sepsis research with the ability to block them with IL-1 receptor antagonist and
(extensively reviewed elsewhere [6,9-11]), research into personalized anti-TNF antibodies, were the basis for several clinical trials. However,
immunotherapy using established immunomodulation agents is under­ both the anti-TNF antibody afelimomab and human recombinant IL-1
way utilizing novel diagnostics and tailored therapies targeting specific receptor antagonist anakinra were not effective when studied in the
immune endotypes [4,12]. In parallel, the exploration of patients fulfilling the sepsis-1 criteria [29,30], but did show positive
non-conventional immunomodulatory strategies is on the rise, reflecting results when patient stratification based on IL-6 levels or features of
a growing interest in diverse therapeutic possibilities. Macrolides are macrophage activation-like syndrome (MALS) was used [31,32]. In
also reported to have a beneficial anti-inflammatory effect in the treat­ patients with elevated baseline IL-6 level afelimomab demonstrated a
ment of sepsis, which is described elsewhere [13,14]. After providing a small but significant reduction in 28-day mortality in those patients with
short summary of developments in conventional immunotherapy, this IL-6 levels > 1000 pg/mL [31]. In a post-hoc analysis anakinra usage led
review focuses on adjunctive treatments with herbal-based medicine to a 30 % decrease in patients with features of MALS [32]. Since the
[15], immunonutrition [16], vasopressors [17], sedative treatments discovery of Toll-like receptors (TLRs) in the 1990s, they have garnered
[18], and targeted temperature management [19], all of which have interest as therapeutic targets for sepsis [8]. However, clinical trials
shown potential immunomodulatory effects that might benefit sepsis investigating TLR4 blockade, including eritoran (a synthetic lipid A
outcomes (Fig. 1). analog) and TAK-242 (a specific TLR4 inhibitor), have failed to reduce
mortality in severe sepsis patient cohorts [33–36].
2. Developments in immunotherapy in sepsis since the 1960s When it became well established that most sepsis patients also
display signs of profound immunosuppression, various targeted
Historically the dominating theory has been that sepsis was mainly immune-enhancing therapies have been investigated [37,38]. This in­
the result of an excessive inflammatory host response to an infection, cludes Granulocyte Colony-Stimulating Factor (G-CSF),
which has led to numerous strategies trying to dampen inflammation Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), inter­
[6]. Following this perspective, the first clinical trials with supra­ feron-γ (IFN-γ), IL-7 and programmed cell death protein-1 (PD-1) in­
physiological doses of glucocorticoids aiming to reduce the immune hibitors [39]. The results of clinical trials using G-CSF and GM-CSF in
response were performed in the 1960s, showing no important treatment sepsis are inconsistent; G-CSF did not improve hospital mortality in
benefit [20,21]. However in a trial entailing 172 septic shock patients patients with septic shock [40,41], whereas GM-CSF showed a reduced
published in 1976, high-dose methylprednisolone resulted in an abso­ hospital stay in patients with abdominal sepsis [41]. IFN-γ can restore
lute mortality reduction of 28 % [22]. Studies in the 1980s and 1990s the levels of human leukocyte antigen DR (HLA-DR) expression and the
focused on blocking endotoxin. Initially volunteers were immunized ability of monocytes to secrete pro-inflammatory cytokines, without
with Escherichia (E.) coli bacteria, and their plasma was given to sepsis affecting patient’s outcome [42–44]. Activated protein C (activated
patients, resulting in a promising reduction in mortality rates by 12 to drotrecogin alfa) became of interest in the beginning of the 2000s. In
17 % [23,24]. Later HA-1A, a human monoclonal IgM antibody that 1271 severe sepsis patients treatment with activated drotrecogin alfa
binds to endotoxin, was produced, but it yielded discouraging result (no resulted in a significantly lower 28-day mortality compared to treatment
mortality reduction in 621 patients) [25]. In the 1980s, intravenous with placebo (26.5% vs. 33.9 %) [45]; however this beneficial effect was
immunoglobulins (IVIG) also became a treatment of interest since they refuted in subsequent randomized clinical trials (RCTs) and a Cochrane

Fig. 1. Graphical overview of non-conventional immunotherapies for sepsis. Graphical overview of conventional versus non-conventional immunotherapies eval­
uated in patients with sepsis, in which the administration of non-conventional immunotherapies is demonstrated in a patient admitted to the intensive care.

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M.A. Slim et al. European Journal of Internal Medicine xxx (xxxx) xxx

review [46,47]. IL-7 has been shown to be able to reverse sepsis-induced explained how the onset of sepsis was defined, and the trial did not
lymphopenia, which is an independent predictor of adverse clinical include many patients with severe disease (the mean Acute Physiology
outcomes in sepsis [48,49]. and Chronic Health Evaluation (APACHE) II score was approximately 12
One of the newer immunotherapies is PD-1 inhibitor, which is safe, in both groups). Lastly, it would be desirable to validate these results in
well-tolerated and able to restore lymphocyte counts and HLA-DR other regions of the world and also to include a varied group of patients
expression [50–52]. Further efficacy studies are needed. Recent ap­ with sepsis at different levels of severity at baseline, along with
proaches aim to personalize immunotherapy. In the ImmunoSep RCT, well-defined criteria for identifying the onset of sepsis and the mea­
sepsis patients are categorized based on their ferritin and monocyte surement of biochemical markers related to the working mechanism of
HLA-DR levels. Patients with elevated ferritin, indicating hyper­ XBJI.
inflammation, are treated with anakinra, while those with reduced Another TCM is Shenfu injection (SFI), mainly composed of ginse­
monocyte HLA-DR, indicating immune suppression, are treated with nosides and aconitine alkaloids [53]. SFI demonstrated significant
IFN-γ [12]. anti-inflammatory and immune-modulatory properties in a rabbit model
of lipopolysaccharide (LPS)-induced septic shock and resulted in
3. Non-conventional immunomodulatory therapies reduced serum concentration of lactate dehydrogenase, aspartate
aminotransferase (AST) and glutamate transaminase (ALT), enhanced
Recent years have seen an increase in the number of studies inves­ myocardial metabolic function, and preserved tissue integrity in the
tigating non-conventional immunomodulatory strategies in sepsis heart, liver, and kidney [63]. Two RCTs studying SFI vs placebo in septic
(Table 1). These include adjunctive treatments such as herbal-based shock patients showed increased numbers of CD4+ and CD8+ T cells,
medicine, immunonutrition, vasopressors, sedative treatments, and increased HLA-DR expression on monocytes and lower plasma
targeted temperature management. biomarker levels of endothelial dysfunction [64,65]. Moreover, SFI
treatment was associated with a shorter length of ICU stay, but not with
3.1. Herbal-based medicine a lower 28-day mortality rate [64,65].
Septimeb™ is another form of herbal medicine (a combination of
For over 2000 years herbal-based medicines have played a vital role extracts from Rosa canina, Urtica dioica, Tanacetum vulgare, selenium,
in the treatment of sepsis in East Asia [53]. Sepsis, when defined using flavonoids, and carotenes) [66], which is known to reduce hyper­
clinical symptoms, can be classified within the "febrile diseases" cate­ inflammatory cytokines [67]. Animal studies have shown that Septi­
gory of traditional Chinese medicine (TCM) [54]. TCM’s approach to meb™ is effective through inhibition of oxidative stress by reducing free
treating sepsis primarily involves the following techniques: clearing heat radicals via inhibition of involved cytokines [68]. In a small RCT with 51
and detoxifying toxins (termed Qingrejiedu in Chinese), promoting blood sepsis patients admitted to the ICU, Septimeb™ use was associated with
circulation and removing blood stasis (Huoxuehuayu), and promoting a reduction in the severity of sepsis and mortality rate (8% vs. 25 %
the recovery of physiological function (Fuzhengguben) [54,55]. patients receiving standard of care) [67].
Numerous preclinical studies of sepsis have demonstrated the potential The TCM JinHong Formula (JHF) is derived from rhubarb and
of some of these herbal-based medicines to dampen inflammation, Moutan Decoction and has anti-inflammatory and antioxidant proper­
inhibit oxidative stress and maintain cellular homeostasis [53]. Here we ties. possibly due to their roles in the IL-17 and TNF signaling pathways
provide an overview of studies evaluating the efficacy of the TCM’s [69]. In a mouse model, JHF blocked the migration of gut microbiota to
Xuebijing, Shenfu, Septimeb™ and JonHong in patients with sepsis. the lung by restoring the intestinal barrier by up-regulating tight junc­
Xuebijing injection (XBJI) is prescribed as an injection and contains tions and hence accumulation of E. coli in the lungs, thereby preventing
the herbs, paeoniae radix rubra, Szechuan lovage rhizome, angelicae severe acute lung-injury associated with sepsis [70]. In a RCT including
sinensis radix, and salviae miltiorrhizae [53]. When used in mice, XBJI 114 sepsis patients recruited from the emergency department or the ICU,
reduced the number of Th17 T cells, downregulated the expression of 28-day mortality was significantly reduced in the treatment group (38%
inflammatory cytokines and inhibited the infiltration of neutrophils in vs. 58 %, p = 0.031) [69]. Various other herbal-based treatments have
lung and kidney tissue [56]. Two studies have evaluated the impact of been evaluated for sepsis [53,71], and practice guidelines have been
XBJI on sepsis-induced cytokine release in patients: an interventional published on which TCM can be applied, e.g. suggesting that XBJI is the
study with Chinese patients with sepsis-induced acute kidney injury preferential treatment in patients with sepsis, while SFI in patients with
(XBJI vs. placebo) [57] and a randomized controlled trial with septic shock [72].
sepsis-induced acute respiratory stress syndrome (ARDS) (XBJI vs.
standard care). In both investigations XBJI decreased the levels of the 3.2. Immunonutrition
proinflammatory cytokines IL-6, IL-8 and TNF [58]. Furthermore, XBJI
has been reported to ameliorate diffuse intravascular coagulation (DIC) Immunonutrition is defined as the potential to modulate the immune
in 171 sepsis patients in a non-randomized interventional study [59] and system using interventions with specific nutrients [73]. One of the most
in lowering the pneumonia severity index in 710 patients with severe well-researched immunonutritional interventions is selenium supple­
community-acquired pneumonia (CAP) in an RCT studying XBJI vs. mentation. In vitro, selenium upregulates expression of IL-2 receptors on
placebo [60]. When used as an intervention in patients with severe CAP, activated lymphocytes and natural killer cells leading to clonal expan­
XBJI administration was associated with a remarkable 16 % reduction in sion of T cells, enhancement of the lymphocyte response to antigen
28-day mortality [60] and a mortality reduction of 14 % in patients with stimulation and an increase in the ability to develop into cytotoxic
severe sepsis with DIC [59]. A very recent placebo-controlled RCT, lymphocytes [74]. Selenium deficiency has been linked to impairment of
called EXIT-SEP and conducted across 45 Chinese intensive care units both cellular and humoral immunity [74]. In a murine model, selenium
(ICUs), corroborated these findings: 28-day mortality was significantly deficiency was associated with genomic mutation of previously aviru­
(p<0.001) lower in the XBJI group (18.8 %, 165 out of 878 patients) lent viruses to virulent ones, which might partly explain the relatively
than in the placebo group (26.1 %, 230 out of 882 patients), with an high emergence of newly mutated influenza strains coming from areas of
absolute risk difference of 7.3 (95 % CI, 3.4–11.2, p<0.001) [15]. This China that have notably selenium depleted soil [75]. This has led to
large study was conducted in patients aged 18 to 75 years fulfilling the several trials investigating the potential role of selenium as a therapeutic
sepsis-3 criteria [1] and patients could be included within 48 h of their strategy for sepsis. High-dose selenium supplementation plus standard
sepsis diagnosis. Two editorial comments on the EXIT-SEP study therapy was associated with a lower occurrence of ventilator-associated
underscored its significance but also highlighted the limitations [61,62]. pneumonia (VAP) among 54 patients with sepsis or septic shock, when
EXIT-SEP did not investigate the therapeutic mechanism of XBJI, it is not compared in an RCT with standard therapy without selenium

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Table 1
Highlighted randomized controlled trials on non-conventional immunomodulation in sepsis published over the last 5 years.
Compound Authors Type Location Treatment Study population Sepsis Main outcome Main results
criteria parameters
used

Herbal based medicine

Xuebijing Song et al. Double China; 33 XBJ + standard care Severe CAP N/A PSI score at day 8, 28- All outcomes
[60] blinded hospitals (n = 334) vs. placebo patients day mortality and significantly better in
RCT + standard care (n = duration of mechanical treatment group
331) ventilation and ICU
stay
Liu et al. Double China; 45 XBJ + standard care Sepsis patients Sepsis-3 ICU- and 28-day all- Lower mortality, more
[15] blinded medical (n = 911) vs. placebo on ICU (18 - 75 cause mortality, SOFA ICU- and mechanical
RCT centres + standard care (n = years old) and APACHE II score, ventilation free days in
906) duration of mechanical treatment group
ventilation and ICU
stay
Shenfu Wang et al. Double China; 1 Shenfu + standard Septic shock Sepsis-3 Sublingual Somewhat improved
[64] blinded hospital care (n = 20) vs. patients on ICU microcirculation, microcirculation at
RCT placebo + standard (18 - 80 years inflammatory plasma certain time points,
care (n = 20) old) markers, vital and lab lowered inflammatory
parameters and SOFA markers and some
score improved clinical
outcomes in treatment
group
JinHong formula Wu et al. Double China; 1 JHF + standard care Sepsis patients Sepsis-3 SOFA score, 28-day all- Significantly lower
[69] blinded hospital (n = 66) vs. placebo + on ICU and ED cause mortality, length mortality and SOFA
RCT standard care (n = 48) (18 - 80 years of hospital stay and score on day 7 and 15 in
old) inflammatory plasma treatment group
biomarkers

Immunonutrition

Selenium Guo et al. Double Germany, Intravenous selenium Severe sepsis Sepsis-1 Plasma cytokine levels No difference in
[79] blinded 1 hospital (n = 40) vs. placebo patients on ICU in ex vivo stimulated cytokine levels between
RCT (n = 36) blood groups
Nano-curcumin Karimi Double Iran, 2 Oral nano-curcumin Sepsis patients Physician Inflammatory Significant
et al. blinded hospitals (n = 20) vs. placebo on ICU diagnosis biomarkers, improvement in
[88] RCT (n = 20) endothelial markers inflammatory end
and clinical outcomes endothelial markers,
decrease in SOFA score
and duration of
mechanical ventilation
in treatment group
Vitamins Cherukuri Double USA, 1 Vitamin A (n = 32) vs. Sepsis patients Unknown Blood stream No significant
et al. blinded hospital placebo (n = 32) on the ICU infection, length of differences between
[90] RCT ICU stay, ventilator groups
requirement and
vasopressors

Sedatives

Dexmedetomidine Hughes Double USA, 13 Dexmedetomidine Mechanically Sepsis-3 Delirium and No significant
and propofol et al. blinded hospitals sedation (n = 216) vs. ventilated sepsis ventilator free days, differences between
[105] RCT propofol sedation (n patients on the cognitive function groups
= 216) ICU after 90 days, and
mortality
Ohta et al. Open- Japan, 8 Dexmedetomidine Mechanically Sepsis-1 Inflammatory plasma Improved CRP, PCT and
[104] label hospitals sedation (n = 100) vs. ventilated sepsis markers, mortality, albumine levels in
RCT non- patients on the albumin levels and treatment group
dexmedetomidine ICU coagulopathy
sedation (n = 101)

Temperature management

Temperature Drewry Open- 1 hospital, External warming + Mechanically Sepsis-3 Monocyte HLA-DR Lower 28-day mortality,
management et al. label USA standard therapy (n = ventilated sepsis expression, CD3/ more hospital free days
[113] RCT 28) vs. standard patients on the CD28-induced IFN-γ at 28 days in active
therapy (n = 28) ICU with production, mortality, warming group
temperature and 28-day hospital-
<38.3 ◦ C free days

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CAP, community-acquired pneumonia; CRP, C-reactive protein; ED, emergency depart­
ment; ICU, intensive care unit; IFN-γ, interferon-γ; JHF, JinHong formula; HLA-DR, human leukocyte antigen DR; HLJD, HuangLian JieDu; N/A, not applicable; PCT,
procalcitonin; SOFA, Sequential Organ Failure Assessment; RCT, randomized controlled trial; USA, United Stated of America; XBJ, Xuebijing.

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supplementation [18]. It did not, however, reduce cytokine levels or augmented production of anti-inflammatory cytokine IL-10 in vitro
28-day mortality among these patients [18]. In a prospective observa­ [98]. Beta-adrenergic stimulation by norepinephrine also diminishes
tional study, a reduction in mortality amongst 72 ICU patients with natural killer cell cytotoxicity and downregulates IL-2 production by
sepsis that received intravenous selenium as part of routine clinical care Th1 cells, thereby skewing the immune response from a Th1 toward a
was seen, when compared to patients receiving placebo [76]. However, Th2 phenotype [99]. In both experimental endotoxemia induced by
these findings are contradicted by a number of studies that did not find intravenous LPS injection in healthy volunteers, and in sepsis patients on
any significant differences in clinical outcome among sepsis patients the ICU, intravenous norepinephrine was associated with
receiving selenium supplementation therapy [16,77-79]. It could be of anti-inflammatory effects. Norepinephrine led to immune paralysis and
importance to consider selenium levels at baseline as selenium-depleted increased bacterial dissemination in a mouse model of sepsis [17].
individuals are in theory more likely to benefit from supplementation Administration of dopamine, another important vasopressor, also has
therapy [74]. been reported to have a dampening effect on the immune response. It
Eicosanoids have been associated with both pro- and anti- has been associated with suppression of neutrophils and reduction in
inflammatory effects in sepsis patients [80,81]. In an RCT among 21 synthesis of cyto- and chemokines, such as IL-6, IL-8 and TNF amongst
ICU patients with systemic inflammatory response syndrome (SIRS) and others in vitro and in vivo [100].
a suspected infection, administration of omega-3 fatty acids was asso­ Several sedatives have also been reported to have immunomodula­
ciated with marked suppression of the plasma concentrations of tory effects, which has led to the term immunosedation [101]. In a
pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-10 and TNF [81]. In murine model of abdominal sepsis dexmedetomidine reduced TNF, IL-6,
another RCT, it was also demonstrated a marked decrease in IL-6 and splenic caspase-3 expression (a marker for apoptosis), and mortality,
IL-10 levels after administration of fish oil in 25 patients, admitted to the when compared to saline control [102]. This effect seemed to be
ICU with SIRS and an infection, compared to patients receiving usual mediated through activation of α2 receptors, since concomitant
parenteral nutrition. Furthermore, the treatment group had a signifi­ administration of α2 antagonists mitigated the anti-inflammatory effects
cantly shorter length of hospital stay and an improved gas exchange on of dexmedetomidine [101]. Subsequent RCTs evaluating dexmedeto­
the ventilator [82]. Among ARDS patients, enteral feeding with fatty midine in sepsis patients yielded conflicting results, however. In 63
acids and antioxidants also improved gas exchange and length of ICU sepsis patients admitted to 2 ICU in the Unites States of America (USA),
stay [83]. The safety of administration of omega-3 fatty acids and its patients receiving dexmedetomidine were at a lower risk of death at 28
effectiveness in reducing biochemical inflammation markers has been days and had more delirium/coma- and ventilator free days, compared
demonstrated in several other studies as well [84,85]. to patients receiving lorazepam as a sedative [103]. Also, CRP and PCT
Nano-curcumin is the modified form of curcumin in which curcumin levels were lower in patients treated with dexmedetomidine [104].
particles have been converted in the form of small particles for better However, in a large RCT conducted in 13 centres in the USA, no sig­
delivery, solubility and absorption; curcumin is a substance in turmeric, nificant difference was found in delirium- and ventilator free days,
a member of the ginger family [86]. Administration of nano-curcumin cognitive function and mortality between 422 mechanically ventilated
has been associated with reduced levels of procalcitonin (PCT) and sepsis patients receiving dexmedetomidine versus propofol sedation
TNF, lower duration of mechanical ventilation and reduced Sequential [105]. Propofol has been associated with anti-inflammatory effects due
Organ Failure Assessment (SOFA) scores among ICU patients with sepsis to disability of the innate immune system through impairment of
[87,88]. Large-scale research investigating the effect of nano-curcumin neutrophil and macrophage function mostly [106]. In vitro [107] and in
administration in sepsis patients is however lacking. Vitamin A and D vivo models, using rabbits [108], have shown that propofol might have a
have been investigated in several trials among patients with sepsis but negative influence on bacterial clearance in the lung and spleen, which
have not yet yielded any significant result in terms of improved clinical would seriously limit its potential therapeutic implication in sepsis [107,
outcomes [89–91]. Amino-acid enriched nutrition has also been inves­ 108].
tigated for its immunomodulatory effects. Among elderly patients with Lastly, management of body temperature has immunomodulatory
sepsis (APACHE II score of 16–28), supplementation with glutamine has effects as well, but its potential role in sepsis management is not clear. A
been associated with a reduction in C-reactive protein (CRP) and total lower body temperature upon hospital presentation is associated with
lymphocyte count and an increase in HLA-DR expressing CD14 positive higher mortality among sepsis patients whilst fever is associated with
monocytes [92]. These results were not reproduced in a cohort of reduced mortality [19,109,110]. In a retrospective analysis among 525
moderately ill ICU patients with sepsis (APACHE II score of 10–20), sepsis patients on Dutch ICUs, of which 186 had hypothermia (tem­
wherein glutamine did not reduce inflammatory markers in a conclusive perature <36 ◦ C), hypothermia was associated with higher mortality at
way [93]. Vitamin C exhibits various biological actions, such as several time points, higher occurrence of acute kidney injury (AKI), and
anti-inflammatory and immunomodulatory effects, which could offer higher concentrations of fractalkine, an endothelial-cell-derived che­
potential advantages in the treatment of sepsis. Nevertheless, extensive mokine, but no substantial difference in other host response biomarkers
RCTs investigating vitamin C’s use in sepsis patients have been negative was found [111]. Gao et al. divided a cohort of Chinese sepsis patients
(reviewed in more detail elsewhere [94–96]). on the ICU with a body temperature >39C into a low- and
high-temperature group (target temperatures of 36.5–38 ◦ C vs.
3.3. Immunomodulatory effects of supportive treatment with 38.5–39.5 ◦ C respectively). Target temperatures were actively achieved
vasopressors, sedatives and temperature management resulting in lower levels of pro-inflammatory cytokines (IFN-y, PCT, IL-6
and TNF) in the low-temperature group whilst some anti-inflammatory
Several supportive treatments for sepsis have been found to exert cytokines (IL-4 and IL-10) levels were higher in the low-temperature
potential beneficial effects on immune function. Norepinephrine has group. In the high-temperature group length of ICU stay was signifi­
been associated with both pro- and anti-inflammatory effects, depending cantly lower and mortality showed a lower trend in that group [112].
on the concentration. In low concentrations norepinephrine activates Conversely, Drewry et al. randomly allocated 56 afebrile mechanically
mostly the alpha-adrenoreceptor (α-AR) which has been shown to ventilated sepsis patients in the U.S. to either therapeutic hyperthermia
augment TNF production by macrophages in vitro [97]. In higher con­ (goal temperature 1.5C above lowest temperature measured in 24 h
centrations norepinephrine activates the beta-adrenoreceptor (β-AR), before) or standard-of-care treatment. No differences were found in
leading to potent inhibition of the immune system. By enhancing cAMP monocyte HLA-DR expression or IFN-y production by peripheral blood
levels intracellularly, activation of β-AR receptors leads to inhibition of mononuclear cells between the groups. However, the hyperthermia
nuclear factor k-light-chain-enhancer of activated B cells (NF-kB), group displayed lower 28-day mortality and more hospital-free days at
resulting in reduced synthesis of pro-inflammatory cytokines and day 28 [113]. Although large-scale evidence is lacking, current

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literature suggests that a higher body temperature increases odds of [14] Karakike E, et al. Effect of intravenous clarithromycin in patients with sepsis,
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favourable outcomes among sepsis patients [19,109,110,112,114]. This
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