ISSN 2398-2993      

Systemic inflammatory response syndrome


Synonym(s): SIRS, Sepsis, Septic shock, Multiple Organ Dysfunction, MODS, Endotoxemia


The definitions below have been extrapolated from human medical terminology and are increasingly being used in veterinary literature. The terminology used has been subject to significant change in recent years and this can be confusing when studying the literature.
  • SIRS: systemic inflammatory response syndrome is a condition associated with an exaggerated defense response of the body to noxious stimuli, whereby there is activation of multiple inflammatory pathways. SIRS can be initiated by several conditions, including (but not limited to) gram-positive and negative bacterial products including endotoxin from gram-negative organisms, infection, trauma, surgery, reperfusion, malignancy and burns. The exact terminology used may reflect the presence or absence of underlying infection; whereby SIRS is a clinical manifestation of systemic inflammation resulting from either an infectious insult (septic SIRS) or a non-infectious insult (non-septic SIRS).
  • Sepsis: The distinction between the terms “SIRS” and “sepsis” has been subject to changing terminology over the recent decades but at the time of writing the author understands that “sepsis” is simply SIRS with an underlying infectious insult and therefore the terms “Sepsis” and Septic SIRS may be used interchangeably.
  • Septic shock: a subset of septic SIRS in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients have sepsis persistent hypotension that is unresponsive to fluid resuscitation (or inotrope and pressor administration).
  • Multiple Organ Dysfunction (MODS): the sequelae of systemic inflammation (SIRS) can lead to a syndrome of MODS, characterized by abnormalities in organs that were not affected by the original insult.
  • Endotoxemia: endotoxin is a structural component of the outer cell membrane of gram-negative bacteria. Endotoxin is a potent inflammatory stimulant capable of direct and indirect induction of multiple host inflammatory and immunological processes when released into the circulation. The term “endotoxemia” is now outdated, unless discussing experimental studies and has been replaced by the term SIRS. This is due to the fact that it is the inflammatory response to endotoxin and not the endotoxin per se that causes the clinical signs seen.
  • Bacteremia: presence of bacteria in the blood stream. Bacteria are visible on stained blood smears viewed with a microscope.
  • Pyemia: a type of septic SIRS/sepsis that leads to widespread metastatic abscesses. See Pyemia for further details.



Other risks


It is the response of the individual animal that determines whether sepsis occurs. One animal may show no clinical signs of disease, but their carcass may have multiple abscesses found at meat inspection whereas another, exposed to the same feed, bacteria etc may develop SIRS or sepsis.
  • Systemic circulation of products from both the surface proteins of gram-positive and also gram-negative organisms in the form of lipopolysaccharide (LPS) are a common cause for triggering SIRS.

Bacteria have been found to be the primary cause of sepsis in cattle, with Escherichia coli Escherichia coli the most common bacteria isolated at post-mortem examination.
  • In the case of gram-negative organisms, LPS binds to either lipopolysaccharide binding protein (LBP), which in turn binds to CD14 (macrophage membrane bound endotoxin receptor) or directly to CD14 (skipping the step with LBP).
  • CD14 interacts with another membrane bound protein (MD2) to transfer a signal to Toll like receptor 4 (TLR-4).
  • TLR-4 is a transmembrane spanning receptor that transduces the signal to an intracellular signaling cascade which is comprised of a number of enzymatic steps of various kinases, culminating in the intra-nuclear activation of NF-KB.
  • Once the nucleus is activated transcription of proinflammation genes ensues. Representatives of these genes include TNF-α, IL-1, IL-6, IL-8, Platelet Activating Factor (PAF).
  • The genetic transcription of these proinflammatory cytokines/mediators leads to activation of:
    • The coagulation cascade leading to endotoxin-induced coagulopathies.
    • Systemic inflammation (SIRS) prostaglandin and leukotriene mediated.
    • The complement pathway and macrophage lysis.
  • The cumulative effects of these pathways (most particularly systemic inflammation) are responsible for cardiovascular depression, pulmonary hypertension, and arterial hypoxemia Hypoxemia.
  • These effects can then lead to endotoxin induced decreased tissue perfusion and peripheral hypoxia.
  • Eventually perfusion to major organ systems can be compromised and lead to multiple organ dysfunction syndrome (MODS) and death.
  • Gram-positive bacteria can also activate a similar cascade via their surface proteins, as can viral or parasitic infections.
  • Bacterial components such as peptidoglycan and lipoteichoic acid activate the host defense by engaging pattern recognition receptors (such as NOD-1 and NOD-2) and toll-like receptors (particularly TLR-2) of the innate immune system.
  • TLR-2 is a transmembrane receptor similar to TLR-4 which initiates an intracellular enzymatic cascade that ends with NFkB translocation and subsequent gene expression of proinflammatory cytokines and mediators (TNF-α, IL-1, IL-6, IL-8).
  • Similar to the response seen with gram-negative bacteria, these mediators can lead to cardiovascular depression, pulmonary hypertension, arterial hypoxemia, decreased tissue perfusion, peripheral hypoxia, and ultimately, multiple organ dysfunction syndrome (MODS) and death.
  • In cattle, it is postulated that fatty liver disease Ketosis and fatty liver predisposes to sepsis, as bacteria enters the systemic circulation, rather than the portal circulation and thus bypass the phagocytic action of Kuppfer cells in the liver.


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Further Reading


Refereed Papers

  • Recent references from PubMed and VetMedResource.
  • Adams J (2022) Sepsis in adult cattle. Livestock 27 (4), 158-163 VetMedResource.
  • Constable P D, Trefz F M, Sen I  et al  (2021)  Intravenous and oral fluid therapy in neonatal calves with diarrhea or sepsis and in adult cattle.  Front  Vet  Sci 7, 603358  PubMed.
  • Faridon B S, Zamri-Saad M & Salleh A (2021) A retrospective analysis of the incidence aetiology and risk factors of sepsis based in post mortem examination record in ruminants. Thai J of Vet Med 5 (2) 285-291 VetMedResource.
  • Constable P D et al (2021) Intravenous and oral fluid therapy in neonatal calves with diarrhoea or sepsis and in adult cattle. Front Vet Sci 7 PubMed.
  • Arai  S  (2019) Effect of endotoxemia on rumen motility, abomasal motility and liver function in cattle. Japanese J Large Anim Clin 10  (1), 1-16 CABI.
  • Nabi I, Singh D & Sood N K (2019) A comparative evaluation of different treatment regimens in endotoxemic buffalo calves - A physio-pathological perspective.  J  Biomed  Sci  Engineer  12 (4), 12 SciRes.
  • Smith G (2005) Supportive therapy of the toxic cow.  Vet Clin North Am21  (3),  595-614 PubMed.
  • Pankey G A & Sabath L D (2004) Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clin Inf Dis 38 (6),  864-870 PubMed.
  • Goff et al (2003) Oral glycerol as a gluconeogenic precursor in the treatment of ketosis and fatty liver. Acta Vet Scand 44, 40 ActaVetScandi.
  • Burvenich C et al (2003) Severity of E coli mastitis is mainly determined by cow factors. Vet Res 34 (5) 521-564 PubMed.
  • Andersen P H (2003) Bovine endotoxicosis - some aspects of relevance to production disease. Acta Vet Scand 44, 57 VetMedResource.
  • Andersen P H (2003) Bovine endotoxicosis - some aspects of relevance to production diseases. A review. Acta Vet Scand 98, 141-155 DNB.
  • Fecteau G et al (1997) Use of a clinical sepsis score for predicting bacteremia in neonatal dairy calves on a calf rearing farm. Can Vet J 38 (2), 101-104 PubMed.
  • Shuster R et al (1997) Survey of diplomates of the American college of Veterinary Internal Medicine and the American College of Veterinary surgeons regarding clinical aspects and treatment of endotoxemia in horses. JAVMA 210 (1), 87-92 PubMed.
  • Moore J N (1991) Rethinking endotoxemia in 1991. Equine Vet J 23 (1), 3-4 PubMed.
  • Lavoie J P et al (1990) Hemodynamic, pathologic, hematologic and behavioral changes during endotoxin infusion in equine neonates. Equine Vet J 22 (1), 23-29 PubMed.

Other sources of information

  • Corley K T T & Hallowell G D (In Press) Treatment of Endotoxemia. In: Equine Acute Abdomen. 2nd edn.

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