Sepsis can lead to the death of an animal if undiagnosed or insufficiently treated. Recording of cases that die as a result of known sepsis out in the field is limited because of a lack of diagnosis as there is a lack of a defined criteria on how to define the disease. One retrospective study by Faridon et al (2021) found that 38.6% of large ruminants submitted to the Post-Mortem Laboratory, University Putra Malaysia died as a result of sepsis. Reading around the subject area, it appears that whether an animal develops sepsis is determined by the individual rather than the cause or site of the infection.
It is vital for the veterinary surgeon to recognise the clinical signs of sepsis, if possible, and pre-empt the effects of an infection if the animal is to survive. Treatment is time costly and by no means successful, something clients need to be aware of as euthanasia may be appropriate if proper treatment is not attempted. There is no set treatment for septicaemia, with the aims being to dampen down the immune response, support the circulatory system, and to remove the infection that has triggered this response. Supportive care is essential and farm staff must be aware of the signs of deterioration of a case, and when they need to call the veterinary surgeon, so that further treatment options or euthanasia can be advised.
What is sepsis?
Sepsis is a known or suspected infection leading to systemic inflammatory response syndrome (SIRS) that is characterised by alterations in body temperature, heart rate, respiratory rate, and leukogram parameters, although this statement is commonly challenged for being ‘too broad’. Two of these findings are sufficient to confirm SIRS (Smith, 2015). Sepsis is commonly thought to be a consequence of Gram-negative infections which in turn lead to endotoxaemia, but sepsis can be a consequence of any bacterial, viral or parasitic infection. Even when Gram-negative bacteria are the cause, Andersen (2003), states that a failure to detect endotoxins in the blood of clearly sick cows has frustrated many researchers and it has been questioned whether the presence of endotoxaemia is necessary for the development of endotoxicosis. What we know is that it is the response of the individual that determines when sepsis occurs and this highlights the importance of doing a thorough clinical examination when determining if sepsis is present, and whether the animal is entering/has septic shock, which is a true emergency because of the speed with which the disease can kill. We also know, from research done by Milner (1973), that tolerance occurs if a cow is exposed to endotoxin in sublethal doses, either repeatedly or continuously, for a period of time.
Causes of sepsis
For sepsis to occur, a pathogen must be present (or suspected to be present) in the bloodstream of an animal to trigger the inflammatory cascade. The retrospective study by Faridon et al (2021) found bacteria to be the primary cause of sepsis in large ruminants, with Escherichia coli the most common bacteria isolated at post-mortem examination.
In adult cattle, these bacteria may have stemmed from a local site of infection (e.g. traumatic reticulo-peritonitis, mastitis, metritis, cellulitis) or be a consequence of ruminal dysfunction. Faridon et al (2021) identified the gastrointestinal tract (GIT) as the primary site for bacterial invasion of the bloodstream. This would point to high producing cattle (dairy cows and feedlot cattle) being more predisposed to sepsis because of the nature of their diets predisposing them to bouts of rumenitis. E. coli is the most common pathogen isolated in metritis and mastitis, common diseases of dairy cows, providing a focus of infection that can then seed around the body. But Credille et al (2014) found that bacteraemia was just as common in healthy cows as those with acute puerperal metritis so bacteraemia does not always mean clinical disease. 60% of feedlot cattle are found to have liver abscesses at post-mortem examination, but many will never have been septic. So what determines when bacteraemia leads to sepsis? The answer is not clear but underlying disease, pathogen load, and individual susceptibility appear to be relevant factors in the development of sepsis.
Looking at the example of coliform mastitis, it is cow factors more than the pathogenicity of the bacteria that determines the severity of the disease (Burvenich et al, 2003). Effective elimination of the pathogen, predominantly by neutrophils, is important for the resolution of infection and the outcome of E. coli mastitis, and cows post calving have been found to have reduced neutrophil function. Bacterial load also appears to be proportional to the extent of the disease seen (Burvenich et al, 2003). But Brennecke et al (2021) found that bacteraemia rarely occurs in cows with severe mastitis, so what triggers SIRS in these animals?
When bacteria from organs such as the uterus and the udder enter the systemic circulation rather than the portal circulation, they avoid the phagocytic actions of the Kuppfer cells in the liver (Figure 1). This is true of cows suffering from liver disease, a common problem in the post-partum cow because of excessive mobilisation of non-esterified fatty acids (NEFAs) in the face of insufficient food intake coupled with excessive body condition score. The build-up of fat molecules in the liver impairs hepatic function which is associated with a decreased capacity for endotoxin clearance in the liver, as demonstrated by Andersen et al (1996), where endotoxin was administered to cows with spontaneously developed subclinical fatty liver, leading to an increased frequency of toxaemia. In these circumstances the liver cannot produce sufficient acute phase proteins necessary to fight off infections. The liver plays an important part in removing infections from the blood stream that originate from the intestines, and this has already been stated as the primary site from which sepsis originates in large ruminants. The negative effects of NEFAs and ketones on the physiology functions of individual animals are not discussed in this article but they do appear to be significant factors in the down-regulation of a cow's immune system, and could therefore be a contributing factor to whether systemic disease does occur.
If dealing with a case in a lower production environment (where GIT dysfunction, pathogen load and concurrent disease would be less of a risk), then concurrent disease such as bovine viral diarrhoea virus (BVDV), infectious bovine rhinotracheitis (IBR), and malnutrition should be considered as they may have predisposed the animal to a systemic infection.
Glossary
- Bacteraemia — presence of viable bacteria in the circulation, with or without clinical signs.
- Endotoxaemia — bacterial death or proliferation of Gram-negative bacteria, which release lipopolysaccharide (LPS), often known as endotoxin, into the circulation with resulting clinical signs. This is a subset of sepsis.
- Septicaemia — the systemic effects of any circulating microorganisms and their products.
- Sepsis — clinical evidence or suspicion of an infection coupled with the presence of a systemic inflammatory response syndrome (SIRS) that is characterised by alterations in body temperature, heart rate, respiratory rate, and leukogram parameters. Two of these findings is sufficient to confirm SIRS (Smith, 2015).
- Multiple organ dysfunction (MODS) — dysfunction of two or more organs in severe sepsis/septic shock, and it is associated with increased mortality in humans.
- Septic shock — the inflammatory cascade leads to vasodilation of the circulatory system leading to lack of venous return and the animal likely dying as a result of the shock. Please be aware that some veterinary papers define sepsis purely based on clinical signs, even if no cause is ever diagnosed, as opposed to human medicine papers that require a pathogen to be diagnosed for sepsis to be confirmed.
Diagnosis
Sepsis is diagnosed based on clinical evidence or suspicion of an infection coupled with the presence of SIRS that is characterised by alterations in body temperature, heart rate, respiratory rate, and leukogram parameters. Two of these findings is sufficient evidence to confirm SIRS (Smith, 2015). In other words, a thorough clinical examination should be sufficient to diagnose sepsis, and continued examinations are required to monitor any deterioration of a case.
History taking may provide some pointers to a potential diagnosis with signalment of the animal indicating the likely diet and other pre-existing stressors the animal is under, which may affect its response to an infection. Learning if there have been previous septic cases on a farm and the response of animals to treatments given, maybe based on previous cultures done, will help to determine the treatments given. The farmer may already have identified an infection in an animal and commenced treatment, but if the parameters are deteriorating, indicating that the animal may be entering septic shock, then fluid therapy is needed.
While in the pen note food and water sources and if intakes can be gauged; the author often finds that sick cow pens tend to have the worst water access and a knocked over bucket would indicate no water intake. Ask how long an animal has been in a pen and if any faecal piles can be attributed to that animal; if so, note number, size and consistency as potential indicators of anorexia, depression and/or gastrointestinal disturbance.
The author can find no universal septic scoring method to be used in adult cattle, but Pardon and Deprez (2018) review those recommended in calves with no firm conclusions over which of the methods suggested ought to be employed. Cattle with early signs of moderate and severe endotoxicosis have reduced urination, defaecation and salivation, with scleral injection seen in calves (Fecteau et al, 1997). The heart rate can increase up to twice the initial rate and the respiratory rates can increase by 3–4 times in those with experimentally induced endotoxicosis (Andersen, 2003).
The only conclusion made was that those with focal infections were more prone to developing sepsis, highlighting the importance of udder and uterine examination. When examining the animal, it is useful to have the farmer in earshot so that the clinical findings can be communicated and markers confirming deterioration of the case identified. Mentation should be observed to gauge potential severity of disease, with obtundation and stupor possibly as a result of changes in perfusion of the forebrain because of hypotension and increased viscosity of blood. In human medicine, a sequential organ failure assessment score (SOFA) was introduced to identify those that need urgent treatment; low blood pressure, high respiratory rate and altered mentation in the presence of a known infection were seen as needing urgent treatment. Successful treatment should alleviate these signs so act as useful markers for clients to monitor treatment success assuming concurrent metabolic disease is also no longer present. The d-lactate acidosis which results in such marked depression in calves is not such an issue in adults.
It is important to record accurate heart rate and respiratory rate data so that these can form the baseline of monitoring treatments if you or a colleague returns to re-assess the case. Not knowing the normal heart rate of an individual, coupled with no practical way of measuring the blood pressure, can make interpretation difficult but the author would suggest that cows with heart rates over 80 beats per minute (bpm) should be viewed with caution and not assumed to be healthy. Tachycardia does not diagnose sepsis in an infected animal, as electrolyte derangements are likely in periparturient and acidaemic animals, but may be a pointer of a developing process. Low peripheral temperature would add weight to the case for reduced perfusion of an animal. A case of pneumonia would fulfil the definition of sepsis as written above, so attempt to rule this in/out as a diagnosis while being mindful that a cow with sepsis will be tachypnoeic as a result of hypovolaemia, metabolic acidosis and pain to varying degrees. Septic animals are prone to developing pneumonia, meaning that if this disease is diagnosed in an animal with a known infection at another site in the body, then sepsis should be assumed. Fever is not a consistent finding, with the initial fever only lasting about an hour, with a second peak 4 hours later depending on the dose of endotoxin (Andersen, 2003).
The GIT is the other common entry point for infection so thorough assessment is needed, with reduced rumen contraction frequency, length and strength more pronounced than that of an animal that has been inappetent for a day or two. Faecal output will be initially reduced at the onset of enteritis and acidosis because of toxin release or a sudden increase in volatile fatty acids, and there may be a history of intermittent scouring if rumen dysfunction has been an ongoing problem. Prostaglandins affect the tonus and motility of the GIT, although the administration of non-steroidal anti-inflammatory drugs (NSAIDs) does not prevent GIT stasis because of other inflammatory mediators such as cathecholamines and kinins having similar effects. The cause may not be apparent, but any degree of acidosis or enteric disease will lead to enterocyte damage, which allows bacteraemia to develop. The health of the individual will then determine the extent of disease seen.
Haematology is not always consistent and must be interpreted while looking at the whole clinical picture. Leukopenia is proportional to dose of endotoxin, with leucocytosis following as the host mounts an immune response (Smith, 2015). Neutropenia with a left shift is found in acute infections, especially those caused by Gram-negative bacteria leading to sepsis. Despite respiratory distress, metabolic acidosis has only been observed in cases of experimentally induced endotoxicosis in cows suffering from hepatic lipidosis (Andersen et al, 1996). Development of metabolic alkalosis is a much more consistent pattern because of hypochloraemia caused by chloride trapping in the atonic forestomachs (Andersen et al, 2003).
Hypocalcaemia is a common finding, not surprising if the case concerns a peri-parturient cow; displaced abomasums are a common finding in sick cattle in the peri-parturient period and may reflect a high level of sub-clinical hypocalcaemia in the herd. Anderson (1996) found that cattle with endotoxicosis are hypocalcaemic as a result of lipolysis when calcium is adhered to the adipocytes and the effect of the absorption of GIT endotoxin. Procalcitonin, is a biomarker looked for in humans to differentiate sepsis from inflammation; this prohormone of calcitonin would account for why septic patients tend to be hypocalcaemic. On biochemistry, increases in renal and hepatic markers are likely to be raised because of reduced perfusion leading to organ dysfunction, damage to the tissue cells by the endotoxins and infiltration of the liver with lipid molecules.
Treatment
Sepsis therapy has three priorities:
- Immediate stabilisation of the patient (airway breathing and circulation)
- Removal of bacteria from the bloodstream as soon as possible
- Treatment of the original focus of infection (Pardon and Duprez, 2018).
Fluid therapy is essential to restore circulation volume, which will allow pH and electrolyte derangements to be corrected. Oral fluid therapy in an animal with forestomach atony will not be sufficiently fast enough at restoring the circulation. It is not practical to rehydrate a cow with 10% dehydration, so hypertonic saline is a time- and cost-effective option; the fluid may have some acidifying effects, but adult cattle tend to be alkalotic, so this is not a concern. Giving 2–4 ml/kg of hypertonic saline over a 15-minute period will allow fluid to be drawn into the circulation by osmosis and has been shown to increase renal removal of lactate (Constable et al, 2021). In cattle with ruminal acidosis, intravenous administration of 3 litres of 8.4% hypertonic sodium bicarbonate solution is preferable to giving hypertonic saline (Constable et al, 2021).
Oral rehydration should follow once hypertonic solutions have been given intravenously (IV) — avoid giving plain water as this can lead to hyponatraemia as a result of translocation of water from the forestomach into the extracellular space. All oral fluids need to contain sodium, potassium and chloride ions. Ideally calcium should be given too but avoid combining with phosphate salts as these can precipitate and prevent uptake in the rumen. Sodium prevents potassium uptake from the rumen so it may be worth separating administration of these electrolytes. Up to 60 litres of fluid can be given as a bolus and Constable et al (2021) recommend mixing this with 250 g NaCl. If you choose to use commercially available electrolyte powders then dose as instructed. Ideally warmed fluids should be given to prevent cold shock to ruminal microorganisms, and hypothermia and hypoventilation to the patient.
Removal of the infection from both the bloodstream and the focus of infection is the next priority. Smith (2015) advises uterine lavage using warm saline as a treatment for metritis, with care needed not to perforate the uterus. Evidence as to the benefit of stripping mastitic quarters in order to remove the pathogens is minimal; giving these animals oxytocin prior to stripping the quarters may be detrimental to the animal, so is not advised. In terms of systemic antibiotics, Pardon and Duprez (2018) recommend using a product that can be administered IV because of the faster increases in blood concentrations. A broad-spectrum antimicrobial is advised as a bacterial culture is time consuming and can yield negative results despite obvious infections. It is a good idea to culture (both blood and from the focus of infection) these animals to help determine which antibiotics to use if presented with further cases, and to aid in the prevention of disease within the population. Trimethoprim-sulfadiazine (TMPS) is the primary choice for sepsis in cattle, with broad spectrum beta-lactams as secondary choice (Pardon and Duprez, 2018). Treatment should be carried out for 7–10 days to remove the focus of infection and prevent other foci of infection forming in other organs such as the liver. Be aware of any previous resistance noted on the farm when choosing which antimicrobials to utilise.
If the bacteria cannot be removed from the blood stream then NSAIDs are vital to help mitigate the effects of the bacteria. NSAIDs are essential to stop the release of the inflammatory mediators which lead to forestomach stasis and the vasodilatory effects which lead to hypovolaemic shock. Flunixin meglumine abolishes endotoxin-induced reticulorumen stasis, tachycardia, and synthesis of arachidonic acid metabolites (Eades, 1993). Steroids are not considered useful as their main function is to slow the formation of cytokines, and this has likely already happened in animals that present with sepsis. Removal of the inflammation by the NSAIDs provides analgesia to the patient, which will hopefully encourage the animal to eat and drink.
The article discusses hypocalcaemia as a problem in septic animals, which leads to forestomach stasis, and is a likely reason for displaced abomasums seen in animals in recovery. Hypocalcaemia is commonly seen in animals with naturally occurring coliform mastitis, but IV administration of 40% calcium borogluconate is contraindicated in these cases. Administer calcium sub-cutaneously to be safe or give oral boluses. These do rely on the forestomach being able to absorb the calcium and peripheral circulation being effective enough to absorb a sub-cutaneous source.
This article also discusses the negative effects of hepatic lipidosis on the ability of an individual to counteract the toxins. The author does measure NEFAs in nearly all sick peri-parturient cows to gauge the extent of liver compromise and to give an idea of prognosis. Glycerol enters the gluconeogenic pathway at the level of dihydroxyacetone phosphate and 3-phosphoglyceraldehyde (Goff and Horst, 2003). This is several biochemical steps closer to glucose than the traditional gluconeogenic precursors, propionate and propylene glycol, so is beneficial in animals with sub-optimal liver function. In these cases where liver function has been affected, administration of propylene glycol may be less effective than a glycerol-based energy supplement.
KEY POINTS
- There is no one cause of sepsis in adult cattle, but bacteria account for most cases, with most of these infections originating from the gastrointestinal tract.
- Animals that may be compromised as a result of chronic disease, or acute metabolic disease, are more susceptible to becoming toxic.
- You cannot predict how an individual cow will respond to an infection and if they will become septic, hence the need for close monitoring of animals with a known infection.
- Treatment consists of reversing the effects of shock, meaning that intravenous and oral fluid therapies are essential, as well as anti-inflammatories and treatment to remove the infection if it is known.
Conclusion
Sepsis in adult cows in likely a more common occurrence that we think, as a result of infections of the uterus and udder, coupled with impaired liver function and a degree of rumentitis. No clear framework has been written to determine if a cow is or is not suffering from sepsis, but any rapid deterioration in an animal with a known infection, with reduced mentation, reduced urination, and increased respiratory rate seen as key clinical signs of sepsis. These signs should be noted and acted on, even if infection is detected on clinical examination. Therapies should be intense and focus on fluid therapy, NSAID administration and treatment of the infection. Post sepsis, displaced abomasums and liver abscesses are seen as likely sequalae.