Treatment of Endotoxaemia and Septicaemia in The Equine Patient

J. vet. Pharmacol. Therap. doi: 10.1111/jvp.
12329
REVIEW ARTICLE
Treatment of endotoxaemia and septicaemia in the equine patient

A. H. WERNERS
Department of Anatomy, Physiology and
Pharmacology, School of Veterinary
Medicine, St. Georges University,
True Blue Campus, St. Georges, Grenada,
West-Indies
Werners, A. H. Treatment of endotoxaemia and septicaemia in the equine

patient. J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12329.
Endotoxins, constituents of the cell wall of gram-positive and gram-negative
bacteria, regularly result in severe illness and death in horses. In endotoxaemia, these constituents are present in the systemic circulation; in septicaemia, whole microbes invade normally sterile parts of the body. Interaction
of these endotoxins with pathogen recognition receptors leads to an inflammatory response that cannot always be sufficiently contained and hence
needs direct treatment. Over the last decennia, our understanding of the
pathophysiology of endotoxaemia and septicaemia has significantly increased.
Based on improved understanding of the interaction between receptors and
endotoxins as well as the subsequent downstream signalling pathways, new
therapeutic targets have been identified in laboratory animal species and
humans. Important species differences in the recognition of endotoxins and
pathogens by their receptors as well as the inflammatory response to receptor
activation hamper extrapolation of this information to the horse (and other
species). Historically, horses with endotoxaemia and septicaemia have been
treated mainly symptomatically and supportively. Based on the identified
therapeutic targets, this review describes the current knowledge of the treatment for endotoxaemia and septicaemia in the horse with reference to the
findings in other animal species and humans.
(Paper received 22 October 2015; accepted for publication 2 May 2016)
Arno H. Werners, Department of Anatomy, Physiology and Pharmacology, School
of Veterinary Medicine, St. Georges University, True Blue Campus, St. George,
Grenada, West-Indies. E-mail: awerners@sgu.edu
INTRODUCTION
Endotoxins play a pivotal role in many pathophysiological
states and diseases in horses and foals. Often times, they are
the leading cause of severe illness and death in this animal
species (Moore & Barton, 2003). Endotoxaemia refers to the
presence of endotoxins (constituents of the cell wall of gramnegative and gram-positive bacteria) in the systemic circulation; during septicaemia, microbes invade normally the sterile
parts of the body leading to systemic illness (Lever & Mackenzie, 2007). Gram-negative and gram-positive bacteria may be
equally important in disease pathogenesis (Cohen & Abraham,
1999), as has been shown in equine neonatal septicaemia
(Corley et al., 2007; Russell et al., 2008), as well as in adult
horses (Johns et al., 2009). Because the largest body of evidence comprises studies on the treatment of LPS-mediated disease and gram-negative sepsis, this review will mainly address
the treatment modalities for the effects gram-negative bacteria
and LPS cause in horses and other animal species. Pathogens
and pathogen-associated molecular patterns (PAMPs) implicated in endotoxaemia and septicaemia are recognized by an
extensive group of pathogen recognition receptors (PRRs)
2016 John Wiley & Sons Ltd
present on phagocytic cells. Important species differences in

the recognition of PAMPS by these PRRs have been described
(Bryant & Monie, 2012; Irvine et al., 2013). Activation of
PRRs by PAMPs triggers the production of pro- and antiinflammatory mediators as well as initiating an adaptive
immune response (Werners & Bryant, 2012). PRRs reside on
the cell surface, in the endoplasmic reticulum, endosomes,
lysosomes, endolysosomes or the cytosol. Receptor activation
requires different subsets of extracellular and intracellular
(adaptive) proteins, followed by intracellular signalling cascades, including nuclear factor-jB (NF-jB), mitogen-activated
protein kinase (MAPK) and interferon regulatory factor (IRF)
pathways, ultimately leading to the production of a plethora
of pro- and anti-inflammatory mediators (Bentley et al., 2002;
Werners et al., 2005).
Treatment of endotoxaemia and septicaemia in the horse has
been focussed on the prevention and treatment of the inflammatory response (Sykes & Furr, 2005). In humans and mice,
treatment strategies explore a variety of (molecular) targets
(Fig. 1) that might prove beneficial in horses (ONeill et al.,
2009). This review describes the therapeutic targets and treatment modalities for endotoxaemia and septicaemia in equine
1
2 A. H. Werners
medicine, with reference to the findings in other animal species

and humans.
Therapeutic interventions at the ligand level
Pathogen-associated
molecular
patterns:
antibody
strategies. Immunoglobulins (IgG and IgM) bind and neutralize
LPS in many species. The immune complexes activate the
complement pathway, bind to cellular receptors and are
cleared in different organs (Buttenschoen et al., 2010).
Antibodies against LPS are directed against the O-antigen
(strain specific), the inner core of LPS or lipid A (broad crossreactivity). WN1 222-5, a monoclonal antibody against the
core region of LPS, prevents the binding of E. coli, Salmonella
spp. and Shigella spp. LPS to TLR4 in a dose-dependent
manner, blocking fever in rabbits and lethality in mice (Di
Padova et al., 1993). In a randomized, double-blind, placebocontrolled trial in humans, antilipid A antibodies only
demonstrated beneficial effects in patients with sepsis and
gram-negative bacteraemia (Ziegler et al., 1991). Follow-up
studies reported no improvement in mortality rates in human
patients suffering from gram-negative bacteraemia or septic
shock (McCloskey et al., 1994). Anti-O-polysaccharide
monoclonal antibodies protected mice against a challenge with
virulent Salmonella Typhimurium (Colwell et al., 1984) as well
as Pseudomonas aeruginosa peritonitis (Sawada et al., 1987).
E. coli O111-mutant J5 polyclonal sera resulted in reduced
mortality in human patients with gram-negative septicaemia
and septic shock (Ziegler et al., 1982), but these findings could
not be reproduced (Calandra et al., 1988). Studies in the horse
evaluating the use of both antilipid A and anticore LPS
antibodies show similar contrasting results. The in vitro effects
of equine-derived anti-LPS hyperimmune plasma on three
strains of gram-negative bacteria resulted in bacterial cell
membrane destruction shortly after bacterial agglutination
(Gaffin & Wells, 1987). Treatment of neonatal foals suspected
of septicaemia with antiserum to core lipopolysaccharide or
with Salmonella Typhimurium antiserum had no beneficial
effects on survival rates (Morris & Whitlock, 1987) or on
clinical
and
haematological
parameters
in
horses
experimentally challenged with LPS (Durando et al., 1994).
However, in horses with evidence of endotoxic shock, the
application of hyperimmune anti-LPS core antigen plasma
decreased the mortality rate significantly (Spier et al., 1989). A
more recent experimental study showed no evidence of
improvement of clinical signs, but was able to demonstrate
reduced TNF-a bioactivity (Forbes et al., 2012). Vaccination of
ponies using a murine anti-idiotypic antibody that shares an
epitope with lipid A proved to be safe, but no significant
increase in antilipid A antibodies could be detected in the
vaccinated ponies (BonenClark et al., 1996). Immunization of
horses with the J-5 mutant of E. coli O111:B4 (Ziegler et al.,
1982), and the R595 mutant of Salmonella Minnesota, resulted
in an increase in antibody titres against core LPS, without any
effect on the in vitro production of thromboxane A2 or PGI2
(Morris & Moore, 1989). The administered dose of the
antibody might have played a role in the efficacy of the

particular antibody; different doses might have led to more
beneficial effects (Table 1 contains a current list of therapuetics
used in the horse and their dosage).
LPS neutralizing agents: polymyxin B. The first reports on the
protective role of the cyclic cationic peptide antibiotic polymyxin
B studied the inhibition of LPS-induced complement activation
in chick embryos (Rifkind & Palmer, 1966) and lethality in mice
(Rifkind, 1967). In the following decades, the role of polymyxin
B in endotoxaemia has been studied intensively in different
species (van Miert & van Duin, 1977; From et al., 1979; Hughes
et al., 1981; Durando et al., 1994; Endo et al., 1994).
Polymyxin B interacts directly with the lipid A 2-keto-3deoxyoctulosonate region of the LPS molecule forming a stable
molecular complex (Morrison & Jacobs, 1976). This compound,
however, shows nephrotoxic, neurotoxic and neuromuscularblocking effects in humans and several animal species (Falagas
& Kasiakou, 2006). A new strategy developed in Japan in the
1990s removes circulating LPS externally through its
absorption to polymyxin B covalently immobilized to
polystyrene-derived fibres. The first report investigated the
effects of plasmapheresis over a polymyxin BSepharose column
and was able to demonstrate the protection from leukopenia,
thrombocytopenia and death starting 15 min after the
administration of LPS in a rat model of endotoxaemia (Cohen
et al., 1987). This technique of polymyxin B hemoperfusion has
been proposed to circumvent the adverse effects caused by this
antibiotic (nephrotoxicity and neurotoxicity) (Hanasawa et al.,
1988; Zavascki et al., 2007; Ronco & Klein, 2014) and was
recently followed by the start of a randomized controlled trial in
humans in the USA in 2014 (Klein et al., 2014). In equine
in vivo and ex vivo models of endotoxaemia, polymyxin B caused
a significant dose- and time-dependent decrease in TNF-a release
and residual LPS activity (Parviainen et al., 2001; Barton et al.,
2004). Although the effects were more profound when animals
were pretreated with polymyxin B, beneficial effects were also
observed when polymyxin B was administered 30 min after LPS
challenge (Barton et al., 2004). Concentrations of 5000 and
1000 U/kg body weight polymyxin B i.v. were used in this study
and did not lead to an increase in urinary GGT/creatinine ratio
(Barton et al., 2004). Even when administered every 8 h for 5
treatments at a dose of 6000 U/kg body weight, polymyxin B
did not lead to an increase in urinary GGT/creatinine ratio
(Morresey & Mackay, 2006). In 3- to 5-month-old foals,
polymyxin B decreased the synthesis of TNF-a and IL-6 and
improved the clinical parameters when administered before an
LPS challenge (Durando et al., 1994). To minimize the adverse
effects of PMB, a polymyxin Bdextran 70 conjugate was used in
a mouse model of gram-negative infection as well as in LPSinfused horses (Bucklin et al., 1995; MacKay et al., 1999).
Conjugation to dextran will reduce toxicity, but will retain the
LPS binding ability of polymyxin B. In both mice and horses
pretreated with this conjugate, the LPS-induced changes for
several clinical and chemical parameters could be completely
blocked. The polymyxin B concentrations used to bind LPS are
Treatment of endotoxaemia and septicaemia in the equine patient 3
considerably lower (25 times) compared to the dose used to

treat bacterial diseases in humans. This might explain the
absence of adverse effects in the horse. It, however, remains of
critical importance to monitor the kidney function in dehydrated
patients and patients that already have compromised renal
function when polymyxin B is part of the treatment protocol.
The value of polymyxin B in the treatment for carbapenamaseproducing bacterial infections in humans warrants a careful
selection of individual equine patients in which polymyxin B is
used. The extracorporal removal of LPS through external
filtration over a polymyxin B-impregnated column might prove
beneficial in horses and circumvent both the adverse effects of
the drug and concerns regarding the development of
antimicrobial resistance.
Toll-like receptor 4 antagonists. Antagonism at TLR4 is
challenging because of the species specificity in lipid A
recognition. LPS from Rhodobacter sphaeroides is a TLR4
antagonist in humans and mice, but an agonist in horses and
hamsters (Lohmann et al., 2003). E5531, a synthetic compound
based on the lipid A structure of Rhodobacter capsulatus, is an
antagonist in mice, humans and equine cell models, but an
agonist in an equine whole-blood model (Bryant et al., 2007).
Eritoran (E5564) is a potent antagonist of LPS in humans
(Rossignol & Lynn, 2002) and in horses (Figueiredo et al.,
2008). The compound has successfully undergone phase I and
II clinical trials in humans; in phase III clinical trials however, it
did not meet its primary endpoint (reduced 28-day mortality)
after which further investigations were abandoned (Opal et al.,
2013). In the horse, E5564 dose dependently inhibited TNF-a
production and LPS-induced pro-coagulant activity in whole
blood and isolated monocyte models (Figueiredo et al., 2008).
Several other TLR4 antagonists are currently being investigated
for the treatment of different acute and chronic inflammatory
diseases (Svajger et al., 2013).
Inhibition of the nuclear factor (NF-)jB and mitogen-activated
protein kinase (MAPK) signalling pathways
NF-jB-specific oligodeoxynucleotide (ODN) decoys block the
transcription factor activity and have been successfully applied
in various animal models (Zingarelli et al., 2003). Pharmacological agents inhibiting NF-jB function include glucocorticosteroids (Auphan et al., 1995), nonsteroidal anti-inflammatory
drugs (NSAIDs) (Tegeder et al., 2001), phosphodiesterase inhibitors (Liu et al., 2000) as well as natural compounds and
anti-inflammatory cytokines.
Glucocorticoids. Reports on the use of glucocorticoids in
experimental endotoxaemia in horses indicate beneficial effects
of this group of drugs in the treatment of inflammatory
diseases, including endotoxic shock (Frauenfelder et al., 1982;
Milam et al., 1992; Culpitt et al., 2003). Activated
glucocorticoid receptors antagonize the activation of the NF-jB
pathway through de novo synthesis of IjB-a in mice and
cultured murine cells (Auphan et al., 1995). Direct interactions
of the glucocorticoid receptor with NFjB family members p65

and p50 has been described in COS7 cells, F9 cells and HeLa
cells (Scheinman et al., 1995). Dexamethasone and the
glucocorticoid receptor both inhibit the binding of p65, p50
and another NF-jB family member c-rel to DNA in different
in vitro systems (Scheinman et al., 1995; Almawi &
Melemedjian, 2002), blocking the activation of the
transcription of NF-jB-dependent genes (Hayden & Ghosh,
2004).
Dexamethasone inhibits c-Jun phosphorylation induced by
JNK (c-Jun amino-terminal kinase) in vitro, and this effect is
mediated by the glucocorticoid receptor (Hirasawa et al.,
2003). The MAPK p38 is also negatively regulated by glucocorticoids, resulting in phosphatase-mediated destabilization of
the COX-2 reporter (Lasa et al., 2001, 2002). Induction of
MKP-1 and inhibition of its degradation by glucocorticoids are
responsible for the inhibition of extracellular-regulated signalling kinase ERK1/2 (Kassel et al., 2001).
Endotoxaemia and septicaemia are characterized by a transient dysfunction of the hypothalamicpituitaryadrenal
(HPA) axis, defined as an inadequate cortisol response to disease (Peeters et al., 2015). Although there is no such evidence in adult horses, reports in foals confirm the dysfunction
of the HPA axis in hospitalized foals with a prevalence of 40
60% (Hart et al., 2009). Foals with a dysfunctional HPA axis
are more likely to exhibit clinical signs of shock and are less
likely to survive (Hart et al., 2009). The HPA dysfunction
leads to a significantly higher basal cortisol concentration
(Gold et al., 2007; Hart et al., 2011). Based on these findings,
the use of high concentrations of glucocorticoids in foals with
septicaemia needs to be carefully considered. Results from
large intervention studies in humans with septicaemia have
generated conflicting results (Annane et al., 2004; Sprung
et al., 2008), and the cortisol replacement therapy currently
recommended for people and infants with critical illnessrelated corticosteroid insufficiency has not yet been evaluated
in neonatal foals (Hart & Barton, 2011). Dexamethasone
(2 mg/kg i.v.) and prednisolone (10 mg/kg i.v.) administered
to horses 5 min after LPS injection and at 3, 9 and 24 h had
no effect on increased prostaglandin production or on systemic arterial hypotension that occurred in the first 2 h (Templeton et al., 1987). In the same species, insulin sensitivity
significantly decreased after dexamethasone treatment (20 mg
p.o. for 15 days) and was exacerbated by the infusion of LPS,
indicating the potential role glucocorticoids might play in the
development of LPS-induced insulin resistance (T
oth et al.,
2010). In septic children, adjunctive treatment with glucocorticoids did not result in improvement in outcomes (Zimmerman & Williams, 2011). There was no difference between
long-term versus short-term administration of hydrocortisone
in human patients showing a poor response to fluid resuscitation and vasopressors (Huh et al., 2011). Hydrocortisone-treated septic human patients suffered more episodes of
superinfections, new septicaemia and septic shock, although
shock was reversed more rapidly compared to placebo
(Sprung et al., 2008). Others demonstrated improved
4 A. H. Werners
Fig. 1. LPS signalling pathway and the different

therapeutic targets. 1. Antibody strategies (LPS
antibodies against the O-antigen, inner core or
lipid A); LPS neutralizing agents (polymyxin B;
phospholipid emulsions); TLR4 antagonists.
2. De novo synthesis of IjB (glucocorticoids;
b2 agonists). 3. Interference with IjB
phosphorylation and degradation (NSAIDs).
4. Interaction with NF-jB family members
(glucocorticoids; NSAIDs; phosphodiesterase
inhibitors; DMSO; ethyl pyruvate). 5. Inhibition
of translocation of NF-jB into the nucleus and
its interaction with DNA (glucocorticoids;
NSAIDs; phosphodiesterase inhibitors;
ketamine). 6. Inhibition of p38 activity
(glucocorticoids; phosphodiesterase inhibitors;
SB203580). 7. Inhibition of JNK activity
SP600125). 8. Inhibition of ERK activity
PD098059). 9. Inhibitors of mediator synthesis
(cytokine antibodies; TACE inhibitors;
haemofiltration; NSAIDs; ethyl pyruvate).
hemodynamic parameters, inhibition of systemic inflammation

and maintenance of Th1-related immune responsiveness (Keh
et al., 2003). The overall results obtained in clinical trials in
humans and experimental animals are contradictory leading
to debate around the use of this class of drugs in septicaemia
and endotoxaemia (Minneci et al., 2003; Sessler, 2003; Kotsaki & Giamarellos-Bourboulis, 2012). This indicates the need
for more studies into the role of critical illness-related corticosteroid insufficiency in mortality, the selection of appropriate
glucocorticoids, the dose used and the duration of treatment
(Leclerc et al., 2011), as well as a re-evaluation of the usefulness of these compounds in equine endotoxaemia and septicaemia. Reports on the adverse effects of glucocorticoids in
horses are scarce; a report by Simon et al. failed to show toxic
actions of a combination of dexamethasone and prednisolone
in healthy horses (Simon et al., 1990). Although laminitis has
anecdotally been linked with the use of glucocorticoids, the
scientific evidence is still inconclusive (Katz & Bailey, 2012).
Yi et al. (2008) mentioned an increased risk for bacterial
infections after an intravitreal injection of triamcinolone acetonide. Despite the limited numbers of papers describing the
adverse effects of this group of drugs in healthy and diseased
horses, glucocorticoids should still be used with caution in
horses with endotoxaemia and septicaemia.
Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs interfere

with the pathway that leads to phosphorylation and degradation
of the NF-jB inhibitor IjB (Kopp & Ghosh, 1994). Carprofen and
flunixin meglumine inhibit NF-jB translocation in LPSstimulated murine macrophages (Bryant et al., 2003), and
inhibitory effects have also been demonstrated for ibuprofen,
sodium salicylate, aspirin and sulfasalazine in a variety of cell
systems (Scheuren et al., 1998; Wahl et al., 1998; Yin et al.,
1998). The inhibition of NF-jB has not been shown for
indomethacin (Tegeder et al., 2001). The high concentrations of
NSAIDs necessary to inhibit NF-jB activation require cautious
evaluation of these compounds in clinical cases.
Phosphodiesterase inhibitors. The phosphodiesterase enzymes
exist in five distinct classes (IV) (Beavo & Reifsnyder, 1990),
of which phosphodiesterase IV is typically expressed in
lymphocytes and monocytes (Thompson et al., 1976).
Phosphodiesterase inhibitors control the intracellular
degradation of cAMP/cGMP (Haddad et al., 2002a), affecting
the cytokine production through complex mechanisms
involving the regulation of NF-jB signal transduction
pathways (Haddad et al., 2002b). cAMP also activates or
inhibits extracellular-regulated signalling kinase (ERK) in a
cell-dependent manner (Stork & Schmitt, 2002). In a rat model

Table 1. Doses of commonly used treatment modalities in equine endotoxaemia and septicaemia
Compounds
Polymune (Veterinary Dynamics, Templeton,
CA, USA)
Polymune Plus antiendotoxin Ab (Veterinary
Dynamics, Templeton, CA, USA)
Equiplas E (Plasvacc Pty. Ltd., Queensland,
Australia)
Polymyxin B sulphate
Polymyxin Bdextran 70 conjugate

Dexamethasone
Prednisolone
Pentoxifylline
Clenbuterol
Flunixin meglumine
Eltenac
Meloxicam
Etodolac
Phenylbutazone
Dimethyl sulphoxide (DMSO)
Ketamine
Ethyl pyruvate
Phospholipid emulsions
Dose
Foals <25 kg 1 L over the 1st 624 h i.v.
Foals >25 kg 2 L over the first 624 h i.v.
Foals <25 kg 1 L over the 1st 624 h i.v.
Foals >25 kg 2 L over the first 624 h i.v.
Adult horses 2 L over 60 min i.v.
5000 U/kg BWT i.v.
6000 U/kg BWT every 8 h for 5 treatments i.v.
10 000 U/kg BWT i.v.
50 000 U/kg BWT polymyxin B i.v.
2 mg/kg BWT i.v.
10 mg/kg BWT i.v.
7.5 mg/kg BWT bolus injection followed by 1.5 mg/kg/h for
3 h i.v.
7.5 mg/kg BWT bolus injection followed by 3 mg/kg/h for
3 h i.v.
10 mg/kg BWT q12h for 8 days p.o.
0.75 lg/kg BWT i.v. single administration
0.8 lg/kg BWT p.o. single administration
0.25 mg/kg BWT q8h i.v.
0.5 mg/kg BWT i.v. single administration
23 mg/kg BWT q12h i.v.
4.4 mg/kg BWT i.v. single administration
15 mg/kg BWT i.v. followed by 10 mg/kg BWT at 6 h and
10 h i.v.
20 mg/kg BWT i.v. single administration
1 g/kg BWT i.v. single administration
1.5 mg/kg/h i.v.
Loading doses of 4.8; 3.6; 3.0; 2.4 mg/kg/h in 10-min
intervals i.v., followed by a maintenance rate of 1.5 mg/kg/h
for 320 min
150 mg/kg BWT in 1L lactated Ringers solution infused over
60 min
200 mg/kg BWT infused over a 2-h period
100 mg/kg BWT infused over a 30-min period
of
acute
pancreatitis,
pentoxifylline
inhibited
the
phosphorylation of both JNK and ERK1/2 (Pereda et al.,
2004). The effects of pentoxifylline on endotoxaemia and
septicaemia in different animal species were initially described
in the last two decades of the 20th century (Zabel et al., 1989;
Tighe et al., 1990; van Miert et al., 1997; Quezado et al.,
1999). More recent evidence suggests a role of pentoxifylline
in the management of septic shock in people (Coimbra et al.,
2004) and neonatal septicaemia as shown by decreased
mortality and decreased length of hospital stay (Pammi &
Haque, 2015). Pentoxifylline administered before, at the same
time or after LPS resulted in a dose-dependent inhibition of
TNF-a and IL-6 activity in a whole-blood model of equine
endotoxic shock (Barton & Moore, 1994). Only when
administered
before
LPS
stimulation,
pentoxifylline
administration resulted in the inhibition of tissue factor
(Barton & Moore, 1994). When administered to healthy horses
References
Peek et al. (2006)
Peek et al. (2006)
Forbes et al. (2012)
Barton et al. (2004)
Morresey and Mackay
(2006)
Parviainen et al. (2001)
MacKay et al. (1999)
Templeton et al. (1987)
Templeton et al. (1987)
Barton et al. (1997a,b)
Barton et al. (1997a,b)
Liska et al. (2006)
Laan et al. (2006)
Cudmore et al. (2013)
Semrad et al. (1987)
Naylor et al. (2014)
MacKay et al. (2000)
Naylor et al. (2014)
Tomlinson et al. (2004)
King and Gerring (1989)
Burrows (1981)
Kelmer et al. (2008)
Reeves et al. (1990),
Kelmer et al. (2008)
Lankveld et al. (2006)
Alcott et al. (2011)
Schroeder et al. (2011),

Jacobs et al. (2013)
Winchell et al. (2002)
Moore et al. (2007)
at a dose of 7.5 mg/kg bolus injection followed by a threehour infusion of 1.5 mg/kg/h, pentoxifylline resulted in a
transient increase in 6-keto-prostaglandin F1a concentration;
compared to untreated blood, TNF-a concentrations were
significantly inhibited when the blood of these horses was
stimulated with LPS (Barton et al., 1997a). Rectal temperature
and respiratory rate were significantly lower in horses treated
with pentoxifylline (7.5 mg/kg bolus injection followed by the
3-h infusion of 3 mg/kg/h) and challenged with LPS compared
to control horses (Barton et al., 1997b) Combined with
flunixin meglumine, pentoxifylline was more effective in
treating the hemodynamic effects of LPS in horses (Baskett
et al., 1997). Pentoxifylline, however, seems to have dose- and
time-dependent beneficial and deleterious effects in rat, swine
and canine models, respectively (Fletcher et al., 1992; Ridings
et al., 1994; Quezado et al., 1999); despite the decreased TNF-a
production, no effect on survival was observed in a murine
6 A. H. Werners
model of lethal endotoxaemia (Netea et al., 1995). In the

horse, pentoxifylline is rapidly eliminated after intravenous
administration, warranting continuous rate infusion for the
treatment of endotoxaemia (Crisman et al., 1993; Liska et al.,
2006). Absorption after the oral administration is rapid;
effective concentrations of both pentoxifylline and the 5hydroxyhexyl metabolite could be measured in plasma
throughout the 8-day treatment protocol (10 mg/kg q12h)
(Barton et al., 1997a,b; Liska et al., 2006). In dogs however,
continuous rate infusion resulted in an increased mediator
release as a result of delayed LPS clearance (Quezado et al.,
1999). No adverse effects were observed in horses after the
dose of a 7.5 mg/kg bolus injection followed by a 1.5 mg/kg
or 3 mg/kg continuous rate infusion for 3 h (Barton et al.,
1997a,b). Rolipram, a selective PDE-IV inhibitor, regulates
cAMP-responsive element-binding protein (CREB) and p38
phosphorylation in U937 cells (MacKenzie & Houslay, 2000).
Decreased concentrations of TNF-a have been described in
in vitro studies in humans (Semmler et al., 1993; Prabhakar
et al., 1994; Sullivan et al., 1995), a murine model of
rheumatoid arthritis (Ross et al., 1997) and a murine hepatitis
model, including the effects on isolated Kupffer cells (Taguchi
et al., 1999). Rolipram significantly inhibited TNF-a, NO, IL-12
and IFN-c production independent of IL-10 production in
murine endotoxaemia (Hasko et al., 1998) and had an effect
on spontaneous but not formylmethionyl-leucyl-phenylalanine
(FMLP)-stimulated superoxide generation in guinea pig
peritoneal macrophages (Turner et al., 1993). Similarly, in
equine neutrophils, rolipram significantly inhibited the
superoxide formation when stimulated with human
recombinant C5a, but not with zymosan (Rickards et al.,
2001). PDE4 is the main isoenzyme in equine neutrophils and
rolipram inhibits thromboxane production, but had limited
effects on lung function and neutrophil accumulation
(Rickards et al., 2000, 2003). From the available evidence, one
can conclude that both nonspecific and specific inhibitors of
PDE can be beneficial as adjuncts to other therapeutic
modalities in the treatment for endotoxaemia and septicaemia.
Timing, dose and dose interval are important in the efficacy of
pentoxifylline; insufficient information is available on the
in vivo effects of rolipram, including pharmacokinetic and
pharmacodynamic information in horses.
b2-Adrenergic receptor agonists. Activated b2-adrenergic
receptors stimulate adenylate cyclase, converting adenosine
triphosphate (ATP) to cAMP, which in turn activates cAMPdependent protein kinase, resulting in the phosphorylation of a
variety of intracellular proteins (Van Miert, 2002). cAMP
binding to a cAMP-responsive element-binding protein (CREB),
and subsequently DNA results in the regulation of gene
expression with effects on cytokine formation and release
(Parry & Mackman, 1997). The b-agonists regulate NF-jB
activation by increasing cytosolic IjBa that results from a rise
in intracellular cAMP concentration (Farmer & Pugin, 2000).
Evidence in mice, rats and dogs suggests a positive role of b2agonists in septicaemia (Szabo et al., 1997; Deng et al., 2004).
In vitro studies using human peripheral blood mononuclear

cells and porcine alveolar and liver macrophages showed the
suppressive effects of b2-agonists on pro-inflammatory cytokine
production, which coincides with an increase in the release of
the anti-inflammatory cytokine IL-10 (Yoshimura et al., 1997;
Izeboud et al., 2000). In vitro effects of clenbuterol on LPS-,
Aspergillus fumigatus- and hay dust suspension-exposed equine
alveolar macrophages revealed a significant suppression of the
production of TNF-a, but not of IL-1b (Laan et al., 2005). In
horses with recurrent airway obstruction stimulated with LPS
or hay dust, 3 days pretreatment with clenbuterol (0.75 lg/kg
i.v.) resulted in a decrease in the expression of
pro-inflammatory cytokines TNF-a, IL-1b and IL-8 in alveolar
macrophages (Laan et al., 2006). Horses challenged
intravenously with 30 ng/kg LPS and pretreated orally with
clenbuterol (0.8 lg/kg; 2 h prior to LPS injection) showed
significantly
lower
rectal
temperature
and
TNF-a
concentrations compared to controls (Cudmore et al., 2013).
Where in most of the experimental studies b2-agonist are
administered before the onset of endotoxaemia, terbutaline
(0.3 mg/kg i.v.) inhibited TNF-a production in rats even when
the drug was administered 30 min after the induction of
endotoxaemia (Liaw et al., 2003). The described results
warrant further studies into the use of b-agonists in clinical
cases of equine endotoxaemia.
Inhibitors of the mitogen-activated protein kinase (MAPK)
pathway: specific MAPK inhibitors. To date, five distinct groups
of MAPKs have been characterized of which the extracellularregulated signalling kinases 1 and 2 (ERK), c-Jun aminoterminal kinases (JNK) and p38 are the most extensively
studied (Roux & Blenis, 2004). The MAPK p38 plays a role
in LPS-stimulated equine platelets (Brooks et al., 2007), in
equine digital vein endothelial cells (Brooks et al., 2009), in
equine leucocytes (Neuder et al., 2009), in cyclooxygenase
gene expression in equine leucocytes (Eckert et al., 2007) and
is activated in the muscles of horses after submaximal
exercise (van Ginneken et al., 2006). The use of inhibitors of
p38 MAPK resulted in an increased cytokine production in
mouse models of pneumococcal pneumonia and tuberculosis
(van den Blink et al., 2001). In healthy human volunteers,
the p38 inhibitor RWJ-67657 resulted in a dose-dependent
inhibition of TNF-a, IL-6 and IL-8 (Fijen et al., 2001). More
recently, SB203580, a specific p38 MAPK inhibitor, reversed
the effects of LPS on PGE2-, ACh- and KCl-induced duodenal
contractions in a rabbit model (Gonzalo et al., 2010). c-JunN-terminal kinase (JNK) binds to and phosphorylates c-Jun, a
component of the AP-1 transcription complex, playing an
important role in the regulation of cytokine gene expression
(Johnson & Lapadat, 2002). Recent reports describe the
beneficial effects of JNK inhibition on LPS-induced heart
dysfunction in a mouse model (Drosatos et al., 2011), and
the direct anti-inflammatory effects of the JNK inhibitor
SP600125 in an in vitro murine model of Group B
streptococcal infection, including the improved survival in a
mouse neonatal septicaemia model (Kenzel et al., 2006).
Improved survival and reduced expression of JNK, NF-jB,

TNF-a and high-mobility group box-1 (HMGB-1) were
observed in a murine caecal ligation and puncture model
(Pizzino et al., 2015). JNK has been described in osmoticinduced stress in equine spermatozoa (Garcia et al., 2012),
and the up-regulation of JNK1/2 in a carbohydrate model of
laminitis in horses (Gardner et al., 2015). Many authors
described the role of extracellular-regulated signalling kinases
1 and 2 (ERK1/2) in LPS-induced inflammation (Schumann
et al., 1996; van der Bruggen et al., 1999; Roux & Blenis,
2004). In a human monocyte model, the specific (ERK1/2)
inhibitor PD098059 had a stronger effect on ERK2 than on
ERK1 (van der Bruggen et al., 1999) and protected the
medullary thick ascending limb from a decrease in HCO
3
absorption in a murine caecal ligation and puncture model
(Watts et al., 2013). Based on information in humans and
laboratory animal species, especially the inhibition of p38 can
be beneficial in the treatment for endotoxaemia in the horse;
however, information on the effects of p38, ERK1/2 and JNK
inhibition in equine endotoxaemia is currently not available.
Anticytokine therapy
Two meta-analyses of controlled anticytokine trials reveal a
consistent reduction in mortality but only in human patients
with the most severe risk of death (Eichacker et al., 2002; Lv
et al., 2014). Murine monoclonal antibodies against TNF-a
reduced the haematological and clinical responses in horses
given LPS intravenously (Cargile et al., 1995); murine and rabbit polyclonal TNF-a antibodies did not lead to beneficial effects
in horses in vivo, but did decrease equine TNF-a activity
in vitro (Barton et al., 1998). Inhibition of TNF-a-converting
enzyme (TACE) prevents the release of TNF-a from U973 cells
and equine bone marrow-derived macrophages (Wijnker et al.,
2004).
There was no evidence that the extracorporal removal of
cytokines (haemofiltration) in humans with acute renal failure
of septic and cardiovascular origin, or in horses with experimentally induced endotoxaemia, achieved a reduction in
plasma concentration of cytokines (Heering et al., 1997; Veenman et al., 2002). When administered to mice, the spin-trap aphenyl-N-tert-butylnitrone (trapping of reactive oxygen species)
significantly improved survival (Miyajima & Kotake, 1995)
and, in the horse, resulted in decreased heart rate and respiratory rate following the LPS challenge (Harkins et al., 1997).
Despite the promising preclinical testing, anti-inflammatory
agents designed to inhibit the specific host mediators during
septicaemia failed to show convincing clinical effects (Eichacker
et al., 2002). This can be explained by the fact that the host
inflammatory response becomes pathogenic in severe septicaemia and septic shock (Minnich & Moldawer, 2004; Vilcek &
Feldmann, 2004) and that the effectiveness of the different
agents is related to the patients risk of death (Minneci et al.,
2003). Hence, the relationship between risk of death and the
choice of the right therapeutic protocol should be taken into
account in future investigations.
Inhibition of mediator synthesis, conventional anti-inflammatory

therapies
Nonsteroidal anti-inflammatory drugs. Early investigations
showed a significant decrease in prostaglandin production in
horses treated with 15 mg/kg phenylbutazone 30 min before a
LPS challenge (Burrows, 1981). In the horse, a small dose of
flunixin meglumine suppresses the production of thromboxane
B2, 6-keto-PGF1a and lactate. Reduction in the clinical signs of
endotoxaemia by flunixin meglumine was dose dependent
(Semrad & Moore, 1987), and combined with pentoxifylline,
the effects of flunixin meglumine were more profound (Baskett
et al., 1997). The use of eltenac significantly protected horses
against LPS-induced changes in clinical, haematological and
biochemical parameters (MacKay et al., 2000). The effects of
NSAIDs on the equine intestines have been extensively
reviewed by Little et al. (2007) and Marshall and Blikslager
(2011), and a detailed description of these effects is beyond the
scope of this review. Flunixin meglumine and etodolac inhibit
the restoration of the normal barrier function of the equine
jejunum after an ischaemic insult (Tomlinson et al., 2004),
suggesting the restricted use of these agents in colic patients
suffering from ischaemic bowel disease. Meloxicam showed
significantly better recovery rates compared to flunixin
meglumine (Little et al., 2007). Meloxicam resulted in
significantly increased neutrophil counts and flunixin
meglumine lead to an enhanced pain relief in horses with
strangulating small intestinal lesions (Naylor et al., 2014). The
clinicians in this study were not blinded, the doses used
exceeded the labelled doses and the numbers of horses and
diverse character of their condition makes comparison with
other studies difficult. The COX-2 inhibitor deracoxib did not
impair the recovery of intestinal barrier function in ischaemic
equine jejunum in vitro (Tomlinson & Blikslager, 2005), but
evidence in human medicine suggests a possible exacerbation
in clinical signs during the progressive stages of septic shock
(Schildknecht et al., 2004). Although there is currently no
evidence of the benefits or potential deleterious effects of COX-2
inhibitors in horses with endotoxaemia or septic shock, the
above-mentioned concerns in humans warrant a thorough
investigation into the potential use of selective COX-2
inhibitors in horses.
When used in critically ill horses, NSAIDs primarily affect
the gastrointestinal mucosa and the kidneys. An in-depth discussion on the adverse effects is beyond the aim of this manuscript; the reader is referred to the recent review by Cook &
Blikslager (2015).
Dimethyl sulphoxide (DMSO). Although not supported by
scientific evidence, dimethyl sulphoxide (DMSO) has been
extensively used by equine clinicians (Shuster et al., 1997).
Pretreatment with a high dose of DMSO had minimal effects
on the clinical signs of LPS-challenged horses, but significantly
decreased fever (Kelmer et al., 2008). DMSO modulated NF-jB
and decreased mRNA expression of cytokines IL-6, TNF-a,
macrophage inflammatory protein 1-a (MIP1-a) and MIP1-b in
8 A. H. Werners
LPS-treated murine macrophages (Kelly et al., 1994). In rats,

DMSO reduced LPS-induced pulmonary dysfunction through a
protective effect on pulmonary capillary endothelial cells
(Breen et al., 1983) and decreased the activation of both NFjB and AP-1, as well as the inhibition of septicaemia-induced
ICAM-1 mRNA expression in peritonitis-induced septicaemia
(Chang et al., 2001). These results could not be repeated in
other species. DMSO prevented the ischaemia/reperfusioninduced increased vascular resistance (Arden et al., 1989), but
had no effect on ischaemia/reperfusion injury in the equine
jejunum (Horne et al., 1994), or the large colon (Reeves et al.,
1990). The results indicate that DMSO has no major beneficial
effects in horses with endotoxaemia.
Ketamine. The dissociative anaesthetic agent ketamine downregulates LPS-induced NF-jB signalling in human glioma cells,
in equine macrophages in vitro (Sakai et al., 2000; Lankveld
et al., 2005) and in intact mouse brain cells in vivo (Sakai
et al., 2000). LPS-challenged and healthy horses, dogs and
mice administered subanaesthetic concentrations of ketamine
did not show adverse effects (Sakai et al., 2000; Lankveld
et al., 2006; Alcott et al., 2011). No changes in plasma TNF-a
or TXB2 concentrations were observed in LPS-challenged
horses receiving ketamine (Alcott et al., 2011), in contrast to
the findings in rats where LPS-induced cytokine response,
hypotension and metabolic acidosis were inhibited by
pretreatment with ketamine (Taniguchi et al., 2001). In LPStreated dogs, ketamine resulted in a blunting of the plasma
concentration of TNF-a, but had little effect on haemodynamic
stability or WBC counts (DeClue et al., 2008). The
pharmacokinetic results from a 1.5 mg/kg/h CRI dose of
ketamine in healthy horses (Lankveld et al., 2006) and the
in vitro results in a equine bone marrow-derived macrophages
(Lankveld et al., 2005) indicate the potential beneficial effects
of ketamine as an adjunct therapeutic in the prevention
and/or treatment of endotoxaemia. Because the plasma
concentration obtained after the anaesthetic dose of ketamine,
used in the induction of general anaesthesia, exceeds the
effective dose reported in the in vitro studies, it is likely that
the induction of anaesthesia with ketamine contributes to the
control of endotoxaemia and septicaemia.
Ethyl pyruvate. Reactive oxygen species have been implicated
in septicaemia, septic shock and small intestinal ischaemia in
the horse (Maranon et al., 2009). Ethyl pyruvate inhibits the
formation of reactive oxygen species and interacts with NF-jB
subunits p65, p50 and RelA in murine macrophages (Han
et al., 2005; Mizutani et al., 2011). In the same experimental
set-up, ethyl pyruvate had no effect on the degradation of I-jB
and p50 binding, but significantly inhibited the binding of p65
to DNA (Han et al., 2005). Ethyl pyruvate, more stable and
lipophilic than pyruvate, has proven efficacy in ischaemia/
reperfusion intestinal injury models in rats (Sims et al., 2001),
lethal septicaemia and systemic inflammation in mice (Ulloa
et al., 2002), systemic inflammation and organ damage in pigs
(Dong et al., 2010) and in in vitro and in vivo models in the
horse (Cook et al., 2011; Jacobs et al., 2013). In LPSmodulated equine monocytes, ethyl pyruvate down-regulated
TNF-a, IL-8 and COX-2 expression, but not IL-6 or IL-1b (Cook
et al., 2011). No significant effects on physical examination
parameters, electrocardiograms or clinicopathological variables
were observed in healthy horses given ethyl pyruvate. Whole
blood from horses that received ethyl pyruvate was stimulated
with LPS, resulting in a significant reduction in TNF-a, IL-1b
and IL-6 gene expression at 6 h following the LPS
administration (Schroeder et al., 2011). In horses challenged
with LPS, flunixin meglumine significantly decreased pain
scores between 30 and 180 min after the start of flunixin
meglumine infusion; ethyl pyruvate inhibited pain scores at
30 min. Ethyl pyruvate decreased and flunixin meglumine
increased IL-6 gene expression; ethyl pyruvate and flunixin
meglumine inhibited TNF-a gene expression after 120 min
(Jacobs et al., 2013).
Phospholipid emulsions. Phospholipid emulsions change serum
lipoprotein concentrations in septic and endotoxic human
patients (Levels et al., 2003) and high-density lipoproteins
neutralize LPS (Levine et al., 1993). Phospholipid emulsions
(92.5% soya phospholipid, 7.5% soya triglyceride and 18 mM
sodium cholate) revealed no significant adverse effects in
humans. Three different doses (75, 150 and 300 mg/kg)
administered to healthy volunteers resulted in lipid levels
expected to protect against the effects of bacterial endotoxins
(Gordon et al., 2003). A dose of 200 mg/kg over a two-hour
period to LPS-challenged horses resulted in decreases in rectal
temperature, heart rate, pulmonary arterial pressure and TNFa concentrations. Starting two hours after the end of the
phospholipid emulsion, haemolysis was observed (Winchell
et al., 2002). Lower concentrations of the phospholipid
emulsion and a shorter infusion time resulted in similar
haemolytic responses, decrease in TNF-a concentrations and
clinical responses in horses that received LPS (Moore et al.,
2007). Studies in equine monocytes showed a decrease in the
cytokine production and a decrease in the cellular expression
of tissue factor (Moore et al., 2007). In contrast to the equine
studies, phospholipid emulsion infusion in human volunteers
resulted in a significant decrease in IL-6 concentrations
(Gordon et al., 2005). Phospholipid concentrations of 500 mg/
dL or higher resulted in the greatest effects in the study
subjects (Gordon et al., 2005). This concentration has not been
achieved in the horse studies and could be the reason why an
effect on IL-6 concentrations was not observed in the equine
studies. Phospholipid emulsion infusions of up to 1200 mg/kg
over a 2-h period were safe in pigs. An increased survival rate
and an improved cardiopulmonary function were observed in a
porcine peritonitis model (Goldfarb et al., 2003).
Conclusions and future perspectives. Despite an increased
understanding of the pathophysiology of endotoxaemia and
septicaemia in equine and other patients, reports on and trials
of a variety of anti-inflammatory agents have only shown
limited beneficial effects that were often not (clinically)
significant. Species differences in pharmacokinetics and

pharmacodynamics, as well as the differences in
pathophysiology, will have to be taken into account when new
treatment modalities are considered for use in the horse.
Investigations into the species-specific pharmacokinetics and
pharmacodynamics should be performed for proper inclusion
into the therapeutic protocol. All in all, the treatment of the
equine patient with clinical signs of endotoxaemia starts with
aggressive supportive care. Many of the therapeutic agents
described in this review can play a role as adjunct treatment
to those veterinary medicinal products currently in common
use to treat the endotoxic or septic patient. Conventional
therapy, consisting of supportive fluid therapy, and the
administration of NSAIDs can best be combined with ethyl
pyruvate, b-agonists or low doses of ketamine as a continuous
rate infusion in the postoperative care of horses with
endotoxaemia or septicaemia. Polymyxin B as well as
polymyxin B haemoperfusion should be considered in the early
phases of the condition.
ACKNOWLEDGMENT
The author would like to express his gratitude to Dr. D. Stone
for her critical evaluation of the manuscript.
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Treatment of Endotoxaemia and Septicaemia in The Equine Patient

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J. vet. Pharmacol. Therap. doi: 10.1111/jvp.

Treatment of endotoxaemia and septicaemia in the equine patient

Werners, A. H. Treatment of endotoxaemia and septicaemia in the equine

present on phagocytic cells. Important species differences in

medicine, with reference to the findings in other animal species

antibody might have played a role in the efficacy of the

Treatment of endotoxaemia and septicaemia in the equine patient 3

considerably lower (25 times) compared to the dose used to

of the glucocorticoid receptor with NFjB family members p65

Fig. 1. LPS signalling pathway and the different

hemodynamic parameters, inhibition of systemic inflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs interfere

Treatment of endotoxaemia and septicaemia in the equine patient 5

Polymyxin Bdextran 70 conjugate

Dimethyl sulphoxide (DMSO)

Schroeder et al. (2011),

model of lethal endotoxaemia (Netea et al., 1995). In the

In vitro studies using human peripheral blood mononuclear

Treatment of endotoxaemia and septicaemia in the equine patient 7

Improved survival and reduced expression of JNK, NF-jB,

Inhibition of mediator synthesis, conventional anti-inflammatory

LPS-treated murine macrophages (Kelly et al., 1994). In rats,

Treatment of endotoxaemia and septicaemia in the equine patient 9

significant. Species differences in pharmacokinetics and

2016 John Wiley & Sons Ltd

broadly cross-protective monoclonal antibody binding to Escherichia

2016 John Wiley & Sons Ltd

Treatment of endotoxaemia and septicaemia in the equine patient 11

2016 John Wiley & Sons Ltd

by extracorporeal hemoperfusion with polymyxin B immobilized

2016 John Wiley & Sons Ltd

Treatment of endotoxaemia and septicaemia in the equine patient 13

2016 John Wiley & Sons Ltd

2016 John Wiley & Sons Ltd

Treatment of endotoxaemia and septicaemia in the equine patient 15

2016 John Wiley & Sons Ltd

Werners, A.H., Bull, S. & Fink-Gremmels, J. (2005) Endotoxaemia: a

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