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# Comparison of six crossmatch test methods for establishing blood transfusion incompatibility in cats

Alexandra Nectoux

► To cite this version:

Alexandra Nectoux. Comparison of six crossmatch test methods for establishing blood transfusion incompatibility in cats. European Veterinary Emergency and Critical Care Congress, Jun 2019, Tallin, Estonia. 2019. hal-05079711

HAL Id: hal-05079711

https://hal.science/hal-05079711v1

Submitted on 22 May 2025

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# Contents

<table><thead><tr><th></th><th>Tutor</th><th>Page no.</th></tr></thead><tbody><tr><td colspan="3"><strong>THURSDAY REFRESHER</strong></td></tr><tr><td>Enteral nutrition: time to get it right</td><td>Barfield</td><td>1</td></tr><tr><td>Parenteral nutrition</td><td>Adamik</td><td>4</td></tr><tr><td>General management of the intoxicated patient: what is the evidence</td><td>Dörfelt</td><td>8</td></tr><tr><td>Non-steroidal anti-inflammatory drug toxicity</td><td>Lynch</td><td>11</td></tr><tr><td>Gastrointestinal endoscopy</td><td>Willard</td><td>15</td></tr><tr><td>Analgesia for abdominal pain</td><td>Dörfelt</td><td>25</td></tr><tr><td>Hepatic encephalopathy</td><td>Lynch</td><td>27</td></tr><tr><td>When things don't go as planned in transfusions</td><td>Goy-Thollot</td><td>32</td></tr><tr><td colspan="3"><strong>THURSDAY ADVANCED</strong></td></tr><tr><td>Protein losing enteropathy: acute presentation of a chronic problem?</td><td>Salavati</td><td>38</td></tr><tr><td>Acute haemorrhagic diarrhoea syndrome: where are we now?</td><td>Barfield</td><td>42</td></tr><tr><td>Enteral feeding: should we worry about gastric residual volumes</td><td>Chan</td><td>45</td></tr><tr><td>Where did immununnutrition go?</td><td>Chan</td><td>48</td></tr><tr><td>Refeeding syndrome – phantom menace</td><td>Chan</td><td>56</td></tr><tr><td>Probiotics in the ICU with reference to their use in inflammatory bowel disease</td><td>Salavati</td><td>59</td></tr><tr><td colspan="3"><strong>THURSDAY NURSING</strong></td></tr><tr><td>Refreshing GI physiology: a juicy story</td><td>Borgmann</td><td>63</td></tr><tr><td>Dealing with difficult wounds</td><td>O'Dwyer</td><td>66</td></tr><tr><td>It is as easy as ABC: nursing the dog with a GDV</td><td>O'Dwyer</td><td>73</td></tr><tr><td>How to interpret blood gas</td><td>Dodd</td><td>79</td></tr><tr><td>Personal hygiene: new challenges with resistant bacteria</td><td>Kuntz</td><td>82</td></tr><tr><td>Antibiotic stewardship: time for real infection control</td><td>O'Dwyer</td><td>83</td></tr><tr><td>Vascular access: placement and use with less side-effects</td><td>Kuntz</td><td>87</td></tr><tr><td>How to manage the contagious patient: a demonstration</td><td>Borgmann</td><td>88</td></tr><tr><td colspan="3"><strong>FRIDAY REFRESHER</strong></td></tr><tr><td>Top tips for trauma</td><td>Lynch</td><td>90</td></tr><tr><td>Management of the head trauma patient</td><td>Adamik</td><td>94</td></tr><tr><td>Management of potassium disorders in the emergency room</td><td>Hoehne</td><td>99</td></tr></tbody></table>
<table><tr><td>10 things to consider managing septic peritonitis</td><td>Barfield</td><td>105</td></tr><tr><td>How to avoid mistakes in ICU</td><td>Barfield</td><td>108</td></tr><tr><td>Acute abdomen in the ER – initial steps</td><td>Dörfelt</td><td>111</td></tr><tr><td>Imaging: G-I disease shall I bring it to theatre or not?</td><td>Benigni</td><td>114</td></tr><tr><td>Immune mediated haemolytic anaemia: treatment updates</td><td>Lynch</td><td>117</td></tr></table>

## FRIDAY ADVANCED

<table><tr><td>Pancreatitis associated acute kidney injury</td><td>Lynch</td><td>122</td></tr><tr><td>Scil Grant Award Endovascular shedding markers in critically ill patients</td><td>Briganti</td><td>126</td></tr><tr><td>Gastrointestinal bleeding</td><td>Willard</td><td>127</td></tr><tr><td>Raw food diets in the ICU: recipe for disaster</td><td>Chan</td><td>130</td></tr><tr><td>Challenging abdominal imaging cases</td><td>Benigni</td><td>134</td></tr><tr><td>Respiratory endoscopy: when is it an emergency?</td><td>Willard</td><td>137</td></tr><tr><td>An update on hydroxyethyl starch: debate on current use</td><td>Goy-Thollot / Adamik</td><td>141</td></tr><tr><td>Clinical nutrition in the intensive care unit</td><td>Lepp</td><td>149</td></tr></table>

## FRIDAY NURSING

<table><tr><td>Decontaminate: approach to toxicological emergencies</td><td>Yagi</td><td>150</td></tr><tr><td>How to: place and maintain chest drains</td><td>Abreu</td><td>156</td></tr><tr><td>How to place and manage a tracheostomy tube</td><td>Babau</td><td>159</td></tr><tr><td>How to: place and maintain central lines</td><td>Abreu</td><td>164</td></tr><tr><td>How to: place and maintain abdominal drains</td><td>Babau</td><td>168</td></tr><tr><td>Critical care nursing of the GI patient</td><td>Yagi</td><td>172</td></tr><tr><td>What is on the menu: nutritional support of the critical patient</td><td>O'Dwyer</td><td>177</td></tr><tr><td>Why your parvo (and other GI) patients should be fed right away</td><td>Yagi</td><td>182</td></tr><tr><td>Anaesthesia and analgesia consideration for the gi patient</td><td>O'Dwyer</td><td>188</td></tr></table>

## SATURDAY REFRESHER

<table><tr><td>GI motility and ileus in the ICU: should we be worried about it?</td><td>Boysen</td><td>192</td></tr><tr><td>Acute canine pancreatitis</td><td>Willard</td><td>195</td></tr><tr><td>Parvovirus update</td><td>Goy-Thollot</td><td>201</td></tr><tr><td>Imaging of the dyspnoeic cat</td><td>Benigni</td><td>207</td></tr><tr><td>Transfusion: blood compatibility testing</td><td>Goy-Thollot</td><td>210</td></tr></table>

## SATURDAY ADVANCED

<table><tr><td>Haemorrhagic shock: pathophysiology diagnosis and treatment</td><td>Hoareau</td><td>215</td></tr><tr><td>Gastrointestinal microbiome: the forgotten organ</td><td>Cambournac</td><td>220</td></tr><tr><td>Resuscitative endovascular ballon occlusion of the aorta (reboa)</td><td>Hoareau</td><td>224</td></tr><tr><td>Gastrointestinal complications in mechanically ventilated patients</td><td>Hoehne</td><td>227</td></tr><tr><td>Plenary Session</td><td>Starkopf</td><td>232</td></tr><tr><td>Traumatic abdominal injury and surgical management</td><td>Talving</td><td>233</td></tr><tr><td>Extracorporeal therapy: beyond hemodialysis and apheresis</td><td>Hoareau</td><td>234</td></tr><tr><td>Volume assessment: where are we?</td><td>Boysen / Gommeren</td><td>236</td></tr></table>
## SATURDAY NURSING

<table><tr><td>Wellness in your practice and your life</td><td>Dodd</td><td>244</td></tr><tr><td>Mythbusters: ecc nursing myths and facts</td><td>Yagi</td><td>247</td></tr><tr><td>Evidence-based cpr: the recover guidelines</td><td>Yagi</td><td>254</td></tr><tr><td>Road traffic accidents – how can we help?</td><td>O’Dwyer</td><td>260</td></tr><tr><td>Can buster save felix: autotransfusion and xenotransfusion</td><td>Yagi</td><td>266</td></tr></table>

## ABSTRACTS

<table><tr><td>Oral presentations</td><td>272</td></tr><tr><td>Original study posters</td><td>280</td></tr><tr><td>Case report posters</td><td>288</td></tr></table>
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# ENTERAL FEEDING: TIME TO GET IT RIGHT

Dominic Barfield BSc BVSc MVetMed DACVECC DECVECC FHEA MRCVS
The Royal Veterinary College, North Mymms, Hertfordshire, UK

While critically ill patients are often not regarded as in urgent need of nutritional support given their more pressing problems, the severity of their injuries, altered metabolic condition, and necessity of frequent fasting (repeat sedation/general anaesthesia), place these patients at high risk of becoming malnourished during their hospitalization. Identification of these patients and careful planning and execution of a nutrition plan can be key factors in the successful recovery of these patients.

Nutritional status in people is an important determinant of outcome following surgery, with studies showing a clear association between malnutrition and poor clinical outcome. We do not have similar studies in veterinary species and are therefore unsure of this association. That being said malnutrition imparts a similar metabolic effect in animals and it is fair to assume that nutritional support is equally as important. We then need to consider how soon and aggressively we should implement a nutritional plan.

## Metabolic Changes Related to Illness and Disease

Animals requiring surgical interventions may be afflicted with serious conditions. The metabolic responses to illness or severe injury are complex and place these animals at high risk for malnutrition and its deleterious effects. These effects, which are likely to negatively impact overall survival, include alterations in energy and substrate metabolism, compromised immune function, and impaired wound healing. These effects are of particular interest in surgical patients where proper wound healing is of paramount importance.

While generalizations tend to oversimplify complex systems, the concept of “ebb/flow” offers a basic description of the metabolic response to critical illness or severe injury. According to this model, there is an initial hypometabolic response (“ebb phase”), followed by a period of a more prolonged course of hypermetabolism (“flow phase”). The ebb phase is usually a period of hemodynamic instability associated with decreased energy expenditure, hypothermia, mild protein catabolism, decreased cardiac output, and poor tissue perfusion. Without intervention, this may progress to a state of refractory or irreversible shock characterized by severe lactic acidosis, decreased tissue perfusion, multiple organ failure, and death. Nutritional intervention at this stage carries a greater risk of complications such as electrolyte abnormalities, which may result in further detrimental effects to some critically ill animals. Following successful resuscitation, patients enter the flow phase during which profound metabolic alterations occur. Increases in energy expenditure, glucose production, insulin and glucagon concentrations, cardiac output, and profound protein catabolism are the hallmarks of this response. Provision of nutritional support during this stage of illness can attenuate and sometimes reverse the detrimental effects of malnutrition and this forms the basis for perioperative nutritional support. There is some controversy of the applicability of these models of metabolic responses with clinical patients and the ideal timing for initiation of nutritional support in animals has not been determined.
## Nutritional planning in the trauma patient

Trauma patients tend to present acutely and usually do not have other chronic morbidities. So despite their injuries they have a normal nutritional status. However, as previously mentioned, traumatic injury will lead a stressed metabolic condition, whereby the inflammatory response will shift the body towards metabolizing protein rather than fat stores. So what becomes a major decision point is whether a traumatized patient that requires surgery will also require a feeding tube to facilitate nutritional support. Part of this decision will largely depend on the severity and extent of injuries, and whether these injuries will impede the patient from eating adequately postoperatively. For example, a patient with severe facial trauma can be assumed to be at high risk of not eating sufficiently post-operatively. Therefore, placement of an oesophagostomy tube at the time of surgery may be quite useful. However, in a multi-trauma patient that has a prolonged surgery, should one extend the time under anaesthesia for placement of a feeding tube? In patients that are not particularly stable under anaesthesia, delaying the placement of a feeding tube is sensible. Since a cardiovascularly unstable patient will be unlikely be eating in the immediate post-operative period, the placement of a feeding tube could be delayed. How long? Unfortunately, the ideal period for commencing feeding in small animals is unclear but it is likely before the patient becomes catabolic.

## Enteral Nutrition

The enteral route of nutritional support is usually the preferable route. Enteral nutrition is safer and less expensive than parenteral nutrition, and helps to maintain intestinal structure and function. Even with the use of feeding tubes, patients can easily be discharged for home-care with good owner compliance. The majority of complications with feeding tubes include tube occlusion and localized irritation at the tube exit site. More serious complications include infection at the exit site or rarely, complete tube dislodgment and peritonitis if the tube was a gastrostomy or jejunostomy tube. Complications can be avoided by using the appropriate tube, proper food selection and preparation and careful monitoring.

Although the enteral route should be utilised if at all possible there are contraindications to its use. Contraindications include persistent vomiting, severe malabsorptive conditions, and an inability to guard the airway. If the enteral route is chosen for nutritional support, the next step is selecting the type of feeding tube to be used. Feeding tubes commonly used in dogs and cats include naso-oesophageal, oesophagostomy, gastrostomy, and jejunostomy tubes. Once the desired feeding tube is placed, radiography or fluoroscopy should be used to confirm satisfactory tube placement.

Based on the type of feeding tube chosen and the disease process being treated, an appropriate diet should be selected. This will also depend upon the animal's clinical parameters and laboratory results. The amount of food is then calculated and a specific feeding plan devised. Generally, feedings are administered every 4-6 hours and feeding tubes should be flushed with 5-10mL of water after each feeding to minimise clogging of the tube. By the time of discharge however, the number of feedings should be reduced to 3-4 times/day to facilitate owner compliance. Commercially-available veterinary liquid diets should be used for naso-oesophageal and jejunostomy tube feedings. Jejunostomy tubes are primarily for in-hospital use because they require administration of a liquid diet by continuous rate infusion and this technique also requires more vigilant monitoring. Oesophagostomy and gastrostomy tubes are generally larger (> 12 Fr.) and allow for more calorically-dense, blenderised diets to be administered. This decreases the volume of food necessary for each feeding. These tubes
can be used for long-term enteral feeding. A volume of 5-10 mL/kg per individual feeding is generally well tolerated but this may vary with the individual patient. In patients that are generally healthy but cannot consume food orally, e.g., jaw fracture, larger volumes of food per feeding (15-20 mL/kg) may be tolerated. As enteral diets are mostly composed of water (most canned food are already >75% water) the amounts of fluids administered parenterally should be adjusted accordingly to avoid volume overload. Prevention of premature removal of tubes can be accomplished by using an Elizabethan collar and by wrapping the tube securely. Care should be taken to avoid wrapping too tightly as this could lead to patient discomfort and even compromise proper ventilation.

## Monitoring and Reassessment

Body weights should be monitored daily in patients receiving nutritional support. However, the clinician should take into account fluid shifts in evaluating changes in body weight. The use of the resting energy requirements (RER) as the patient's caloric target is merely a starting point. The number of calories provided may need to be increased to keep up with the patient's changing needs, typically by 25% if well tolerated. In patients unable to tolerate the prescribed amounts, the clinician should consider reducing amounts of enteral feedings or supplementing the nutritional plan with parenteral nutrition.

Possible complications of enteral nutrition include mechanical complications such as clogging of the tube or early tube removal. Metabolic complications include electrolyte disturbances, hyperglycaemia, volume overload, and gastrointestinal signs (eg, vomiting, diarrhoea, cramping, bloating). In critically ill patients receiving enteral nutritional support, the clinician must also be vigilant for the development of aspiration pneumonia. Monitoring parameters for patients receiving enteral nutrition include body weight, serum electrolytes, tube patency, appearance of tube exit site, gastrointestinal signs (eg, vomiting, regurgitation, diarrhoea), and signs of volume overload or pulmonary aspiration.

## Summary

Adequate nutrition is still not being delivered in the majority of hospitalised patients and we need to make sure that we consider and implement nutritional support as required.

**Notes kindly reproduced from Prof Dan Chan**

**References available on request**
# PARENTERAL NUTRITION

Katja-Nicole Adamik, PD Dr. med. vet., DACVECC, DECVECC, Vetsuisse Faculty, University of Bern, Switzerland

Initially, the nutritional status of the patient has to be evaluated. During clinical examination, body weight, body condition and muscle mass are evaluated, in addition to the presence of ascites, peripheral oedema, and mucosal or cutaneous lesions. The sick or injured patient will often present with adequate or even excessive fat stores while at the same time have significant muscle wasting. Careful examination is necessary, which involves palpation of skeletal muscle mass over bony prominences, such as the scapulae or vertebral column, to avoid misclassifying the patient as overweight or even obese. Hypoalbuminaemia, anaemia, or low blood urea nitrogen (BUN) levels may occur secondary to malnutrition. Some underlying diseases such as protein-losing enteropathy, protein-losing nephropathy, chylothorax, burns, and draining wounds cause excessive loss of body protein, requiring an aggressive nutrition plan to meet caloric and protein needs.

## Enteral or parenteral nutrition?

Enteral feeding is always the preferred route of feeding, because it is physiologically sound, less costly, and safe. Advantages of enteral feeding include prevention of intestinal villous atrophy, maintenance of intestinal mucosal integrity (decreased risk of bacterial translocation), and preservation of GI immunologic function. However, contraindications for enteral feeding are uncontrolled vomiting, GI obstruction, ileus, malabsorption or maldigestion, or inability to protect the airway (animals in a coma, animals on the ventilator).

In these animals, parenteral nutrition allows provision of nutrients via intravenous administration of variable mixtures of amino acids, lipids, and dextrose, along with vitamins, minerals and electrolytes. Relative contraindications for parenteral nutrition are sepsis, generalized thrombophlebitis, thromboembolic diseases and a functional GI tract. Exclusive use of parenteral formulations for nutritional support should be performed with the understanding of the negative effects on the gastrointestinal barrier function and the development of mucosal atrophy.

## Stepwise parenteral nutritional plan:

### 1. When to start

For acutely ill or injured patients in a good condition, consideration for providing nutritional support should occur within 3-5 days of anorexia. In animals that are more debilitated, are growing, have inadequate muscle mass or adipose stores, that are not expected to consume food voluntarily within the next 2-3 days, or in cats which are at risk of hepatic lipidosis, intervention should be more immediate.

### 2. How much to feed

The caloric goal is the provision of the **resting energy requirement (RER)**. The RER is defined as the amount of energy (calories) needed to maintain homeostasis in the fed state in a thermoneutral environment. Most hospitalized patients are not expending much more energy than RER since they are caged. RER can be calculated by allometric formulas such as (70 x BW in kg)⁰.⁷⁵. An easier formula
is RER = kg x 30 + 70 for dogs and cats. RER for a 6 kg cat is therefore RER = 6 kg x 30 + 70 = 250 kcal/day. "Illness factors" are no longer widely used in critical care nutrition. Overfeeding has risks and should be avoided. It can result in hyperglycaemia and hyperlipidaemia.

### 3. Partial (peripheral) or total (central) parenteral nutrition

Several types of parenteral nutritional solutions are available. They differ in their osmolarity. Total parenteral nutrition (TPN) has an osmolarity of >800 mOsm/L and has to be administered via a large (central) vein because of the risk for phlebitis. Partial or peripheral parenteral nutrition can be given via either a central or a peripheral vein.

### 4. Technical aspects of parenteral nutrition

Regardless of the chosen form of administration (central vs. peripheral), intravenous nutrition requires a dedicated catheter that is placed using an aseptic technique (clip, surgical scrub and placed with sterile gloves). IV sets and extension sets should be changed every 24-48 hours, but otherwise not be manipulated and any disconnection should be avoided (e.g. the fluid bag is not disconnected if the patient needs to be moved or walked). If the parenteral nutrition has to be disconnected (e.g. occlusion of the venous catheter), the complete IV set and extension set have to be renewed and the patient has to be reconnected in as sterile a fashion as possible. An in-line 1.2-micron filter prevents fat embolization if the PN solution contains a lipid component. The fluid rate should be controlled by an infusion pump and parenteral nutrition fluids need to be taken into account when assessing fluid rates. Concurrent administration of other fluids or medications through the same catheter should be avoided, if this is not possible, compatibility must be guaranteed. Opened bags should be used within 24-48 hours and should be labelled with the date and time to ensure that they are discarded after 48 hours along with the entire tubing set. Due to the sensitivity of some nutrients to ultraviolet light, the solution bag and infusion lines should be kept covered. Amino acids and B vitamins are most susceptible to such degradation.

### 5. Composition of the solution

Parenteral nutrition solutions are composed primarily of three base elements: amino acid solution, fat emulsion solution, and glucose (dextrose) solution. In commercially available human parenteral nutrition solutions, total parenteral nutrition solutions contain 40-50% glucose solution as an important component of energy. In contrast, human peripheral/ partial parenteral nutrition contains less concentrated glucose (5-10%). In case of glucose intolerance (hyperglycaemia), partial instead of total parenteral nutrition solution should be administered. However, a higher fluid rate will be necessary to meet the energy requirement, and other fluids need to be reduced. The administration of B vitamins is important. With the exception of a small amount of vitamin B₁₂ in the liver, there is no storage of B vitamins in the body. These are important nutrients for metabolism and efficient use of energy, protein, fat, and glucose. Specific patient needs can be accommodated by adjusting the proportions of calories coming from protein, fat, and carbohydrate. For example "low carb" solutions may be useful for patients with compromised pulmonary function and hypercapnia, and "low prot" solutions are used for patients with hepatic encephalopathy or renal disease. Provided that blood lipid clearance is normal, parenteral fat infusions are generally safe for patients with pancreatitis because exocrine pancreatic stimulation results from nutrients in the small intestine.
The preferred formulation of parenteral nutrition includes the use of *individual* amino acid solutions, lipid solutions, and dextrose solutions. Ideally, parenteral nutrition is adapted to the needs of the individual patient and the compound is freshly prepared in a hospital pharmacy.

The calculation and composition of the desired parenteral solution is carried out as follows:

1. Calculation of energy requirements (RER)

2. Protein requirements: Calculation of energy requirements provided by amino acids:

a. Dogs: 15-20% of total calories should be supplemented with amino acids. The remaining calories are divided 50%:50% between dextrose and fat solutions

b. Cats require 25-35% of total calories as proteins, the remaining calories are given as 60% lipids and 40% dextrose.

3. According to the caloric density of the amino acid solution, the required amount (mL) of the amino acid solution is calculated.

4. Calculation of lipid- and dextrose requirements and calculation of the amount of fluid according to the caloric density of the solution used.

Several commercially available human formulations are available and are appropriate for short-term use in dogs (1-3 days). If using a human commercial product, calories from protein should match species specific protein requirements. If prefabricated formulations are used, the required fluid amount is calculated based on the RER of the patient and caloric density of the solution. The calculated fluid dose may have to be adjusted in order to avoid overinfusion of the patient.

**6. How to start**

There are two reasons for starting slowly and gradually increasing the rate of parenteral nutrition: (1) refeeding syndrome and (2) possible hyperglycaemia. In patients with prolonged anorexia, gastrointestinal compromise, or metabolic derangements, the caloric goal should be achieved over several days. Typical feeding protocols might provide 30% to 50% RER on day 1, with the goal of reaching full RER over the next several days. In stable patients without prolonged anorexia (young, previously healthy dog with polytrauma in which enteral feeding is not possible) it is possible to start with 25% RER for 6 hours, increase to 50% RER in the next 6 hours and increase to 100% thereafter after 24 hours. However, it is important to closely check blood glucose levels to avoid hyperglycaemia. Blood glucose target ranges between 100-250 mg/dL (5.5-13.9 mmol/L).

**7. Monitoring**

Before starting parenteral nutrition: Body weight, Electrolytes: Na, K, P, Mg; blood glucose, haematocrit, albumin, BUN. After start of the infusion: Glucose check every 4h, cardiorespiratory parameters. After full infusion rate is archived, assess at least once daily for 2-3 days: Body weight, electrolytes: Na, K, P, Mg; haematocrit, catheter insertion site (q4h), thoracic auscultation, body temperature.

In addition, perfusion and hydration status must be assessed because, depending on the rate of the parenteral nutrition, the patient may need additional fluid therapy.
## 8. Complications

Complications can be metabolic, mechanical or septic. Mechanical complications of PN include catheter related problems such as catheter occlusion, accidental removal, or line disconnection. If the catheter is not 100% within the vessel, it must be removed and replaced as there is a very high risk for tissue necrosis if the hyperosmolar parenteral fluid is given perivascularly. Thrombophlebitis may manifest as swelling, redness, and pain at the catheter site. The most common metabolic complications are hyperglycaemia, lipaemia, hyponatraemia, and hypokalaemia. Hyperglycaemia is a common complication after initiation of PN, particularly in patients under physiologic stress associated with trauma, surgery and sepsis, as well as in cats. Hypoglycaemia may occur upon abrupt discontinuance of PN, especially if voluntary eating or enteral support is not concurrent with PN withdrawal. TPN should be withdrawn over a 2-3 day period to prevent this complication. Alternatively, dextrose can be added to an infusion of crystalloids. Hypokalaemia, hypophosphataemia, hypomagnesaemia, and thiamin deficiency may occur upon initiation of enteral or parenteral nutrition, especially after a prolonged catabolic state. This condition is termed "refeeding syndrome" and results from a rapid rise in insulin and a shift of plasma potassium, magnesium and phosphates into the intracellular compartment. Thiamin is a co-factor in carbohydrate metabolism. Profound weakness, gastrointestinal ileus, vomiting, diarrhoea, neuromuscular and cardiac rhythm disturbances can result. Hypophosphataemia can manifest as haemolysis. Hypomagnesaemia can result in tetany, seizures, panting, cardiac arrhythmias, and hypertension. Potassium phosphate, potassium chloride, and magnesium sulfate supplementation may be necessary. Hypertriglyceridaemia is seen with insulin resistance and catabolism associated with starvation. An increase in serum triglycerides may overwhelm liver metabolism and lead to steatosis. Hypertriglyceridaemia may require a decrease in parenteral nutrition application or adjustment of the composition of the solution. Other metabolic derangements include hyperammonaemia and bilirubinaemia. The administration of hyperosmolar solutions that are composed of lipid, amino acid and dextrose solutions provides an excellent growth media for bacteria. While PN related sepsis used to be a common complication, strict hygiene and catheter monitoring decreases the likelihood of septic complications to 3-16%. Patients showing clinical signs of infection and sepsis should be actively examined for the likelihood of PN solution contamination or catheter related infection. Cultures of PN solution or catheters should guide antibiotic therapy.

References upon request
# GENERAL MANAGEMENT OF THE INTOXICATED PATIENT: WHAT IS THE EVIDENCE?

René Dörfelt, DVM, Dr. vet. med., DECVECC, DECVAA

Clinic of Small Animal Medicine, LMU Munich, Germany

Suspected and real intoxications are common causes of presentation to the emergency service.

Different scenarios of patient presentation may occur:

* Asymptomatic animals with observed or suspected exposure to toxins

* Symptomatic animals with suspected exposure to toxins

* Symptomatic animals with observed exposure to toxins

For all presentation scenarios, a toxicologic analysis is helpful to identify the toxin. Vomited material, gastric content, urine or serum can be sent in for analysis. It is of high importance to give the toxicologist a detailed history to enable a pre-differentiation of suspected toxins. Analysis usually requires several days. For some common toxins such as ethylene glycol and anticoagulants, point of care tests are available, which help to confirm a suspicion of intoxication in the emergency service.
In patients with known exposure to toxins, the name and amount of the toxin ingested should be evaluated so that the properties of the toxin, such as toxic dose, lethal dose (LD) 50, LD 100, time to symptoms, time to maximal plasma levels, half-life, volume of distribution, water solubility, fat solubility (Log P), molecular weight, and protein binding can be identified.

For asymptomatic patients we should consider decontamination, antidote therapy if available and enhancing excretion if possible.

In symptomatic patients the first step is to triage the patient and treat the most life-threatening symptoms. This is followed by decontamination, antidote therapy and enhancement of excretion of the toxin.

Symptomatic treatment depends on the symptoms. Common signs observed at triage are cardiovascular abnormalities such as shock, bradyarrhythmia and tachyarrhythmia, but also respiratory issues, seizures, anaemia, vomiting and diarrhoea, hyper- and hypothermia, local tissue irritation and pain.

The type of decontamination depends on the contact area. Toxins exposed to the skin should be washed from the skin. It is also helpful to clip the contaminated fur. Usually these toxins are fat soluble. Therefore, washing should be performed using mild shampoo. Toxins leading to local irritation of the oral and oesophageal mucous membranes should be diluted with water. If the toxin is a known acid or base, some mild neutralizing agents such as bicarbonate for acids and citrate for alkalic substances help to decrease further injury. Decontamination should be performed as soon as possible after exposure to minimize tissue damage.

Gastrointestinal exposure can be decontaminated by inducing emesis, performing gastric lavage, or administering activated charcoal.
Efficacy of all decontamination techniques depends on timing, type and formulation of the toxin. Some drugs in liquid or tablet formulation are fully absorbed within a few minutes. For these toxins, decontamination after a few hours is not helpful. Some other toxins such as metaldehyde may stay in the intestinal tract for a longer period, so decontamination may be helpful even hours after exposure. Induction of emesis should only be performed in animals without neurologic symptoms and with intact swallowing reflexes. Inducing emesis is not indicated if acids, alkali substances, alcohol, oily substances or paraffin have been ingested. Using emetics, about 50% of the substance can be retrieved. This also depends on the physical properties of the substance. If it sticks to the gastric wall, often less than 50% of the toxin can be removed. Sometimes it is helpful to feed the patient before inducing emesis.

Emesis can be induced with apomorphine in dogs. It acts at the chemoreceptor trigger zone, and subsequently binds to μ-opioid receptors in the vomiting center and stops vomiting, thus it produces self-limiting vomiting. The effect is faster and shorter after IV application compared to subcutaneous or intramuscular routes. It may cause bradycardia, tachycardia and sedation. The antiemetic effect, but not the cardiovascular effects, can be antagonized by naloxone. Maropitant and metoclopramide will also antagonize the emetic effect. It has also been proven to be effective after conjunctival application, but causes conjunctival irritation via this route.

Hydrogen peroxide ($H_2O_2$) is also effective in inducing emesis in dogs, but may cause bloat and leads to intestinal irritation and mucosal injury. Syrup of ipecac and sodium solutions are not recommended to induce emesis in dogs.

In cats, xylazine is used as a standard emetic drug. The effective dose 50 (ED 50) is 0.27 mg/kg, the ED 100 is 1 mg/kg. With higher doses, the incidence of sedation is high. Subcutaneous and IM application is more effective compared to IV. Alternatively, dexmedetomidine has been used at doses of about 10 µg/kg to induce emesis. The ED 50 and 100 to induce emesis in cats is unknown. The effect can be antagonized with atipamezole.

Activated charcoal adsorbs mostly fat-soluble substances due to the high surface area. It only has a minor effect for alcohol, paraffin and alkalic substances. It decreases intestinal motility and will also adsorb other enterally administered substances and drugs. For some drugs with enterohepatic circulation, elimination can be enhanced by repeated dosing. The effective dose is about 1–4 g/kg. The effect is slightly reduced by adding food to the charcoal. Laxatives, such as sorbitol, added to charcoals shorten the passage time and enhance toxin elimination. The effect of charcoal has not been studied for many toxins. Ideally, one should search for studies on the effect of charcoal on toxin plasma levels in the target toxin and species.

Gastric lavage is often used to decontaminate the GI tract. The substance is often not removed completely. For lavage, the patient should be anaesthetized and intubated. Lavage should be performed with water or isotonic solutions. A volume of 10 mL/kg lavage fluid is recommended, which is infused and drained from the stomach via a large bore tube with a Murphy eye. Adding bicarbonate may increase gastric pH and decrease metabolism of some substances in the gastric acid. Colonic lavage is also helpful to eliminate residual toxins, that may be resorbed in the colon.
For some toxins such as anticoagulants, paracetamol, organophosphate and ethylene glycol, antidotes are available. These should be administered early in the course of treatment.

Elimination of the toxin from the circulation is mandatory if the animal was exposed to toxic or lethal doses of the substance. For small sized, water soluble toxins, fluid diuresis may be helpful. It is often recommended to add a diuretic to improve elimination. The effect of furosemide or mannitol has not been studied for many toxins and remains unclear. Alternatively, these small sized, water-soluble toxins with a low volume of distribution may be removed by haemodialysis or peritoneal dialysis. The effect has been proven for some toxins. Especially for fat soluble substances elimination via charcoal haemoadsorption is possible. In human medicine some of these toxins have also been treated with large bore haemodialysis. Protein bound toxins, such as many NSAIDs, have been successfully removed using plasmapheresis. The type of extracorporeal treatment has to be adapted to the physical properties of the toxins.

Intravenous lipids are commonly used these days to treat severe intoxications with fat soluble toxins characterized with a Log P > 1. There is limited evidence on the effect of IV lipids in animals. Many case reports describe successful management. Metanalysis of experimental studies have proven a positive effect of IV lipids in cardiac arrest due to local anaesthetic intoxication. One prospective study in veterinary medicine has proven a positive effect in cats with permethrin intoxication. Side effects should be kept in mind. Additionally, toxin adsorption can be enhanced with IV lipid treatment if no decontamination has been performed in advance of the application.
# NON-STEROIDAL ANTI-INFLAMMATORY DRUG TOXICITY

Alex Lynch, BVSc(Hons) DACVECC MRCVS

North Carolina State University, Raleigh, NC

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used routinely in human and veterinary medicine as anti-inflammatory, analgesic and antipyretic agents.¹ It is very likely that pet owners will have over-the-counter NSAIDs in their homes for their own use and potentially NSAIDs prescribed for their animals too. Consequently, NSAID intoxication is one of the most common encountered in small animals. This lecture will briefly review pharmacology of NSAIDs, organ system dysfunction associated with toxicity, decontamination strategies for asymptomatic patients, and a review of traditional and novel therapies for NSAID intoxication.

## NSAID pharmacology

NSAIDs are direct cyclo-oxygenase (COX) inhibitors.¹,² Arachidonic acid becomes liberated from plasma membranes following trauma or during inflammation. Arachidonic acid may be converted to a diverse group of chemicals, called eicosanoids, under the action of COX. The eicosanoids represent several chemical groups including prostaglandins, thromboxanes, and leukotrienes. Different isoforms of COX exist and traditionally a distinction has been made between the functions of the COX-1 and COX-2 enzymes. It has been suggested that COX-1 enzymes are primarily 'housekeeping' enzymes, leading to eicosanoid production necessary for maintenance of homeostasis, while COX-2 are inducible enzymes upregulated during periods of inflammation. This distinction is likely an oversimplification but has led to the development of drugs with increased selectivity for COX-2 over COX-1 with the hope of a more favourable safety profile. Aspirin is the prototypical NSAID and is a non-selective, irreversible COX inhibitor. Most modern NSAIDs used in people and animals are reversible and have COX-2 selectivity. Paracetamol (acetaminophen) is sometimes erroneously thought to be an NSAID but is not a COX inhibitor and will not be discussed further in this lecture. Most NSAIDs are absorbed rapidly from the GI tract with peak plasma concentrations typically occurring 2-4 hours after ingestion. They are highly protein bound and therefore have a small volume of distribution. Most NSAIDs undergo extensive enterop hepatic recirculation and undergo glucuronidation in the liver before elimination via the urine. The elimination half lives of NSAIDs are quite variable. Naproxen has the longest half-life in dogs (e.g. 74 hours).¹

## Organ dysfunctions in NSAID intoxication

Most NSAID intoxications occur either when owners intentionally provide NSAIDs to their pets or when animals voluntarily ingest them. The latter may occur especially when pets have access to palatable versions of NSAIDs. The major adverse effects associated with NSAID intoxication are gastrointestinal, renal, haematological, hepatic and central nervous system dysfunctions.

**Gastrointestinal system:** Prostaglandins are needed for gastric mucosal health by promoting mucus production in the stomach and maintaining normal perfusion in the intestines. COX inhibition leads to fewer prostaglandins, impaired mucosal protection and risks gastrointestinal ulceration, especially in the stomach and duodenum. NSAIDs also impair the healing of pre-existing ulcers by limiting perfusion to the region. The consequences of NSAID ingestion are dose dependent and common symptoms include inappetance, vomiting, diarrhoea, melaena, and haematemesis ('coffee grounds' vomitus). If
significant GI losses occur, the patient may become dehydrated and even hypovolaemic, especially if
significant haemorrhage occurs. Acute laboratory changes may include regenerative anaemia with
hypoproteinaemia and elevated BUN relative to creatinine. It is important to realize that the
haematological changes in cases of chronic GI bleeding, for example associated with long term NSAID
usage, are different and typically a non-regenerative microcytic hypochromic anaemia develops.

**Kidneys:** Acute kidney injury is concerning particularly when higher doses are ingested or in patients with pre-existing volume depletion. When there is renal hypoperfusion, glomerular filtration rate is reduced and prostaglandins are released from the juxtaglomerular apparatus. These prostaglandins induce vasodilation of the afferent arteriole thereby maintaining renal blood flow and glomerular filtration function despite volume depletion. COX inhibition limits this renoprotective mechanism and glomerular filtration may drop to dangerously low levels. Pathological lesions associated with NSAID nephrotoxicity include papillary necrosis and interstitial nephritis.

**Haematological:** COX inhibition by NSAIDs will impair thromboxane production, which is an activator of platelets, and therefore NSAID intoxication risks development of platelet dysfunction. Therapeutically aspirin is used for this purpose in patients at risk of or with confirmed thromboembolic disease. Aspirin causes irreversible COX inhibition for the life of the platelet (about one week), whereas newer NSAIDs may induce less pronounced platelet inhibition.

**Hepatic:** Liver injury secondary to NSAID intoxication appears to be relatively uncommon. Some idiosyncratic reactions have been reported in dogs following NSAID ingestion at appropriate doses (e.g. Labradors and carprofen). The potential for hepatotoxicity may be more pronounced if pre-existing liver disease exists.

**Central nervous system:** Various symptoms attributable to CNS dysfunction (e.g. depression, seizures, ataxia) may be seen in animals following NSAID ingestion. In people, aseptic meningitis has also been reported.

Management of NSAID toxicity

Prompt treatment should always be instituted in animals exposed to NSAIDs. Decontamination strategies are appropriate for animals that have recently ingested NSAIDs and have not yet exhibited overt clinical signs. Decontamination strategies usually include administration of an emetic substance (e.g. apomorphine to dogs, dexmedetomidine or xylazine to cats) provided no contra-indication exists (e.g. neurological impairment). After induction of emesis, activated charcoal is usually administered. Conventionally, multiple doses have been given especially in light of the enterohepatic recirculation but single doses may be as effective as multiple.³ After decontamination, forced diuresis with intravenous crystalloids has traditionally been recommended often for prolonged periods of time (e.g. three half-lives of the drug according to some sources). Gastroprotectant medications are also often prescribed, which may include a combination of H₂ receptor antagonists (e.g. famotidine); proton pump inhibitors (e.g. omeprazole); synthetic prostaglandin analogs (e.g. misoprostol), and medications to provide a physical barrier to acid injury (e.g. sucralfate). In cases of clinically relevant anaemia secondary to GI bleeding, packed red blood cell transfusions may be indicated in patients. In some instances, gastric ulcerations may perforate and lead to septic peritonitis, for which exploratory
surgery and antimicrobials will be initiated.

Recently there has been growing interest in alternative means of managing NSAID toxicity. One management strategy involves the administration of intravenous lipid.⁴,⁵ Intralipid therapy has been used in small animals for a variety of lipophilic toxins.⁶ The most widely accepted explanation for lipid therapy, is the creation of a lipid sink within the intravascular space into which lipophilic compounds can become sequestered. Adverse effects of lipid therapy appear rare but may include pancreatitis and volume overload in susceptible patients. While intralipid therapy can be performed in most practices without the need for specialist equipment, the emerging gold standard means of managing NSAID toxicity involves extracorporeal therapies. Traditional haemodialysis is unlikely to be effective as a sole treatment since NSAIDs are highly protein bound and do not readily diffuse across traditional dialyzers well.⁷ A more effective method involves the addition of a charcoal cartridge to a haemodialysis circuit.⁷ These filters enable removal of highly protein and lipid soluble drugs and combined haemoperfusion and haemodialysis has been described in a dog that ingested ibuprofen. An alternative blood purification technique involves therapeutic plasma exchange (TPE) or plasmapheresis. This process involves the separation of the plasma and cellular components of blood, with substances confined to the plasma being effectively removed using an extracorporeal circuit, before replacing the patient's blood with donated plasma or a combination of donated plasma and synthetic colloids. This technique has been used extensively in human medicine for decades and is best suited for toxins with high protein binding and small volumes of distribution. There are reports of several NSAIDs intoxications being successfully treated with TPE in dogs and it appears to be a reliable option even when high doses have been ingested.⁸⁻¹¹ Adverse effects have been reported frequently with the technique although they appear not to impact outcome for patients.

## References

1. McLean MK, Khan SA. Toxicology of frequently encountered Nonsteroidal Anti-inflammatory Drugs in Dogs and Cats: An Update. Vet Clin Small Anim 2018;48:969-984.

2. Borchers A. Non-steroidal anti-inflammatory drug intoxications, in *Textbook of Small Animal Emergency Medicine*. Eds. Drobatz KJ, Hopper K, Rozanski EA, Silverstein D. 2018, pp 856-861

3. Koenigshof AM, Beal MW et al. Effect of sorbitol, single, and multidose activated charcoal administration on carprofen absorption following experimental overdose in dogs. J Vet Emerg Crit Care. 2015;25(5):606-10.

4. Bolfer L, McMichael M, Ngwenyama TR, O'Brien MA. Treatment of ibuprofen toxicosis in a dog with IV lipid emulsion. J Am Anim Hosp Assoc. 2014;50(2):136-140.

5. Herring JM, Mcmichael MA, Corsi R, Wurlod V. Intravenous lipid emulsion therapy in three cases of canine naproxen overdose. J Vet Emerg Crit Care. 2015;25(5):672-678.

6. Robben JH, Dijkman MA. Lipid Therapy for Intoxications. Vet Clin North Am Small Anim Pract. 2017;47(2):435-450.

7. Tauk BS, Foster JD. Treatment of ibuprofen toxicity with serial charcoal hemoperfusion and hemodialysis in a dog. J Vet Emerg Crit Care. 2016;26(6):787-792.

8. Rosenthal MG, Labato MA. Use of therapeutic plasma exchange to treat nonsteroidal anti-inflammatory drug overdose in dogs. J Vet Intern Med 2019;1-7.

9. Walton S, Ryan KA, Davis JL, Acierno M. Treatment of ibuprofen intoxication in a dog via therapeutic plasma exchange. J Vet Emerg Crit Care. 2017;27(4):451-457.
10. Walton S, Ryan KA, Davis JL, Acierno M. Treatment of meloxicam overdose in a dog via therapeutic plasma exchange. J Vet Emerg Crit Care. 2017;27(4):444-450.

11. Kjaergaard AB, Davis JL, Acierno MJ. Treatment of carprofen overdose with therapeutic plasma exchange in a dog. J Vet Emerg Crit Care. 2018;28(4):356-360.
# GASTROINTESTINAL ENDOSCOPY

Michael D. Willard, DVM, MS, DACVIM

Flexible endoscopy is minimally invasive surgery, and as with all surgical procedures, things can go wrong. The problem is that most of the time it is an internist doing the endoscopy, and he/she is not really aware that endoscopic mishaps can be just as life threatening as those that occur with the more classic, "maxi-invasive" surgery. Typically not having possible complications in the forefront of his/her thought, it is easy for the endoscopist not to notice the warning signs that problems are brewing. This often means that when complications do occur, the endoscopist is not prepared to deal with them in an expeditious fashion. Consequently, when things do go wrong, the patient can suffer and/or die.

The main complications that can occur directly as a result of any flexible endoscopy of the gastrointestinal tract are: a) perforation/rupture resulting in septic inflammation and/or accumulation of air in a body cavity, and b) laceration causing severe haemorrhage. There are other complications that are somewhat unique to specific procedures.

# OESOPHAGOSCOPY

Oesophagoscopy is typically done in patients that are also having a gastroduodenoscopy. However, there are some indications for just doing oesophagoscopy. Suspicion of or rechecking known oesophagitis, benign strictures, oesophageal foreign body, tumour and/or hiatal hernia are all potential reasons to do oesophagoscopy without gastroduodenoscopy. Occasionally oesophagoscopy is appropriate to look for Spirocerca lupi infestation and other rare causes of oesophageal disease in pets that are regurgitating. However, oesophagoscopy is seldom useful for evaluating oesophageal motility problems caused by muscular weakness. Oesophageal mucosa is seldom biopsied in dogs unless a mass or an obvious infiltrative lesion is seen. It might be useful to biopsy cats, but that is an area we are now learning about.

The equipment for oesophagoscopy is the same as for gastroduodenoscopy; however, it is generally not as critical to have a small diameter endoscope if one is not interested in entering the pylorus and duodenum. Flexible scopes are typically very superior to rigid scopes when seeking to evaluate the oesophageal mucosa. On the other hand, rigid scopes are much better when trying to remove foreign objects. By using a rigid endoscope, one can use rigid retrieval forceps which allow a firmer hold on objects. However, rigid colonoscopes are not especially long, and it is rare that they can be used to remove foreign objects in dogs that are more than 25 to 30 pounds. Unfortunately, flexible scopes typically must be used in these large dogs.

Preparation is less important as the oesophagus generally does not retain food unless there is weakness or an obstruction, and neither situation is likely to be substantially improved by waiting.

While no special preparation is needed for oesophagoscopy, it is clearly best to avoid barium contrast oesophagrams because they can make the procedure much more difficult.

Anaesthesia is the same as for gastroduodenoscopy. Inhalant anaesthesia is best as it allows one to maintain a patent airway, which is especially important when removing large foreign objects that have
the potential to put pressure on the trachea. In addition, it is important to carefully monitor the patient when using a rigid scope because a malpositioned scope can put too much pressure on the heart, great vessels and airways. The patient is usually best placed in lateral recumbency. If you are using a rigid scope, it is very important to keep the oesophagus as straight as possible. After the patient is adequately anaesthetized, you should pass the scope through a protective mouth gag to the larynx. You must always look through the scope as it is advanced. Air insufflated into the oesophagus can pass into and fill the stomach; therefore, you must be cognizant of the amount of air insufflated. You should keep the center of the oesophageal lumen in the center of the scope's viewing field. Insufflate sufficient air to distend the oesophagus as the tip of the scope is advanced through the cricopharyngeal sphincter and down the oesophagus.

The normal oesophageal mucosa is pale and smooth except just caudal to the cricopharyngeal sphincter; at this point it may be slightly roughened. Submucosal blood vessels can be seen, especially when one is looking at the lower oesophageal sphincter. The distal feline oesophageal mucosa has many small folds. These folds correspond to the site of the herringbone pattern seen on barium oesophagrams. Be sure that you do not over insufflate as you pass the scope through the oesophagus because an excessively distended stomach can put so much pressure on the diaphragm that it becomes difficult for the patient to breathe. In addition to that, over inflation can increase the distance that the tip of the endoscope must travel along the greater curvature as it approaches the pylorus. Thus, excessive distention of the stomach may "make" the scope too short to enter the pylorus. The lower oesophageal sphincter may be open but often appears as a slit. Do not push the scope blindly through this sphincter if it is closed. Instead, you should aim the tip toward the slit and carefully advance it.

## VISUALIZATION PROBLEMS

Sometimes there is so much foam in the oesophagus, stomach or intestines that visualization is significantly impaired. Instilling a solution of 1 part dimethicone or simethicone plus 9 parts water through the biopsy port into the foam will often cause the foam to disappear or at least become thin enough that it can easily be aspirated.

## OESOPHAGITIS

Oesophagitis is usually obvious to the endoscopist. One can typically see erythematous, bleeding and/or ulcerated areas; however, exudate can make it difficult to perceive the ulcerations.

## STRICTURES

Cicatrix (i.e., scarring) may occur after an episode of severe oesophagitis from any cause (including foreign objects). It is particularly easy to miss this problem on a barium swallow if only liquid barium is used. If radiographs using liquid barium are nonrevealing, repeat the study using barium mixed with food, which is more likely to stop at a partial obstruction. Endoscopy is very good at finding these lesions; however, you must keep in mind the size of the patient as you evaluate the oesophageal lumen. A partial stricture will be very obvious in a 5 kg dog or cat but may not be apparent in an 40 kg animal. Balloon-dilatation or bouginage is usually effective; it is also more likely to be successful than surgery and resection of the affected area. In general, surgical resection should be a last ditch resort and only used if oesophageal ballooning or bouginage has failed despite repeated dilatations. However, you must use proper oesophageal balloons because Foley catheters and endotracheal tubes
with inflatable cuffs will often not allow you to dilate a dense or mature stricture. More difficult cases (i.e., those with extensive strictures or with concurrent severe oesophagitis) may benefit from a couple of techniques.

Endoscopic administration of intralesional steroids may help minimize reformation of the stricture. Typically we put 1-2 ml of Vetalog at the site of the stricture either before or after ballooning. Another technique is to make 3-4 equidistant cuts into the stricture using an electrocautery device (i.e., either a snare or a knife) prior to ballooning. This helps the stricture to "break" open at multiple spots with the idea that there will be 3 or 4 smaller, less deep lacerations at the stricture site instead of one major, deep laceration which is more likely to restricture. However, you should not attempt to use cautery through an endoscope unless you have some training lest you cause too much trauma to the tissues or destroy your endoscopic equipment.

Another technique is to "paint" the site where the stricture was broken down with Mitomycin C (NOT mithromycin C, there is a difference). A 5 mg bottle is reconstituted and soaked up into a gauze sponge. Then this sponge is endoscopically placed on the site where the stricture was broken up for 5 min. Then it is flushed off with 60 mL of water.

Finally, for particularly difficult cases, stents may be placed in the oesophagus. These must be sutured in place. The major point to remember is that if an animal starts to have problems days to weeks after anaesthesia, consider strongly the possibility that an oesophageal stricture has developed secondary to oesophagitis. If you are treating an oesophageal stricture, remember that you may need to do 1-15 dilatations. If oesophagitis is diagnosed, you need to treat it aggressively in order to help prevent the stricture from recurring quickly.

## Foreign objects

Foreign objects usually consist of bones but may be rawhide treats, food, dental chew toys, toys, balls, rocks, wood, etc. They usually lodge at the thoracic inlet, base of the heart, or lower oesophageal sphincter. A history of a patient that begins to regurgitate (as opposed to vomit) acutely is very suggestive of acquired oesophageal obstruction due to a foreign object. These patients may continue to drink water, but they typically refuse solid food because the food bolus cannot pass by a partial oesophageal obstruction and causes pain whenever it tries to. A casual, careless history that fails to raise the suspicion of regurgitation will typically lead the clinician to suspect an acute gastritis. However, the realization that the patient is regurgitating (as opposed to vomiting) should be a "red flag". Too often, a pet which has ingested a foreign object is treated conservatively while we wait and see if the supposed gastritis spontaneously resolves. This is problematic because foreign bodies can erode and perforate the oesophagus much quicker than they would stomach or intestines.

Plain radiographs should be performed first. Bones are a common cause of obstruction, and plain films that are made with proper technique and then carefully evaluated are diagnostic in most cases. Remember that poultry bones are not as radiodense as the patient's bones, which means that excellent radiographic technique is required to see them. Foreign bodies in the oesophagus can perfectly mimic pulmonary or mediastinal masses; you often cannot tell the difference with plain radiographs. If poor contrast in the region of the oesophagus, pleural effusion or pneumothorax are seen, one must seriously consider oesophageal perforation and mediastinitis. If plain films are not
diagnostic, then contrast films can be performed. Barium provides better contrast, but iodide is safer if there is an unsuspected perforation. Oesophageal perforation may occur at variable times after ingestion of a foreign object. Even a blunt object, if tightly lodged in the oesophagus, can cause ischaemia and perforation in 2-3 days. The prognosis for animals with oesophageal perforation and severe mediastinitis is guarded to poor, depending upon their condition at the time of diagnosis.

Endoscopy is almost always the preferred method of removing foreign objects, but fluoroscopic and surgical techniques can be effective if the operator is well trained. Rigid endoscopes allow much more control of the foreign object and are preferred to flexible scopes for removal of these foreign objects. It is especially useful to be able to pull the object into a rigid endoscope and then withdraw it and the scope as a unit, thus protecting the oesophagus. The main disadvantage of rigid endoscopes is that they are often not long enough in larger dogs. Finesse is required; brute force can easily lacerate/perforate the oesophagus. If a large object or a bone cannot be easily dislodged, do not force it lest you perforate a previously intact oesophagus; instead, you can use rigid equipment to "chew" it up and hopefully dislodge it. If that fails, passing a large Foley catheter behind the foreign object and inflating the balloon often helps; it distends the oesophagus (thus freeing the foreign object) and then is used to pull the object out. If you cannot pull a foreign object out of the oesophagus, you can try to push it into the stomach. However, do not push bones or other foreign objects into the stomach unless you are sure that it is smooth on the aborad side and will not further damage the mucosa. Finally, be careful if you insufflate the oesophagus lest you rupture a weakened area in the mucosa and/or cause a fatal tension pneumothorax.

Fish hooks terrify many clinicians, but they can often be successfully removed endoscopically. Fish hooks have usually penetrated the mucosa (and sometimes the muscular tunics); you will often have to use rigid equipment to carefully force the tip of the hook back out of the mucosa. A small hole is left, but there are very seldom any complications. After removing the foreign object, retake plain chest radiographs to be sure that a pneumothorax (which would indicate a perforation) is not present. Antibiotics are indicated if there is substantial oesophageal mucosal ulceration (and especially if you remove a fish hook which had been used with various baits that can harbor anaerobic bacteria). Depending upon the amount of damage, corticosteroids may be used to try to prevent cicatrix formation; however, it is not clear that they are effective. Rarely there may be severe haemorrhage.

## GASTRODUODENOSCOPY

The patient should be prepared by holding it off food for at least 24-36 hours as animals with gastrointestinal pathology may not empty their stomachs readily. The patient must be completely anaesthetized (i.e., one bite on your scope may cost you $4,000-6,000 to repair). Avoid narcotic preanaesthetics such as fentanyl as they may make it harder to pass the instrument through the pylorus. The procedure will tend to stimulate the patient, so have the anaesthesia watched carefully. Also remember that as the stomach is distended with air, it will become harder for the patient to take deep breaths, and one may have to bag the patient to ensure that an adequate plane of anaesthesia is maintained.

The basic principals to remember are:

1. Only go where you can see. Do not advance the instrument blindly.
2) If you cannot see well, put more air in and distend the lumen.

3) If you cannot see well, pull the scope back and try to get a panoramic view.

4) if you cannot see well, try aiming the scope into the center of the lumen (i.e., centralize).

I place the patient in left lateral recumbency and insert a mouth gag. One observes through the scope as it is advanced into the mouth and through the cricopharyngeal sphincter. Air is insufflated and one then advances the scope into the oesophageal lumen, observing the mucosa. When the lower oesophageal sphincter is seen, the tip of the scope is advanced through it, and the stomach is insufflated with air (an exception to this is the very large patient in which case it is better to advance the scope into the duodenum first, so that dilation of the stomach does not result in being unable to enter the duodenum.). Once the stomach is dilated with gas, one examines the greater curvature which is front of the scope. The scope is then advanced along the greater curvature and the tip is retroflexed so that the antrum, the incisor angularis, and the body of the stomach (with the lower oesophageal sphincter through which the endoscope is entering) can be seen. Now, the body of the stomach is examined.

Next, the scope is advanced into the antrum until the pylorus is seen. If it is hard to make the tip of the instrument go into the antrum, placing the patient in dorsal recumbency often helps the operator to manipulate the instrument into this area. With the patient in left lateral recumbency, the pylorus is usually off to the left. If the pylorus appears polypoid, it may be particularly hard to pass through. Metoclopramide has not proven useful in passing the instrument into the pylorus, but ketamine seems to cause some degree of relaxation in some cases. The opening of the pylorus should be kept in the center of the viewing field as the scope is advanced. If necessary, push the tip against the pylorus, being sure to keep the opening in the centre of your field of view. Remember that the duodenum often turns to the right, just after one passes through the pylorus. If it seems difficult to get through the pylorus, one may try to sweep the tip to the right while pushing it against the opening, in an effort to slip into the duodenum.

Do not extensively reposition the patient during the procedure lest you cause gastric volvulus. If a gastric volvulus occurs because of your manipulations while the patient has a distended stomach, wait and see. These usually spontaneously resolve.

## HIATAL HERNIAS

Hiatal hernias may be more common than suspected. Shar Peis seem to have a relatively high incidence of hiatal hernias. They can be difficult to diagnose unless you know how to look for them. Sometimes seen on plain radiographs and simple barium contrast radiographs, the more occult cases sometimes need more aggressive diagnostics. Sometimes one must manually put pressure on the abdomen during film exposure to try to push the stomach through the hernia and into the chest so that it can be diagnosed radiographically. Endoscopic diagnosis is not always straightforward. You may need to put the endoscope into the stomach and retroflex it in order to see the abnormality. Even when found, the big question is whether the hiatal hernia is causing a problem or is an "innocent bystander". In particular, if you have an older dog or cat (i.e., > 1-2 years old) that just started having clinical signs, you should strongly consider that the hiatal hernia is a fortuitous finding that is not responsible for the clinical signs.
FOREIGN BODIES

Gastric foreign objects require a variety of special retrieval instruments to reliably remove. The most useful devices include a coin-retrieval device (also called a W-tooth retrieval device, which is effective for many other objects besides coins), a rat's tooth or shark's tooth forceps (which is especially useful for firmly grabbing cloth), and a 4-wire basket. The basket should be made of very flexible wire in order to facilitate its being passed over and around an object; however, this quality makes it easier to bend the wire and ruin the basket. They must open up to a relatively wide diameter (e.g., 40 mm) and be made of very pliable wire. If their maximal diameter is less or if the wire is stiff, it becomes very difficult to get the foreign object into the basket and snare it. By the same token, the best baskets are easily damaged and ruined because they are made of very pliable wire. Other retrieval devices include wire snares, 3-wire grabbers, magnetic tipped probes, and forceps with non-skid rubber. However, these latter instruments are seldom required. Three wire grabbers (i.e., tripod type retrievers) are very popular with salesmen, but not so popular with busy endoscopists. Unless they are very well made, they usually do not do a very good job of holding onto large objects, heavy objects, and those which generate a lot of resistance when being removed (e.g., panty hose).

Each foreign object to be removed must be considered individually lest an ill-planned endoscopic removal be more damaging to the patient than the foreign object. Poor technique may damage or perforate the alimentary tract (or the scope). It is also possible to "grab" a foreign object and then find that it cannot be removed or released, thus necessitating surgery to retrieve the endoscope. This could be extremely embarrassing.

There are numerous techniques for foreign body removal; only a few basic principles will be discussed. The animal is always radiographed immediately before anesthetizing it to remove the object. Some foreign objects that have been present for weeks will pass out of the animal or out of reach of the scope just before the endoscopic procedure is to be performed. A retrieval forceps that will allow a firm grasp on the object is selected. The object may have to be manipulated until the best possible purchase upon it is possible. Once an object is snared, it should not be pulled out against undue resistance. Resistance is expected at the lower oesophageal sphincter (gastric cardia), the base of the heart, the thoracic inlet, and the cricopharyngeal area.

Snare the gastric foreign object, then, draw the object up next to the tip of the endoscope. Flex the tip so that it goes through the cardia without pressing against one side more than the other. If the object is still difficult to pull into the oesophagus, pass the flexible endoscope through a larger diameter rigid endoscope or rubber tube (i.e., an "over-tube"). "Grab" the foreign object and remove it from the stomach by carefully passing the over-tube down the flexible scope until the over-tube enters the stomach. Then, carefully draw the flexible scope, with the foreign object as close to the tip as possible, as far into the over-tube as possible. Remove both the scope and the foreign object as one unit. This technique is also useful for pulling objects through the cricopharyngeal sphincter as well as removing objects with sharp edges (e.g., glass, razor blade, safety pin, etc).

Whenever a foreign object has been removed, the mucosa should be re-evaluated to look for erosion/ulceration and the presence of other foreign objects or lesions. If a foreign object which could penetrate the alimentary tract has been removed, one should radiograph the appropriate body cavity
to look for evidence of perforation (i.e., pneumothorax or pneumoperitoneum).

## LINEAR FOREIGN OBJECTS LODGED AT THE PYLORUS

When removing linear foreign objects which are trailing off into the duodenum, one should attempt to pass the endoscope through the pylorus so that one can grab the distal end (or at least near the distal end) of the object. The distal end is then pulled into the stomach, meaning that little or none of the object remains in the intestine. If there is still a little bit of the foreign object in the intestine, it can usually be removed simply by pulling it into the stomach. If the foreign object is relatively thick (e.g., cloth, cotton), as opposed to thin (e.g., twine, string, narrow strips of cloth), one can try to pull it into the stomach simply by grasping it near the pylorus and pulling. However, this approach risks rupturing the duodenum, especially if the foreign object has been present for more than 2-4 days. Therefore, this approach should only be tried with caution.

## BIOPSIES

While not too exciting to many people doing endoscopy, taking superb tissue samples is the difference between the mediocre, so-so endoscopist and the superb diagnostician. Many clinicians doing endoscopy of the small intestines are taking inferior biopsies and consequently are missing important diagnoses. This is very common. Unfortunately, most people are not too interested in learning to take good biopsies, possibly because some pathologists call everything “mild to moderate, lymphoplasmacytic something or the other”, and hence the client can be handed a diagnosis (regardless of whether it is right or wrong). We will not discuss interpretation of biopsies at this time. The clinician’s job is to provide the pathologist with the absolute best possible tissue sample. That is what we will spend some time discussing now.

Biopsy is typically the major purpose of intestinal endoscopy. If you cannot take a biopsy that is adequate for diagnosis, then you should probably not be doing endoscopy. This takes a lot of practice and patience, plus direct contact with the pathologist so that you know if you are taking good biopsies or not. There are various types of biopsy forceps for use with flexible endoscopes. I prefer ones that have jaws that are a) ellipsoid, b) fenestrated, and c) have serrated jaws. The ellipsoid jaws allow one to obtain a larger mucosal sample than the round jaws, simply because the ellipsoid jaw forceps can encompass more volume. The fenestration in the jaws minimizes compression artifact when larger samples are obtained. I don't know that the serrated jaws make much difference, but they look better and I feel better about using them. I distinctly dislike biopsy forceps with a blade or needle in the center. Forceps with such a blade or needle are designed to allow you to drive the needle into the area you want and then exert more force or pressure against the mucosa without having it slip off the lesion. However, I find that these forceps typically result in a distinctly smaller mucosal sample. Sometimes the sample is literally cut in two by the blade.

Flexible endoscopic biopsy of the alimentary tract has several advantages. It is a) quick (i.e., usually < 20 min to obtain gastric and duodenal samples), b) safe, c) of minimal stress to very ill animals, d) allows you to see and biopsy mucosal lesions which typically cannot be seen from the serosal surface, and e) is typically diagnostic, if done correctly. However, flexible endoscopy is starting to get a bad reputation because of all the inaccurate diagnoses that have occurred in animals that were sampled using this technique. This centres on the comment that flexible endoscopy is typically diagnostic if done correctly. There is a lot of endoscopy that is incorrectly done, especially in regards to obtaining
tissue samples. The problem is that while the smaller diameter endoscopes are very easy to use (i.e., it is easy to put them into small orifices and pass them through small pylori), these are the scopes with the smaller biopsy channels. It is particularly easy to obtain mediocre (or outright inadequate) tissue samples with biopsy instruments designed for scopes with a biopsy channel that is 2.2 mm in diameter. Scopes with a biopsy channel of 2.8 mm typically allow excellent tissue samples to be consistently obtained; however, these scopes are often large in diameter (e.g., > 9.0 mm), making them harder to use in cats and dogs < 3 kg. Therefore, the clinician must make a decision based upon how often he/she will be performing endoscopy, because that usually determines how accomplished they will become and what they can afford. One should use fenestrated, ellipsoidal forceps with a serrated edge. Then, you keep taking sample after sample until you obtain good samples that encompass the full thickness of the mucosa down to and preferentially including the muscularis submucosa. If the sample fragments easily, then it is primarily villus tips and is inadequate. You may submit it, but do not count it. At least 6-8 good tissue samples should be obtained in hopes that at least 2 or 3 will be well oriented. Immediately after obtaining the sample, it is carefully removed from the biopsy forceps with a 25 gauge needle and gently spread out on a tissue cassette sponge such that the luminal side (i.e., the side with the villi) is oriented upwards and the sample is no longer folded. The samples are allowed to adhere to the sponge, but are not allowed to dry out. The sponge with the tissue samples is placed in formalin promptly. The most important points to take home are that substantial attention to tissue handling is critical in order to give the pathologist optimal tissue samples. A lot of endoscopic procedures have been a complete waste of time and money because the tissue samples were either of poor quality or were mishandled. Always take multiple biopsies of an area because some lesions are very spotty and will be found in less than half of the samples from that area. The value of the endoscopic procedure is totally dependent upon how exacting and demanding you are when taking biopsies.

As alluded to, there are some disadvantages to flexible endoscopy of the alimentary tract: a) it requires expensive equipment, b) it is easy to take inadequate samples, c) some lesions are out of reach of the endoscope, and d) some lesions are so dense that you cannot obtain a diagnostic biopsy of them with this equipment. Scirrhous carcinomas and pythiosis are the two major examples of such lesions.

## COLONIC AND ILEAL BIOPSIES

It is becoming apparent that biopsying both the small and large intestines is useful in many patients (especially cats), even though the clinical signs suggest that only the small or large intestine is involved. It is desirable to use a flexible scope when obtaining colonic samples (in addition to the rigid scope) so that the ileo-colic valve area can be inspected and one may obtain ileal mucosal samples. We can usually enter the ileum of dogs weighing > 5-7 kg, but it is rare that the tip of the scope can be advanced into the ileum of cats. However, even in small dogs and cats, the biopsy forceps can usually be passed through the ileocolic valve and ileal tissue obtained by performing blind biopsies of the mucosa.

Flexible colono-ileoscopy is indicated in any animal with signs of large bowel disease (e.g., haematochaenia, mucoid stool, diarrhoea without weight loss), but especially when rigid colonoscopy and biopsy are nondiagnostic. It is also useful for obtaining ileal biopsies in animals with signs of small intestinal disease (e.g., diarrhoea, weight loss, vomiting) and animals with signs of ileal intussusception (e.g., protein-losing enteropathy in young dogs, persistent vomiting/diarrhoea after
an acute enteritis such as parvovirus, elongated mass in abdomen, sudden onset of scant, bloody stools in a vomiting animal with abdominal pain, sudden deterioration in an animal with prior abdominal surgery/disease) or caecal intussusception (e.g., haematochezia despite relatively normal stools, bloody diarrhoea not diagnosed with rigid colonoscopy). Flexible gastroduodenoscopes are preferred; however, larger diameter human colonoscopes can be used. If ileoscopy is desired, it is best to use smaller diameter (i.e., < 9.8 mm) equipment.

Perform a digital rectal examination before the endoscope is inserted into the rectum, to be sure there is not a lesion close to the anus that may be missed or perforated by the rigid scope. Lubricate the tip of the colonoscope and insert it approximately 2-8 cm into the rectum.

With flexible colonoscopy, bends and twists are even more common as the ileo-caeco-colic valve area is approached. In the dog, the ileo-colic valve may vary in appearance, but it usually has a "mushroom" shape and is relatively easy to identify, if the area is clean. However, it is easy to slide past a normal ileo-caeco-colic valve area and into the caecum without realizing that the caecum has been entered. If this happens, the endoscopist will find that the "colon" is making turns that the scope cannot go past and the caecum may be perforated. This area may be less well prepared than the rest of the colon.

The caecal lumen should be examined for whipworms and growths and then biopsied. After that, one should attempt to enter the ileum or blindly pass a biopsy instrument into the ileum. The scope is passed into the ileum in much the same manner as for the pylorus. However, the ileo-colic valve is rarely open and one will usually have to gently push the tip of the scope into the ileum. There may be paradoxical movement (i.e., the tip of the scope does not move even though the insertion tube is being advanced into the colon because the middle of the insertion tube is pushing laterally on the colonic wall and causing it to move to the side) when attempting to push the tip of the scope into the ileum.

The cat caecum is a short, blind pouch whereas in the dog it is a longer, coiled chamber that is easy to enter by mistake. However, it is easier to enter the ileum of the dog than it is the ileum of the cat. The main reason for this is that the feline colon (especially the transverse and ascending) is relatively short and it is difficult to position the tip of the endoscope so that you have a good view of the ileocolic valve or can approach it with the tip of the endoscope in the manner that you desire. Most of the time, all we can do is blindly pass a biopsy instrument into the ileum, and even that can be very difficult.

Rigid colonoscopy is very useful to examine and biopsy the descending colon. Rigid endoscopy is perhaps the easiest and the most cost-effective endoscopy of the alimentary tract that one can learn. Rigid endoscopes are less expensive and yet typically allow the operator to obtain all the information that is needed in the majority of cases. This technique will be diagnostic in probably greater than 80% of cases which need colonoscopy. The rigid scopes used for rigid colonoscopy can also be used for oesophagoscopy, and they are in fact my favorite tools for removing oesophageal foreign objects. Rigid colonoscopy is usually performed using rigid human sigmoidoscopes. In general, one should use the scope with the largest diameter and longest length that a given patient can accept; this maximizes
the ability to examine the mucosa. In all but toy dogs, one can usually use endoscopes with diameters of 19 to 27 mm. Cats often require endoscopes with diameters of 11 to 15 mm.

Rigid proctoscopes are very useful for examining lesions at or near the anus. They absolutely do not replace colonoscopes, but they do have their place. They come in various lengths (e.g., approximately 70 to 130 mm) and diameters (e.g., approximately 8-25 mm). Some have areas of the distal wall cut out and are referred to as operating proctoscopes. This cut-out area allows the clinician to position the scope such that a mass protrudes into the lumen of the scope, making it easier to biopsy or remove it. Proctoscopes are usually used on top of a battery handle, much like an otoscope. Some proctoscopes use transformers that plug into electrical outlets.

The alligator biopsy instrument used with rigid endoscopes needs to be of high quality in order to obtain optimal mucosal samples. One must be able to insert it into the rigid endoscope and have the tip extend beyond the opening (preferably several cm). The author prefers biopsy instruments that have tips that cut and shear the mucosa as opposed to clam-shell biopsy cups that pinch off a piece of mucosa. The latter rapidly become dull and often tear off mucosa, producing substantial artifact. It is helpful to have the tip of the biopsy tip at a 30° or 45° angle, instead of being a straight continuation of the cannula. This alligator biopsy instrument should only be used for sampling soft mucosa; use on foreign objects or other hard material can produce nicks and dulling which will result in inferior biopsy samples.

## ELECTROCAUTERY PROCEDURES

If you are using any of the various endoscopic instruments that have electrocautery capability, you would do very well to spend more time reading the instructions than playing with the instrument, at least the first time you do the procedure. It is important to understand that if the tip of the cautery instrument is too close to the tip of the endoscope, applying an electric current may result in electricity being directed up the endoscope and into the videoprocessor and light source, thereby blowing them out and leaving you with a huge repair bill.

As far as the patient is concerned, there are several potential pitfalls, especially when using electrocautery loops to resect lesions such as polyps. First, do not apply so much current that the burn you create in the mucosa causes worse signs than the original lesion caused. Start with a relatively low voltage (I typically blend cutting and coagulation and use a setting of about 15-20 on each) and work your way up. Second, when you are tightening the snare around the base of the polyp or mass, do not use excessive force or you may end up cutting through the polyp without the benefit of adequate coagulation (and cause substantial haemorrhage as a result). NEVER blindly grab anything with the snare; you need to be able to see well enough to have confidence that you did not include anything in the snare that you do not want to cut.
ANALGESIA FOR ABDOMINAL PAIN

René Dörfelt, DVM, Dr. vet. med., DECVECC, DECVAA

Clinic of Small Animal Medicine, LMU Munich, Germany

Abdominal pain can be caused by multiple disorders and diseases. Intestinal dilation, distension, inflammation and ischaemia and excessively filled organs such as stomach, uterus or bladder lead to visceral pain. Somatic pain can be caused by abdominal wall disorders and surgery. Pain caused by peritonitis and pancreatitis can often not be clearly differentiated as visceral or somatic. Some disease processes, especially post-operative pain after hepatic or colonic procedures, are hard to control. Therefore, treatment of abdominal pain should address the underlying cause instead of using one standard protocol for all patients with abdominal pain.

Assessment of abdominal pain should be performed applying composite pain scales. This is especially true in diffuse visceral pain, where local pressure with palpation is often insufficient to cause reactions. Depending on the underlying cause, proper palpation of the abdomen is mandatory to assess pain. This should be done properly and slowly, without forced and fast movements, as these can cause non-pain related reactions. The potentially painful areas should be properly examined. For pancreatitis, the cranial abdomen should be palpated carefully. For kidney diseases, palpation of the kidneys helps to differentiate acute and chronic processes. Palpation of diseased organs is often painful in acute inflammation as this causes increase of organ volume and pressure on the capsule.

Standard analgesics for moderate to severe abdominal pain are opioids. For most abdominal procedures and postoperative analgesia μ-receptor agonists are used. These are not effective in controlling visceral pain like pain from gastric distension. Mu agonists lead to decreased propulsive intestinal motility, but may also cause increased intestinal and sphincter tone. Therefore, gastric and intestinal sounds often increase after opioid application. The increased sphincter tone may also decrease gastric emptying. The Sphincter of Oddi tone is also increased by μ-agonists. This may lead to decreased bile flow. Clinically, these motility and tone increases do not cause relevant problems. Some opioids such as morphine and fentanyl induce emesis, others as methadone may cause nausea without emesis. This has to be kept in mind if dealing with vomiting patients or patients not eating adequately.

Kappa-receptor-agonists like butorphanol provide analgesia for visceral pain. Due to its short half-life, butorphanol should be given as a constant rate infusion. Side effects are rare. Especially in older patients, sedation after administration of butorphanol may be severe and prolonged. Therefore, reduction of the dose by 50-75% is reasonable in these patients.

Tramadol has μ-agonist, serotoninergic and NMDA effects, which explain its proposed analgesic properties. It is metabolized in the liver to the effective M1 metabolite. In some dogs, the metabolism is insufficient, and M1 is formed inadequately. Tramadol is used systemically but is also instilled into the abdomen for analgesia during laparotomy in humans. Side effects are dysphoria, centrally induced nausea and vomiting and constipation.

Ketamine is often included in analgesia protocols. Also, for abdominal pain, low dose ketamine provides analgesia. Side effects are minor. Due to the short half-life, it should be given as a bolus
followed by a CRI. Commonly ketamine is used in combination with intravenous lidocaine. Lidocaine provides analgesia but has also positive effects on reperfusion injury and arrhythmias. The effect on gastrointestinal motility is questionable. In horses it improved gastrointestinal motility. Studies in dogs could not prove the same effect.

NSAIDs in abdominal pain are controversial. As commonly known, they can cause intestinal ulceration, vomiting and diarrhoea, as well as kidney injury, especially in hypotensive patients. Due to these reasons NSAIDs should only be used if intestinal or kidney injury is excluded and the animal is normotensive. Just recently a new drug, grapiprant was launched. Due to its effect at the EP 4 receptor its potential for intestinal injury may be lower, compared to standard NSAIDs.

Metamizole is a pyrazolon-derivate, belonging to the group of non-acidic-non-opioid analgesics. In some countries it is named dipyrone. It has anti-inflammatory, spasmolytic and antipyretic effects and also acts at the μ-opioid receptor. Studies in rats and dogs evaluated its effect on intestinal integrity and did not find any intestinal injury, even after using high doses of metamizole. There are no studies proving kidney injury after using metamizole in dogs and cats. Side effects of metamizole are salivation after application in cats and hypotension after fast intravenous application. In humans a reversible agranulocytosis is described after prolonged use. This side effect is, to date, not reported in veterinary patients. Due to the positive effects and mild side effects, the author uses metamizole often as a first line drug in cardiovascularly stable dogs and cats with abdominal pain.

Local anaesthesia of abdominal pain has also been described. Intraabdominal application of lidocaine in very painful patients via drains is used as well as epidural anaesthesia. Epidural anaesthesia is especially helpful in severe abdominal pain from pancreatitis or peritonitis. Care must be taken to ensure strict hygiene. As epidural catheters are used for continuous infusion of local anaesthetics or opioids, these catheters must be managed in a strictly sterile fashion.

As histamine release is involved in every inflammatory process, anti-histamines such as diphenhydramine and chlorphenamine are known to have analgesic effects. These drugs are rarely used in veterinary medicine as analgesics. But especially in cases where NSAIDs cannot be used, antihistamines have the potential to provide analgesia alone and increase NSAID or metamizole derived analgesia.

NK1 receptor-antagonists like maropitant have been shown to have an analgesic effect. As its main indication is antiemesis, it is often given in vomiting animals. Because it also decreases nausea and has analgesic properties, application should be considered in many patients with abdominal pain.

As pain is also an emotional experience and well-being is an important factor in the control of pain, non-medical treatment of abdominal pain is also mandatory. From human medicine we know that warming of the abdomen often helps to decrease the pain. An excessively filled stomach will also cause pain, discomfort, decreased mobility and decreased food intake. Therefore it is helpful to empty a massively filled stomach by oro-gastric or nasogastric tubes. In general, the patient should be placed in a quiet environment and on soft and clean bedding. TLC may also improve analgesia in many patients.
HEPATIC ENCEPHALOPATHY

Alex Lynch; BVSc(Hons) DACVECC MRCVS
North Carolina State University, Raleigh, NC

Hepatic encephalopathy (HE) represents a disease state characterized by cerebral dysfunction related to underlying intrinsic liver disease or abnormal hepatic perfusion.¹ The pathophysiology of HE is complex and incompletely understood. While the role of ammonia in HE is well characterized, a multitude of other chemicals are also implicated in its pathogenesis. These include, but are not limited to, glutamate, GABA, endogenous benzodiazepines, aromatic amino acids, mercaptans, opioids, manganese, and alterations in the tryptophan-serotonin system.¹

Diseases causing hepatic encephalopathy

Causes of HE may be categorized as type A (acute), B (bypass) or C (chronic/cirrhosis).²,³ Type A represent acute fulminant liver dysfunction, for example after exposure to hepatotoxicants (e.g. xylitol, amanita mushrooms, sago palm). Type B refer to abnormal liver perfusion secondary to congenital portosystemic shunting (PSS) and is the most common type seen in animals.¹ Type C develops during the terminal stages of chronic hepatopathies where portal hypertension and acquired shunting develop. Different pathological lesions are noted with acute and chronic cases of HE. The prominent feature of acute HE is cytotoxic brain oedema. Chronic cases have only minimal oedema but develop brain histological changes (e.g. Alzheimer type II astrocytosis) after chronic exposure to hyperammonaemia.⁴ Hyperosmotic therapies (e.g. mannitol, hypertonic saline) would generally be appropriate for acute HE.⁵ Corticosteroids are contraindicated however since they may promote water retention and could worsen brain oedema.⁶

Diagnosing hepatic encephalopathy

A diagnosis of HE requires three concurrent features: signs compatible with cerebral dysfunction, hyperammonaemia, and documented abnormal liver function. The clinical signs associated with HE in animals vary in severity. Common symptoms include altered mentation, lethargy, head pressing, inappropriate vocalizing, and seizures. These symptoms may be episodic in nature and triggered by inciting events (e.g. after ingesting a protein meal). Some symptoms are species specific (e.g. ptyalism in cats). Certain clinical presentations (e.g. young small breed dogs with neurological dysfunction) may increase our index of suspicion for HE.

If HE is suspected, measurement of ammonia is a reasonable next diagnostic step. Most ammonia comes from the breakdown of dietary proteins by urease producing bacteria in the GI tract. The unionized form of ammonia (NH₃) can leave the GI tract and is transported to the liver via the portal circulation, while ammonium ions (NH₄⁺) remain trapped within the lumen. A complex series of biochemical events (the urea or Ornithine cycle) occurs in periportal hepatocytes resulting in the conversion of ammonia (NH₃) to urea [(NH₂)₂CO)] for renal excretion. An alternative means of ammonia handling (transamination) occurs within the perivenous hepatocytes, as well as the brain and skeletal muscles. Transamination involves the addition of ammonia to glutamate (i.e. amination) producing glutamine, catalyzed by glutamine synthase. Under normal circumstances, amination is an effective ammonia handling mechanism since it produces the relatively inert glutamine. Glutamate is the major excitatory neurotransmitter in the mammalian CNS. Any excess glutamate is taken up by
astrocytes that limits excitatory stimulation. Within astrocytes, glutamate undergoes amination to produce glutamine that eventually enables regeneration of glutamate. In patients with severe liver dysfunction or in situations where ammonia bypasses the liver due to shunting, the opportunity for ammonia detoxification via the urea cycle or transamination may be missed.

Ammonia can cross the blood-brain barrier and may interfere with the glutamine-glutamate recycling system. Ammonia inhibits glutamine release from astrocytes. While glutamine is usually considered inert, it is osmotically active and excessive intracellular accumulation promotes cellular swelling. This is achieved by the insertion of specific aquaporin-4 channels into astrocyte cell membranes.⁷ Intracellular glutamine moves into the mitochondria, where de-amination occurs producing glutamate and ammonia. This process leads to the deleterious production of reactive oxygen and nitrogen species secondary to ammonia liberation.¹ To this extent, movement of the relatively innocuous glutamine into mitochondria leading to the production of damaging reactive oxygen and nitrogen species is described as the ‘Trojan horse’ hypothesis, due to similarities with its mythical counterpart.

The liver normally has a huge reserve capacity meaning severe disease must be present in order for hyperammonaemia to develop. A clinical diagnosis of HE therefore requires documentation of severe liver dysfunction in light of appropriate clinical signs and hyperammonaemia. Despite its infamous association with HE, ammonia concentration is imperfectly associated with the severity of HE. Alternative differentials for hyperammonaemia may also be encountered (e.g. cobalamin deficiency).⁸ A recent study investigated various diagnostic tests for identification of congenital PSS in dogs, with abnormal fasting bile acids plus documentation of hyperammonaemia in dogs making PSS quite likely. Normal bile acids with a normal ammonia tolerance test in symptomatic dogs, in contrast, effectively ruled out PSS.⁹ Alternative indicators of liver function (e.g. protein C) are used at some institutions.¹⁰ Hyperbilirubinaemia is not a feature of congenital PSS but may be seen in dogs with HE due to intrinsic liver disease.¹¹

The non-ammonia contributors to HE unfortunately are much harder to assess in individual patients since laboratory assays for these substances are rarely available. From a mechanistic perspective, it is helpful to consider the cumulative effects of the non-ammonia factors as tipping the balance between CNS excitation and inhibition. Glutamate reuptake, for instance, is inhibited in hyperammonaemic states and promotes an excitatory environment that could lower the seizure threshold.¹,¹² Overall a predominant inhibitory tendency is most common in animals with HE. The major inhibitory neurotransmitter in the CNS is GABA. Most GABA is of intestinal origin and excessive blood concentrations of GABA may occur if there is acute intrinsic liver failure. Excessive agonism of GABA receptors consequently produces an inhibitory effect. In addition, endogenous benzodiazepines may be produced in animals with HE, which would further stimulate central GABA receptors.¹³

Another interesting contribution to HE in some patients involves the abnormal production of catecholamine neurotransmitters from aromatic amino acids (e.g. phenylalanine, tyrosine, tryptophan). In patients with liver dysfunction or PSS, the ability to convert aromatic amino acids to the typical neurotransmitters may be overwhelmed. In this situation, false neurotransmitters (e.g. octopamine, phenylethanolamine) may be synthesized that also exert an inhibitory effect. Branched chain amino acid concentrations (e.g. leucine, valine) may also be decreased in these patients. Manganese elimination is impaired in dogs with chronic hepatopathies and elevated manganese
concentrations are also noted in dogs with congenital PSS.¹⁴ The tryptophan-serotonin system may also be disrupted in HE patients although its significance is controversial in individual patients.¹ Glutamine, from the amination of glutamate, is exchanged across the blood-brain barrier for tryptophan.¹⁵ Tryptophan is a precursor to serotonin, as well as quinolinic acid that acts upon NMDA receptors.

## Managing hepatic encephalopathy

When faced with a patient with suspected or confirmed HE, the potential for comorbidities contributing to their clinical signs should be considered. The presence of an inflammatory focus has been associated with worsening of HE symptoms.¹⁶⁻¹⁸ Clinical indicators of inflammation (e.g. SIRS criteria, C reactive protein) have also been associated with more severe HE symptoms in dogs.¹⁹,²⁰ Occult sources of infection including blood stream infections, aspiration pneumonia and urinary tract infections should be considered in patients with HE. Urinary tract infections may be particularly relevant, since many dogs with PSS have urate uroliths that could act as a nidus for infection. Animals with inflammation are also more likely to have a prothrombotic tendency compared to normal dogs. One study identified a hypercoagulable tendency was more common in dogs with PSS that had HE.²¹ Arginine is an essential amino acid in cats and a key player in the urea cycle. A deficiency in arginine may occur in cats with hepatic lipidosis following a period of anorexia and may lead to hyperammonaemia in the absence of PSS or intrinsic liver pathology.²²,²³

Several putative factors may augment the severity of HE symptoms, including hypokalaemia, hyponatraemia, metabolic alkalosis, gastrointestinal bleeding, protein ingestion, hypoglycaemia, dehydration, constipation, renal insufficiency, and diuretic administration.²⁴ Hypokalaemia promotes metabolic alkalosis increasing the ratio of NH₃:NH₄⁺ form. Hypokalaemia also significantly increases renal ammonia production and excretion.²⁵ Interestingly, a recent study in dogs did not find any of the aforementioned metabolic derangements were necessarily more likely to be present in dogs with HE at admission to a teaching hospital.²⁴ That said, attention to presence of metabolic derangements is important since therapeutic measures to correct them have been associated with successful amelioration of HE symptoms.²⁴

Most classic treatments for HE are aimed at attenuating the effects of hyperammonaemia. Lactulose is a nonabsorbable disaccharide and is broken down in the gut to acidic byproducts. These products convert unionized NH₃ to NH₄⁺, effectively trapping it within the gut and preventing absorption. Lactulose can either be given orally or as a retention enema in more severely compromised animals. It is also an osmotic cathartic, increasing gastrointestinal transit time that may have additional benefits in the HE patient. Due consideration for patient fluid balance is needed after lactulose administration in case excessive fluid loss via the GI tract occurs. Several antibiotics have been used in the management of patient with HE, with ampicillin and metronidazole being commonly chosen in small animals. Neomycin was used historically but has fallen out of favor given aminoglycoside nephrotoxicity concerns. The rationale behind antibiotic prescription is to reduce the number of urease producing bacteria in the gut. In the long term an optimized diet consisting of a highly digestible protein source (rather than protein restriction) is recommended. Levetiracetam is the current anti-epileptic drug of choice in animals that have seizures as part of their HE syndrome, although pre-emptive administration in animals with PSS prior to surgery may not afford protection against seizures²⁶ as was initially reported.²⁷
References

1. Salgado M, Cortes Y. Hepatic Encephalopathy: Etiology, Pathogenesis, and Clinical Signs. Compend Contin Educ. 2013;E1-E9.

2. Gow A. Hepatic Encephalopathy. Vet Clin N Am Sm Animal. 2017;47:585-599.

3. Lidbury JA, et al. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care 2016;26(4):471-87.

4. Norenberg MD. The role of astrocytes in hepatic encephalopathy. Neurochem Pathol. 1987;6(1-2):13-33.

5. Mahajan S, et al. Cerebral oedema: Pathophysiological mechanisms and experimental therapies. J Neuroanaesthesiol Crit Care 2016;3:22-28.

6. Anderson P, Roberts I. Corticosteroids for acute traumatic brain injury. Cochrane Database Syst Rev. 2005;(1):CD000196

7. Rama Rao KV, Norenberg MD. Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis. 2007;22(3-4):265-75.

8. Battersby I, et al. Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie. J Small Anim Pract. 2005;46(7):339-44.

9. Van Straten G, et al. Diagnostic value of the rectal ammonia tolerance test, fasting plasma ammonia and fasting plasma bile acids for canine portosystemic shunting. Vet J. 2015;204:282-286.

10. Toulza O, Center SA, Brooks MB, et al. Evaluation of plasma protein C activity for detection of hepatobiliary disease and portosystemic shunting in dogs. J Am Vet Med Assoc. 2006;229(11):1761-71.

11. Adam FH, German AJ, McConnell F, et al. Clinical and clinicopathologic abnormalities in young dogs with acquired and congenital portosystemic shunts: 93 cases (2003-2008). J Am Vet Med Assoc 2012;241(6):760-765.

12. Norenberg MD, et al. The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 1997;21:124-133

13. Zeneroli ML, et al. Benzodiazepine-like compounds in the plasma of patients with fulminant hepatic failure. Scand J Gastroenterol 1998;33:310-313.

14. Kilpatrick S, et al. Whole blood manganese concentrations in dogs with primary hepatitis. J Small Anim Pract. 2014;55:241-246.

15. Holt D. Chapter 88. Hepatic Encephalopathy, in Small Animal Critical Care Medicine, 2nd Ed. Eds. Silverstein DC, Hopper K.

16. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci 2015;62: 2295-2304

17. Coltart I, et al. Inflammation and hepatic encephalopathy. Arch Biochem Biophys. 2013; 536: 189-196.

18. Kilpatrick S, et al. Plasma cytokine concentrations in dogs with a congenital portosystemic shunt. Vet J. 2014;200:197-199.

19. Tivers MS, et al. Hyperammonemia and systemic inflammatory response syndrome predicts presence of hepatic encephalopathy in dogs with congenital portosystemic shunts. PLoS One. 2014;9:e82303.
20. Gow AG, et al. Dogs with congenital porto-systemic shunting (cPSS) and hepatic encephalopathy have higher serum concentrations of C-reactive protein than asymptomatic dogs with cPSS. Metab Brain Dis. 2012; 27: 227-229.

21. Kelley D, et al. Thromboelastographic Evaluation of Dogs with Congenital Portosystemic Shunts. J Vet Intern Med. 2013;27:1262-1267.

22. Stewart PM, et al. Effects of arginine free meals on ureagenesis in cats. Am J Physiol Endocrinol Metab 1981;241:310-315.

23. Morris JG, Rogers QR. Ammonia intoxication in the near-adult cat as a result of a dietary deficiency of arginine. Science 1978;199:431-432.

24. Lidbury J, et al. Putative precipitating factors for hepatic encephalopathy in dogs: 118 cases (1991-2014). J Am Vet Med Assoc. 2015;247:176-183.

25. Han KH. Mechanisms of the effects of acidosis and hypokalemia on renal ammonia metabolism. Electrolyte Blood Press. 2011;9(2):45-9.

26. Mulins RA, Sanchez Villamil C, de Rooster H, et al. Effect of prophylactic treatment with levetiracetam on the incidence of postattentuation seizures in dogs undergoing surgical management of single congenital extrahepatic portosystemic shunts. Vet Surg. 2019;48(2):164-172.

27. Fryer KJ, Levine JM, Peycke LE, et al. Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation. J Vet Intern Med. 2011;25(6):1379-84.
WHEN THINGS DO NOT GO AS PLANNED IN TRANSFUSIONS

Isabelle Goy-Thollot, Dr Vet, PhD, DECVECC

SIAMU, VetAgro Sup, Lyon, France

The use of blood transfusions in veterinary practice has increased dramatically in recent years. Providing safe and effective transfusion therapy is essential. There are many definitions for the term transfusion reaction (TR), but the following is simple and clear: "any adverse event following a blood transfusion, attributed to the transfusion". The risk of a TR is present whenever a blood product is administered. These adverse effects can occur despite appropriate prescreening of donors, blood collection techniques and pre-transfusion compatibility testing. Transfusion reactions can be categorized into acute or delayed immunologic and non-immunologic reactions. Immunologic reactions occur secondary to components within the blood product, including red blood cells (RBC), white blood cells (WBC), platelets (PLT), and plasma proteins (1,15).

Non-infectious aetiologies far exceed infectious causes due to the high level of adherence to donor prescreening standards as recently outlined in the American College of Veterinary Internal Medicine consensus statement on canine and feline blood donor screening for infectious diseases (23). The non-infectious aetiologies can be subdivided into those that cause acute reaction (febrile non-haemolytic reactions (FNHR), transfusion associated circulatory overload (TACO), haemolysis of incompatible red blood cells/plasma, transfusion-related acute lung injury (TRALI), allergic reactions, sepsis, and metabolic and coagulation abnormalities) vs. those that are delayed (immune-mediated haemolysis, iron overload from long-term transfusions, and TRIM being most common). FNHR and TACO are the most common TR in dogs and cats (3). Acute haemolytic transfusion reactions is the most serious and life-threatening. FNHR and allergic complications are the most immediate reactions. Acute complications can occur during or within hours of the transfusion whereas the delayed reactions are typically noted days to months following transfusion (1, 12, 13).

The reported frequency of canine and feline TR varies depending on the product administered and the study performed with values from 1-26% reported in dogs and cats (1,3,10,12,14,15). This very wide range reflects the difficulty in determining whether a TR has occurred when performing a retrospective study and the lack of standardization in determining canine and feline TRs. Much of the veterinary literature in this area focuses more on the clinical findings that led to a diagnosis of a TR (vomiting, dyspnoea), rather than which type of TR was seen. The clinical signs seen are often non-specific to the underlying cause. This lecture aims to describe how to effectively manage transfusion reactions to ensure patient recovery.

<table><caption>Table 1: Classification of transfusion reactions (1,12).</caption><thead><tr><th></th><th>Immunological</th><th>Non-immunological</th></tr></thead><tbody><tr><th>Acute</th><td>- FNHR<br>- Mild allergic<br>- Anaphylaxis<br>- Acute haemolytic transfusion reaction<br>- TRALI</td><td>- TACO<br>- Transfusion related sepsis<br>- Electrolyte disturbances<br>- Hypothermia</td></tr><tr><th>Delayed</th><td>- Delayed haemolytic transfusion reaction</td><td>- Infectious disease transmission</td></tr></tbody></table>
Febrile non-haemolytic reactions (FNHR), transfusion acute cardiocirculatory overload (TACO), transfusion-related acute lung injury (TRALI).

1. Febrile Non-Haemolytic Reactions (FNHR)

**Definition:** These reactions are defined as a temperature rise of 1°C or greater associated with the transfusion (1). FNHR are one of the most common TR seen in human transfusion recipients. A large veterinary retrospective study noted fever in 9% of transfusion recipients (3).

**Cause:** FNHR are caused by pro-inflammatory pyrogenic cytokines. These are either produced in the blood product during storage or by the recipient in response to infused antigen (generally leucocyte associated) due to prior sensitization.

**Clinical signs:** It is usually self-limiting and of little clinical significance. However, although not medically dangerous, it can cause patient discomfort.

**Diagnosis:** Fever can be the first sign of more serious complications such as sepsis, bacterial contamination of the blood unit, or an acute haemolytic transfusion reaction. Therefore, any rise in temperature requires immediate investigation. Diagnosis of a FNHR is a diagnosis of exclusion.

**Treatment:** Aims at slowing or temporarily stopping the transfusion. Active cooling is recommended when temperature >40°C and discontinue once <39.5°C to avoid hypothermia. Administration of a non-steroidal anti-inflammatory medication can be considered and is recommended for temperature over 41.5°C. Antipyretics (e.g. dipyrone), can also be used.

**Prevention:** There is evidence that leukodepletion decreases the likelihood of these reactions (17).

2. Acute haemolytic transfusion reaction (AHTR).

**Definition:** AHTR are caused by antibody-mediated destruction of RBC, either recipient mediated destruction of donor cells or antibodies in the donor product leading to recipient red cell destruction. The recipient is more at risk and AHTR are commonly associated with an incompatible donor. The recipient can have pre-formed circulating naturally occurring antibodies (cats (2,5,9,11,16,21,24)) or acquired antibodies that react against the donor's transfused RBC (mainly dogs (2,5,8,11)).

**Cause:** Complement activation, release of inflammatory cytokines, histamines, bradykinin and vasoactive amines occur resulting in a systemic inflammatory response in the recipient. This reaction is mostly IgG mediated in the dog and IgM mediated in the cat. Intravascular haemolysis of the red blood cells leads to haemoglobinuria, haemoglobinemia, acute renal failure, disseminated intravascular coagulation, circulatory collapse, vasoconstriction, and death (4,6,7,18). The amount of RBC destruction determines the severity of the patient's response (16). Depending on the antibody titre in the recipient these can be fatal. In dogs, it is generally thought that pre-formed antibodies against differing canine blood antigens are not present and so the risk of an AHTR on first transfusion administration is negligible (8).

**Diagnosis:** clinical signs and evidence of haemolysis.

**Clinical signs:** They can include pyrexia, shaking, hypotension, wheezing, nausea, vomiting, pain, restlessness, salivation, incontinence, and shock.

**Treatment:** Is supportive with appropriate fluid therapy and pressors to maintain cardiovascular stability and renal perfusion (due to the risk of haemoglobinemia induced acute kidney injury). Fluid resuscitation aims to maintain mean arterial blood pressure > 70-80 mmHg. Efficacy of glucocorticoids is unproved.
**Prevention:** for a first transfusion: blood typing (dogs and cats), cross-matching (cats). Further transfusion (>4 days after a previous transfusion): blood typing (dogs and cats), cross-matching (dogs and cats) (1).

### 3. Allergic Reactions (Type I Hypersensitivity)

**Definition:** Allergic reactions result from a response to allergens in the donor blood, including RBC, platelets, granulocytes, and plasma proteins (often complement immunoglobulins). Allergic reactions are reported to occur in about 1% of canine and feline transfusions (3) and are again common in humans.

**Causes:** Allergic reactions are caused by a type 1 (IgE mediated) hypersensitivity reaction to plasma proteins (20).

**Clinical signs:** Minor reactions are often cutaneous and include pruritus, urticarial lesions (hives), erythema and angiooedema. They can progress to involve more systemic responses. Clinical signs of these major reactions can include dyspnoea, stridor from laryngeal oedema, wheezing, tachycardia, nausea, vomiting, and diarrhoea. Gastrointestinal signs are often noted.

**Diagnosis:** Clinical signs

**Treatment:** For minor reactions treatment includes temporarily stopping the transfusion and administering an antihistamine. Anti-inflammatory steroids should be considered for more severe reactions with the transfusion discontinued during treatment. Epinephrine should be considered for patients with dyspnoea or those experiencing anaphylaxis.

**Prevention:** In human and veterinary hospitals, clinicians have used anti-histamines as a pre-transfusion treatment to decrease the likelihood of allergic transfusion reaction. The veterinary study by Bruce et al (2015) found an association between pre-transfusion administration of diphenhydramine and decreased allergic transfusion reactions (3).

### 4. Transfusion-Associated Circulatory Overload (TACO)

**Definition:** TACO occurs when the transfusion volume or rate exceeds cardiovascular compensation.

**Causes:** Risk factors include compromised cardiovascular function, a volume overload state (concurrent renal failure, congestive heart failure), high volume fluid infusion, transfusion over a short period, old/young patients, and patients with severe, compensated chronic anaemia (1,12).

**Clinical signs:** Include tachypnoea, dyspnoea, dry cough, orthopnea, cyanosis, murmur or gallop rhythm, weight gain, serous nasal discharge, development of pulmonary oedema or pleural effusion. Patients can have distended neck veins.

**Diagnosis:** Clinical signs. This syndrome clinically appears like TRALI but improves with diuresis.

**Treatment:** is with diuretics (generally furosemide) and oxygen therapy.

**Prevention:** If the patient is at risk, treatment involves slowing the transfusion or discontinuing it if overloaded, dividing the transfusion into smaller aliquots, increasing the transfusion time, administration of diuretics and oxygen support (1).

### 5. Transfusion-Related Acute Lung Injury (TRALI)

**Definition:** TRALI is characterized by its acute onset, severe hypoxaemia, bilateral infiltrates on chest radiographs, and no evidence of left atrial hypertension (absent findings of circulatory overload). TRALI is an uncommon condition in dogs. A prospective veterinary study found that 2/54 cases enrolled had acute onset hypoxaemia and bilateral radiographic infiltrates (22). Bruce et al (2015)
reported dyspnoea in 1% of their transfusions (TACO, TRALI or other pathology) (3). Frequency of TRALI is still unknown in dogs and cats.

**Cause:** TRALI is caused by activated neutrophils damaging pulmonary endothelial cells leading to an inflammatory alveolar infiltrate. It is recognized by bilateral radiographic pulmonary infiltrates and a PaO2/FiO2 ≤ 300 which is not caused by fluid overload or cardiac failure (22).

**Clinical signs:** Clinical signs associated with TRALI include severe dyspnoea, tachypnoea, hypoxaemia, fever, hypotension, cyanosis, diffuse crackles, decreased breath sounds, and tachycardia, with no evidence of circulatory overload. The onset of dyspnoea is usually during or within 6 hours of a transfusion.

**Diagnosis:** Clinical signs. It is similar to TACO in appearance but does not respond to diuretic therapy.

**Treatment:** Treatment is mainly supportive and involves discontinuing the transfusion, supplemental oxygen, intravenous fluids, and possibly mechanical ventilation (22).

**Prevention:** In humans, TRALI may relate to use of plasma from female donors with a history of previous pregnancy. Since canine donors with this history are uncommon, TRALI may not be a major transfusion concern in our recipients. Careful monitoring and slow rates of transfusion in patients with pulmonary disease (1,22).

## 6. Delayed haemolytic transfusion reaction (DHTR)

**Definition:** A haemolytic reaction is classified as delayed if it occurs between 1 and 28 days post transfusion (1).

**Cause:** It is caused by the formation of red blood cell antibodies shortly after transfusion and leads to red cell haemolysis. Antibody formation can also occur to platelets, granulocytes, and plasma proteins. Formation depends on the underlying illness, genetic predisposition, immune status, degree and duration of antigen exposure, degree of antigen disparity with the blood donor, and transfusion to an already sensitized patient. It generally leads to extravascular haemolysis. The question about recognized canine/feline RBC antigens causing delayed haemolytic TR is still pending.

**Clinical signs:** Clinical signs often seen are fever and jaundice. Patient haematocrit decreases.

**Diagnosis:** These reactions may not even be recognized in some cases.

**Treatment:** do not need any specific treatment.

**Prevention:** Prevention involves administering DEA 1 negative blood to DEA 1 negative recipients and cross matching any patients which have had a previous transfusion. Crossmatch compatibility testing may not detect these antibodies if they are present in low volume. Patients should be observed for post-transfusion anaemia and reactions and monitored for decreasing benefit with subsequent transfusions. Unnecessary transfusions should be avoided and when transfusing, attempt to minimize blood group antigen incompatibility to prevent sensitizing patients to future transfusions (1,12).

## 7. Non-Immune-Mediated Haemolysis

This reaction usually results from a physical destruction of the cells in vitro. Temperature damage and cell destruction can occur from freezing or overheating through use of microwave ovens, hot water baths, or malfunctioning blood warmers. Mishandling during collection and processing and improper storage can lead to cell lysis. Additionally, mechanical damage from pressure bags or small bore needles, or osmotic damage through concurrent drug or non-isotonic solution administration with the blood product can cause cell damage. To avoid this problem, hospital protocols should be developed and strictly enforced for collection, processing, storage, administration, and patient monitoring during transfusions (1).
## 8. Metabolic and coagulation abnormalities (1)

Metabolic abnormalities often result from biochemical changes in the blood product during storage and also from constituents of the product's preservative, anticoagulant, and additive solutions. Hyperkalaemia can occur from potassium accumulation during storage as part of the RBC storage lesion and hypo or hyperglycaemia can be present as well.

Coagulopathies develop from dilution of the patient's blood with platelet and coagulation factor-poor RBCs. This is often a result of massive transfusion, resulting in a complex coagulopathy characterized by hypothermia, shock, tissue anoxia and damage, and disseminated intravascular coagulation. Hypothermia can result from administration of chilled blood products rapidly and can impair platelet function and prolong the prothrombin time and activated partial thromboplastin time. Signs of hypothermia include chills, decreased body temperature, irregular heart rate from ventricular arrhythmias, and possibly cardiac arrest. Treatment includes warming the blood and the patient and possibly stopping or slowing the transfusion, depending on the severity of clinical signs.

## 9. Citrate toxicity (1)

This is also a manifestation of massive transfusion of fresh frozen plasma, whole blood, or platelets. Citrate is a common additive in blood components and when these levels rise in the recipient, it binds ionized calcium causing clinical signs of hypocalcaemia. Hypocalcaemia can result in prolongation of the QT interval, decreased left ventricular function, hypotension, hypomagnesaemia, and cardiac arrhythmias. Clinical signs can include tetany, muscular cramps, hyperactive reflexes, seizure activity, laryngeal spasms, and respiratory arrest. Treatment involves slow infusion of the blood product, discontinuation if tetany occurs, and calcium supplementation.

## References

1. Blois SL. Transfusion-Associated Complications. In: Holowaychuk M, Yagi K eds. Manual of Veterinary Transfusion Medicine and Blood banking, 1st ed. Ames, Iowa USA : John Wiley & Sons Inc.; 2016, pp. 376-414.

2. Bovens C, Gruffydd-Jones T. Xenotransfusion with canine blood in the feline species: review of the literature. J Feline Med Surg. 2013; 15:62-7.

3. Bruce JA, Kriese-Anderson L, Bruce AM, Pittman JR, Effect of premedication and other factors on the occurrence of acute transfusion reactions in dogs. J Vet Emerg Crit. 2015; doi: 10.1111/vec.12327.

4. Callan MB, Jones LT, Giger U. Hemolytic transfusion reactions in a dog with an alloantibody to a common antigen. J Vet Intern Med 1995;9:277-279.

5. Euler CC, Raj K, Mizukami K, Murray L, Chen CY, Mackin A, Giger U. Xenotransfusion of anemic cats with blood compatibility issues : pre-and posttransfusion laboratory diagnostic and crossmatching studies. Vet Clin Pathol 2016 ; 76 : 969-974

6. Evans NA, Walker JM. Incidence of acute immunologic transfusion reactions in dogs receiving packed red cell and fresh frozen plasma transfusions (2008-2012). J Vet Emerg Crit Care 2014 [Abstract]:24(S1):S6.

7. Giger U, Gelens CJ, Callan MB, et al. An acute hemolytic transfusion reaction caused by dog erythrocyte antigen 1.1 incompatibility in a previously sensitized dog. J Am Vet Med Assoc 1995;206:1358-1362.
8. Goy-Thollot I, Giger U, Boisvineau C, Perrin R, Guidetti M, Chaprier B, Barthélemy A, Pouzot-Nevoret C, Canard B. Pre- and Post-Transfusion Alloimmunization in Dogs Characterized by 2 Antiglobulin-Enhanced Cross-match Tests. J Vet Intern Med 2017; DOI: 10.1111/jvim.14801

9. Goy-Thollot I, Nectoux A, Guidetti M, et al. Detection of naturally occurring alloantibody by an in-clinic antiglobulin-enhanced and standard crossmatch gel column test in non-transfused domestic shorthair cats. J Vet Intern Med. 2018; 1-8.

10. Holowaychuk MK, Leader JL, Monteith G. Risk factors for transfusion-associated complications and nonsurvival in dogs receiving packed red blood cell transfusions: 211 cases (2008-2011). J Am Vet Med Assoc 2014;244:431-437.

11. Hourani L, Weingart C, Kohn B. Alloimmunisation in transfused patients: serial cross-matching in a population of hospitalised cats. JFMS. 2017; https://doi.org/10.1177/1098612X1668857

12. Humm K. Transfusion reactions: pathogenesis, recognition and treatment. Proceedings 22nd IVECCS Grapevine, TX USA. 2015. pp. 855-857

13. Jagodich TA, Holowaychuk MK. Transfusion practice in dogs and cats: An Internet-based survey. J Vet Emerg Crit Care. 2016; doi: 10.1111/vec.12451.

14. Klaser DA, Reine NJ, Hohenhaus AE. Red blood cell transfusions in cats: 126 cases (1999). J Am Vet Med Assoc 2005;226(6):920-923.

15. Maglaras CH, Koenig A, Bedard DL, Brainard BM. Retrospective evaluation of the effect of red blood cell product age on occurrence of acute transfusion-related complications in dogs: 210 cases (2010-2012). J Vet Emerg Crit Care 2017; 27: 108-120

16. McClosky ME, Brown DC, Weinstein NM, Chappini N, Taney MT, Marryott K, Callan MB. Prevalence of naturally occurring non-AB blood type incompatibilities in cats and influence of crossmatch on transfusion outcomes. J Vet Intern Med. 2018; 32:1934-1942.

17. McMichael MA, Smith SA, Galligan A, et al. Effect of Leukoreduction on Transfusion-Induced Inflammation in Dogs. J Vet Intern Med 2010;24:11311137

18. Melzer KJ, Wardrop KJ, Hale AS, et al. A hemolytic transfusion reaction due to DEA 4 alloantibodies in a dog. J Vet Intern Med 2003;17:931-933.

19. Prittie JE. Controversies related to red blood cell transfusion in critically ill patients. JVECC 2010;20(2):167-176.

20. Shmuel DL, Cortes Y. Anaphylaxis in dogs and cats. J Vet Emerg Crit Care 2013;23(4):377-94.

21. Sylvane B, Prittie J, Hohenhaus AE, Tozier E. Effect of cross-match on packed cell volume after transfusion of packed red blood cells in transfusion-naïve anemic cats. J Vet Intern Med. 2018; 1-

22. Thomovsky EJ, Bach J. Incidence of acute lung injury in dogs receiving transfusions. J Am Vet Med Assoc 2014;244(2):170-4.

23. Wardrop KJ, Birkenheuer A, Blais MC, Callan MB, Kohn B, Lappin MR, Sykes J. Update on Canine and Feline Blood Donor Screening for Blood-Borne Pathogens. Consensus Statement. J Vet Intern Med. 2016; 30:15-35.

24. Weltman JG, Fletcher DJ, Rogers C. Influence of Cross-Match on Posttransfusion Packed Cell Volume in Feline Packed Red Blood Cell Transfusion. J Vet Emerg Crit Care 2014;24:429-36.
PROTEIN LOSING ENTEROPATHY: ACUTE PRESENTATION OF A CHRONIC PROBLEM?

Silke Salavati, Dr.med.vet., PhD, DECVIM-CA, MRCVS

R(D)SVS, University of Edinburgh, Scotland

**Protein-losing enteropathy (PLE)** is not an actual diagnosis, but a descriptive term used to encompass small intestinal disease (dogs > cats) severe enough for protein leakage into the gut lumen to exceed production from the liver. Associated consequences (hypovolaemia, third-spacing, peripheral oedema, hypercoagulable state through concurrent loss of antithrombin) and clinical signs (chronic weight loss, muscle wastage, small intestinal diarrhoea, vomiting, extended abdomen [ascites], pleural effusions, signs associated with thrombus formation) ensue. Causes of PLE are listed in the table below. Dog breeds predisposed to PLE include the Basenji, Yorkshire Terrier, Lundehund, Rottweiler, SCWT and Shar Pei. Besides hypoalbuminaemia, hypoglobulinaemia is common (exceptions: Basenji enteropathy, histoplasmosis, occasionally in alimentary lymphoma), as is hypocholesterolaemia, lymphopenia, hypocalcaemia and hypomagnesaemia. Often extensive investigations (laboratory assessment, diagnostic imaging) are necessary to rule out other causes of hypoalbuminaemia (protein-losing nephropathy, hepatic failure) or extra-gastrointestinal (GI) causes (e.g. exocrine pancreatic insufficiency, renal/ endocrine disease [i.e. hypoadrenocorticism]). Serum cobalamin should be assessed to ascertain the presence of malabsorption, as hypocobalaminaemia has a prognostic and therapeutic consequence. Specialised tests for intestinal permeability and absorption ("sugar tests", ⁵¹Cr-EDTA excretion) or advanced imaging to localise protein loss sites (⁵¹Cr or ⁶⁷Cu labelled albumin/ ceruloplasmin scintigraphy) are not often performed routinely.

<table><thead><tr><td>Causes for PLE</td><td>Examples</td></tr></thead><tbody><tr><td>Intestinal inflammation (severe Inflammatory Bowel Disease; IBD)</td><td>Lymphoplasmacytic, eosinophilic, granulomatous, ulcerative</td></tr><tr><td>Lymphangiectasia</td><td>Primary lymphatic disorder, venous hypertension (right heart failure, hepatic cirrhosis/ portal hypertension)</td></tr><tr><td>Neoplasia</td><td>Alimentary lymphoma</td></tr><tr><td>Infection</td><td>Parvovirosis, Salmonellosis, Histoplasmosis, Phycomycosis</td></tr><tr><td>Gastrointestinal haemorrhage</td><td>Idiopathic (acute haemorrhagic diarrhoea syndrome; AHDS), neoplasia, ulceration (drugs,...)</td></tr><tr><td>Endoparasites</td><td>Giardia, Ancylostoma, Trichuris,...</td></tr><tr><td>Structural</td><td>Intussusception (congestion, exsudation)</td></tr></tbody></table>

Intestinal biopsies are necessary to characterise the underlying pathology further and to rule out or diagnose intestinal neoplasia. In severe IBD or alimentary lymphoma, 3 basic mechanisms contribute to protein loss: lymphatic obstruction leading to lymphangiectasia and lacteal rupture, increased mucosal permeability due to mucosal infiltrations, and mechanical causes (ulcers, erosions, congestion). Lymphatic leakage leads to the formation of lipogranulomas in the intestinal wall or mesentery, which in turn contribute to the obstructive process. The latter are difficult to assess on
endoscopic pinch biopsies, which is why some dogs with severe PLE can have minimal mucosal
inflammation. Poor prognostic indicators in inflammatory PLE are a high Canine Inflammatory Bowel
Disease (CIBDAI) or Chronic Enteropathy Clinical Activity Index (CCECAI), and hypocobalaminaemia.
Prognostic value of third-spacing or thromboembolic events is unclear. Treatment of PLE is generally
aimed at the underlying cause (eg. chemotherapy for lymphoma). For PLE due to IBD, traditionally an
aggressive "step-down" approach is used, combining hypoallergenic or ultra-low fat diet,
antimicrobials, cobalamin, clopidogrel, steroids and early administration of second-line
immunosuppressants (SLI) like cyclosporine or chlorambucil. We have recently challenged this by a
retrospective analysis of dogs with inflammatory PLE, showing that when using a "step-up" approach
to immunosuppression, only 1/3 of dogs needed a SLI, while treatment requirements or outcome
could not be predicted by routine clinicopathological data. It is difficult to translate these findings to
the population of dogs with PLE presenting as emergency cases due to sudden deterioration or
complications.

Interestingly, there might be a condition with significant protein loss via the intestinal epithelium that
does not conform to traditional definitions of PLE, but combines some of its features with **acute
haemorrhagic diarrhoea syndrome (AHDS)**. AHDS (previously termed haemorrhagic gastroenteritis;
HGE) has originally been described to be typical for small breed dogs (ie. Yorkshire Terrier, Maltese,
Pekingese), presenting with acute onset of haemorrhagic small intestinal diarrhoea (see figure below).
The most consistent laboratory abnormality is haemoconcentration due to dehydration. Evidence for
the cause of AHDS is conflicting, with possible associations with *Clostridia* sp. infections, but
antimicrobial treatment is not indicated. Based on this, hypoalbuminaemia can be a potential - but
not predominant - feature of AHDS (due to blood loss). However, we and others are observing an
increasing number of dogs with no history of chronic GI disease, presenting with AHDS-like clinical
signs that lead to rapid and drastic loss of serum proteins. The speaker has termed this condition
"acute protein-losing syndrome" (APLS) for the purpose of this talk (see figure below). In comparison
to dogs with "classic" AHDS, dogs with APLS do not respond favourably or quickly to symptomatic and
supportive treatment. There is continuation of severe diarrhoea (often with significant GI ileus),
hypovolaemia and hypotension, prompting empirical additional treatment.
<figure><img src="image_25.png" /><figcaption>Figure 1. Description of typical features of acute haemorrhagic diarrhoea syndrome (AHDS) and chronic protein-losing enteropathy (PLE), in comparison to "mixed" features of APLS.</figcaption></figure>

As it can be difficult to differentiate AHDS from APLS initially, the ideal time point for more aggressive treatment is unclear. Furthermore, no consensus exists on what type of treatment would be appropriate. Often, antimicrobials (e.g. metronidazole) and immunosuppression (e.g. steroids) are administered, and measures for general support (colloids, albumin, plasma, pressors) as well as nutrition (enteral/tube feeding, partial parenteral nutrition) intensified. It is unclear if and at what stage these patients would benefit from GI biopsies. No infectious agent has been identified as a causative agent as far as the speaker is aware, and histology of GI biopsies is not consistently performed (speaker has seen one case with eosinophilic duodenitis/ ileitis and marked ulcerative colitis with suppurative exudate, involving clusters of invasive *Enterococci* on fluorescent in-situ hybridisation [FISH]). Routine assessment of biopsies (including FISH, immunohistochemistry, electron microscopy) or an intensified search for infectious agents might be needed in the future to characterise this disease further (figure 2). Outcome of APLS seems to be variable, with some dogs needing prolonged treatment, some recovering without the need for long-term medication, and some being euthanized for intractable disease. The speaker would like to invite a discussion on how frequently these types of cases are seen in other centres, if different approaches and outcomes are observed and what speculations there might be on potential causes.
<figure><img src="image_26.png" /><figcaption>Figure 2. Description of typical treatments of acute haemorrhagic diarrhoea syndrome (AHDS) and chronic protein-losing enteropathy (PLE), and suggestions for further workup and treatment of APLS</figcaption></figure>
# ACUTE HAEMORRHAGIC DIARRHOEA SYNDROME: WHERE ARE WE NOW?

Dominic Barfield BSc BVSc MVetMed DACVECC DECVECC FHEA MRCVS
The Royal Veterinary College, North Mymms, Hertfordshire, UK

Idiopathic acute haemorrhagic diarrhoea syndrome (AHDS) in dogs is described as acute onset haemorrhagic diarrhoea, often after vomiting. They have an increased haematocrit level (in half the dogs reported it was above the reference range) and a stress leukogram with neutrophilic left shift. There has been a seasonality reported (more common in winter) and often in young adult small breed dogs (Mortimer et al 2015). Previously it was known as haemorrhagic gastroenteritis, though the histopathological changes have been shown to be in the intestines, not in the stomach (Unterer et al 2014).

We are still unaware of the causative agent and therefore a diagnosis is made by excluding other cases of acute diarrhoea, for example canine parvovirus, salmonellosis, Campylobacter infection, NSAID use. Clostridium species have been identified in dogs with AHDS, though only small numbers were identified and there are other studies which have not identified Clostridial involvement. Clostridial perfringens enterotoxin and Clostridial difficile toxin A/B have also been examined and shown not to be associated with AHDS (Busch et al 2014). This has been postulated to different populations of dogs that have been examined, and even that clostridial overgrowth might be after the initial injury. Viral infection has also been postulated as an independent cause, such as circovirus (Anderson 2017), or even with concurrent clostridial overgrowth. More work needs to be undertaken to understand the causative agent(s) and it appears that the aetiology is far more complex than Koch's postulates.

We are beginning to understand a little more about the influence of the microbiome in the gastrointestinal tract and how that can assist with immune response amongst in addition to assisting with nutritional support. It is apparent that AHDS leads to a dysbiosis and this itself might lead to viral or bacterial organisms influencing the course of the disease. This is the area where novel therapies could be found.

As we do not know the causative agent(s) of AHDS, diagnosis, as mentioned earlier, is by excluding other diseases. Though in a similar way to ruling out all other cause of dysuria for FLUTD cats, often only common conditions are eliminated. Examining a blood smear might assist with the differential diagnosis, as well as parvovirus detection tests (where appropriate). Abdominal imaging might have some utility for the peracute presentation of vomiting if a differential diagnosis is gastrointestinal foreign body. Abdominal radiographs should be performed if that is a concern. Recent literature has argued that a complete abdominal ultrasound in patients presenting with only diarrhoea has no utility in the majority of cases, this did not include the use of patient-side ultrasound in the ICU (Mapletoft et al 2018).

Treatment has included fluid therapy, antiemetics, antacids, gastrointestinal diets, antibiotics and analgesia. Fluid therapy should always be tailored to the individual and restoration of the profound fluid losses needs to be corrected. Despite many of these patients having a higher than normal haematocrit it is not uncommon in the sicker individuals with AHDS to require blood transfusion therapy. Isotonic (replacement) crystalloid fluids are the preferred fluid to use and to tailor to the
individual. Care must be taken to reassess the patient regularly to make sure that the fluid balance is
appropriate.

Antiemetics are utilised in patients that continue to vomit, or are nauseous (e.g. maropitant, ondansetron). Antacids are also often used (ranitidine, famotidine, omeprazole).

Nutrition is important to address, and enteral feeding is the preferred route. More information on
nutrition can be found in notes on enteral feeding.

Antibiotics have been reported not to change the outcome of AHDS and for the most cases of AHDS
antibiotics are not required, however often the majority of veterinarians would prescribe them. It is
difficult to know which patients might require antibiotics, though those patients with a neutrophilic
left shift are unlikely to have any benefit, and in neutropenic patients it might be prudent.

Although there are groups working on identifying the causative agent for these cases, it is a complex
problem. In the meanwhile, improving effective therapies for the sicker patients would be beneficial
to the patients that do not seem to improve with traditional supportive therapy. Clinically the patients
that take longer to improve continue to have haemorrhagic diarrhoea, despite all interventions. A
treatment strategy might be to re-establish the microbiome either with lactobacillus cultures, or
faecal transplantation. The former has only shown to be beneficial in some small animal patients who
have diarrhoea (oncology patients inflammatory bowel disease), though it appears to anecdotally only
be effective when the patients remain on the therapy. There has been a recent case report on the use
or oral faecal microbiota transplantation for Clostridium difficile associated diarrhoea in a dog (Sugita
et al 2019) and last year in puppies with parvovirus, showing a faster resolution of diarrhoea. It seems
prudent that we should examine this therapy in dogs with AHDS.

References

Busch, K., Suchodolski, J.S., Kühner, K.A., Minamoto, Y., Steiner, J.M., Mueller, R.S., Hartmann, K. and Unterer, S., 2014. Clostridium perfringens enterotoxin and Clostridium difficile toxin A/B do not play a role in acute haemorrhagic diarrhoea syndrome in dogs. *Veterinary Record*, pp.vetrec-2014.

Anderson, A., Hartmann, K., Leutenegger, C.M., Proksch, A.L., Mueller, R.S. and Unterer, S., 2017. Role of canine circovirus in dogs with acute haemorrhagic diarrhoea. *Veterinary Record*, 180(22), pp.542-542.

Mapletoft, E.K., Allenspach, K. and Lamb, C.R., 2018. How useful is abdominal ultrasonography in dogs with diarrhoea?. *journal of small animal practice*, 59(1), pp.32-37.

Mortier, F., Strohmeyer, K., Hartmann, K., Unterer, S. (2015) Acute haemorrhagic diarrhoea syndrome in dogs: 108 cases *Veterinary Record* **176**, 627.

Sugita K, Yanuma N, Ohno H, Takahashi K, Kawano K, Morita H, Ohmori K. Oral faecal microbiota transplantation for the treatment of Clostridium difficile-associated diarrhoea in a dog: a case report. BMC veterinary research. 2019 Dec;15(1):11.

Pereira GQ, Gomes LA, Santos IS, Alfieri AF, Weese JS, Costa MC. Fecal microbiota transplantation in puppies with canine parvovirus infection. Journal of veterinary internal medicine. 2018 Mar 1;32(2):707-11.

Unterer, S., Busch, K., Leipzig, M., Hermanns, W., Wolf, G., Straubinger, R.K., Mueller, R.S. and Hartmann, K., 2014. Endoscopically visualized lesions, histologic findings, and bacterial invasion in the
gastrointestinal mucosa of dogs with acute hemorrhagic diarrhea syndrome. *Journal of Veterinary Internal Medicine*, 28(1), pp.52-58.
# ENTERAL FEEDING: SHOULD WE WORRY ABOUT GASTRIC RESIDUAL VOLUMES?

Professor Daniel L. Chan, DVM, DACVECC, DECVECC, DACVN, FHEA, MRCVS
The Royal Veterinary College, North Mymms, Hertfordshire, UK

## Introduction

Critically ill small animal patients require a host of supportive measures including nutritional support to ensure successful management and resolution of the underlying disease. Preservation of nutritional status has important implications for immune function, and wound healing required for recovery. Patients receiving early enteral nutritional support (i.e., within 2 days of admission) have lower risks of developing nosocomial infections, require fewer days of mechanical ventilation and have overall better patient outcomes. However, provision of nutrition in this patient population (i.e., critically ill) is particularly challenging and measures must taken to decrease risk of complications. Aspects of nutritional support that require special consideration include the timing that nutrition should be initiated, the route of feeding, the composition of the diet and other aspects of management that may impact nutritional management. The biggest obstacles for provision of nutrition support in critically ill patients includes intolerance to enteral feeding, difficulties with airway management and the reality that many of these patients may be cardiovascularly unstable, and therefore priority is given to interventions with immediate patient benefits. Cardiovascular instability is regarded as a relative contraindication to enteral feeding and therefore many of these patients are not assessed as ready to receive nutritional support.

During critical illness, patients often develop gastrointestinal dysmotility problems that require a host of medical and nutritional strategies to manage these complications. These include the use of prokinetic agents (Table 1) and adjusted feeding strategies. Human critically ill patients often have gastrointestinal intolerance that is manifested by an increased gastric residual volume (GRV). Published human feeding protocols have tried to define the threshold volume above which feeding should be withheld as well as recommend the frequency of GRV assessment. This issue is of particular interest in mechanically ventilated patients so much of the data is derived from this population. For example, the GRV considered to be excessive in ventilated patients have ranged from 120 to 500 mL per aspiration [1.7 to 7.1 mL/kg assuming a 70 kg person]. A low GRV threshold results in multiple interruptions in enteral nutrition (EN) provision due to frequent assessments of GRV, discarding checked volumes, and withholding feeding or reducing the rate of feeding due to presumed high GRV result in overall decrease in caloric intake, failure to achieve caloric targets, increased use of parenteral nutrition, which may all negatively impact outcome. More recent data have questioned the relationship between increased GRV and higher risk of aspiration pneumonia as well as the need to check GRV more than once daily. In light of these findings, some authors recommend against adjusting enteral feeding unless GRV exceed 500 mL and to reduce checking GRV to only once daily or not at all. Unfortunately, there is virtually no information available in ventilated veterinary patients in regards to GRV and risk of feeding. While some authors recommended checking GRV before every feed, and that GRV should not be allowed to exceed 10 mL/kg, there is currently no data to corroborate whether such guidelines are necessary although such recommendations may be sensible. Holahan and others (2010) could not relate GRV and gastrointestinal complications in dogs fed via nasogastric tubes and some of these dogs have > 200 mL/kg of GRV, however, it is unknown if any of the dogs evaluated were mechanically ventilated. The median (range) GRV in this population of
critically ill dogs was 4.5 mL/kg (0 to 213 mL/kg) (Holahan and others 2010). As current human guidelines (Bankhead and others 2009) state that enteral feedings should not be held unless GRV are >500 mL (approximately 7 mL/kg based on 70 kg person), it may be prudent to use a similar approach and so animals with GRV exceeding 10 mL/kg should be treated with prokinetic agents (See Table 1) and their feed reduced temporarily.

<table><caption>Table1. Prokinetic agents used in small animals for management of gastrointestinal dysmotility disorders.</caption><thead><tr><td>Agent</td><td>Dosage</td><td>Mode of action</td></tr></thead><tbody><tr><td>cisapride</td><td><ul><li>Dogs: 0.2-1.0 mg/kg PO q8h</li><li>Cats: 2.5 - 5 mg/cat, PO q8h</li></ul></td><td>Serotonergic agonist (5HT<sub>4</sub>)<br>Serotonergic antagonist (5HT<sub>1,3</sub>)</td></tr><tr><td>domperidone</td><td><ul><li>0.05 – 0.1 mg/kg PO q12h</li></ul></td><td>Dopaminergic (D<sub>2</sub>) antagonist</td></tr><tr><td>erythromycin</td><td><ul><li>0.5–1.0 mg/kg, IV, PO q8h – q12h</li></ul></td><td>Motilin agonist<br>Serotonergic antagonist (5HT<sub>3</sub>)</td></tr><tr><td>metoclopramide</td><td><ul><li>Constant rate infusion: 1-2 mg/kg/day IV</li><li>0.2-0.5 mg/kg PO, IV, SQ q8h</li></ul></td><td>Dopaminergic (D<sub>2</sub>) antagonist<br>Serotonergic agonist (5HT<sub>4</sub>)</td></tr><tr><td>nizatidine</td><td><ul><li>2.5-5.0 mg/kg PO q24h</li></ul></td><td>H<sub>2</sub>- histaminergic antagonist</td></tr><tr><td>ranitidine</td><td><ul><li>1.0-2.0 mg/kg PO q8h - q12h</li></ul></td><td>H<sub>2</sub>- histaminergic antagonist</td></tr></tbody></table>

## Nutritional management strategies

In people, the provision of enteral nutrition can be delivered via nasogastric or nasojejunal feeding tubes. Nasojejunal feeding has been recommended as the preferred route in patients with a high risk of aspiration as well as in those patients for whom gastric feeding is not tolerated, or who have repeated high gastric residual volumes (McClave and others 2009). Unfortunately there is little veterinary data regarding nutritional support of small animal patients in relation to this problem. Upon reviewing available veterinary clinical studies on mechanical ventilation, as well as veterinary studies on assisted feeding and parenteral nutrition, there are only brief mentions of patients that were ventilated and received some form of nutritional support (King and Hendricks 1994, Reuter and others 1998, Beal and others 2001, Chan and others 2002, Pyle and others 2004, Lee and others 2005, Armitage-Chan and others 2006, Crabb and others 2006, Hopper and others 2007, Campbell and others 2010, Holahan and others 2010, Hoareau and others 2011, Rutter and others 2011, Gajanayake and others 2013, Queau and others 2013, Yu and others 2013, Edwards and others 2014). From the information available, it is clear that in some studies, only a proportion of ventilated patients (40 to 50%) receive any form of nutritional support, that a high proportion receive parenteral nutrition (up to 38%) and in those that have EN, it was stopped in up to 60% of patients due to regurgitation, high GRV and aspiration (Hopper and others 2007, Rutter and others 2011). Therefore formulation of feeding recommendations in ventilated small animals must be mostly extrapolated from information available in other populations and species.
The first question relates to optimal timing of nutritional support initiation. The urgency of initiating nutritional support will depend on the nutritional assessment and nutritional status of the patient. As in other critically ill small animals, nutritional support should only be considered in cardiovascularly stable patients, but should generally be initiated within 48 to 72 hours of mechanical ventilation. Although avoidance of enteral feeding in mechanically ventilated patients may seem reasonable, parenteral nutrition should only be used if there are contraindications to enteral feedings such as persistent vomiting or regurgitation. Enteral access devices for ventilated patients include nasogastric, oesophageal, gastric, and nasojejunal feeding tubes. Nasogastric may be most appropriate for most ventilated patients, although some may benefit from post-pyloric placement of feeding tubes. Enteral feed may be delivered continuously or intermittently as there appears to be little difference in complication rates (Holahan and others 2010, Campbell and others 2010, Yu and others 2013).

## Summary

Critically ill patients are often the most critical and complex cases in any given veterinary hospital and present the veterinary team with a number of challenges. Determining ideal time for initiating nutritional support, the route of delivery, caloric targets, diet composition and closely monitoring for tolerance of feeding, are essential components of the strategy to manage mechanically ventilated patients.

## Keypoints

* Critically ill small animal patients require a host of supportive measures including nutritional support to ensure successful management and resolution of the underlying disease

* Preservation of nutritional status has important implications for immune function, wound healing and recovery

* Provision of nutrition in this patient population is particularly challenging and measures such as use of prokinetic agents, nasogastric or nasojejunal feeding tubes may be necessary

* We do not yet have good data to make firm recommendations about how GRV should alter enteral feeding plans, though a sensible plan may include that GRV should not be allowed to exceed 10 mL/kg

## References available upon request
# WHERE DID IMMUNUNUTRITION GO?

Daniel L. Chan, DVM, DACVECC, DECVECC, DACVN, FHEA, MRCVS
The Royal Veterinary College, North Mymms, Hertfordshire, UK

## Introduction

In critically ill and hospitalized animals, the role of nutritional support in the overall management of patients is well established. However, nutrition is most often simply regarded as a supportive measure. Recently, further understanding of the underlying mechanisms of various disease processes and the recognition that certain nutrients possess pharmacological properties have led to investigations on how nutritional therapies themselves could modify the behavior of various conditions and improve patient outcomes and this has been dubbed ‘therapeutic nutrition.’ (Wischmeyer & Heyland 2010) Nutrients such as certain vitamins, amino acids, and polyunsaturated fatty acids can modulate inflammation and the immune response. (Cahill & others 2010, Hegazi & others 2011) A major focus of nutrition in critically ill human patients now involves the development of strategies that target or modulate metabolic pathways, inflammation and the immune system. (Hegazi & others 2011) Exploiting pharmacological effects of certain nutrients to modulate disease processes and patient outcomes has been the subject of various clinical trials in people, however, a similar focus on clinical veterinary patients has of yet not taken place. The use of nutritional strategies in ameliorating animal diseases has been shown to be beneficial in the areas of chronic kidney disease (e.g., protein and phosphorous restriction) (Bauer & others 1999, Brown & others 1998), and cardiac disease (e.g., omega-3 fatty acids) (Freeman & others 1998, Smith & others 2007). In people, there is mounting evidence that certain nutrients such as glutamine, omega-3 fatty acids and antioxidants can positively impact both morbidity and mortality in critically ill populations. It is hoped that a greater understanding of how these nutrients impart such beneficial effects may lead to developments of novel strategies for modulating various diseases in small animals. To this end, a review of how nutritional strategies could be used to modulate disease, especially in critically ill animals, is the focus of this lecture and is discussed in greater detail.

## Nutritional Management Strategies

### Omega-3 Fatty Acids

As inflammation plays a crucial role in many diseases, modulation of the inflammatory response has become an important target of therapy. Inflammation yields several lipid mediators that are involved in a complex regulatory array of the inflammatory process. Lipid mediators are synthesized by three main pathways, namely the cyclooxygenase, 5-lipoxygenase and cytochrome P450 pathways and they each use polyunsaturated fatty acids (PUFA) such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) as substrates. (Mayer & others 2006) Potent proinflammatory eicosanoids, leukotrienes, and thromboxanes of the 2 and 4 series are produced from arachidonic acid (AA) metabolism. Classically, modulation of inflammation was thought to result from greater substitution of omega-6 fatty acids i.e., AA with EPA and DHA in cell membranes, such that when these PUFAs were cleaved by phospholipases and oxidized by several enzymes led to less inflammatory eicosanoids of the 3 and 5 series. (Mayer & others 2006).

However, it is now clear that the biological anti-inflammatory activities of omega-3 fatty acids are far beyond the simple regulation of eicosanoid production. Namely, these PUFAs can affect immune cell
responses through the regulation of gene expression, subsequent downstream events by acting as
ligands for nuclear receptors and through control of some key transcription factors. (Singer & others
2008) EPA can also inhibit the activity of the proinflammatory transcription nuclear factor B (NF-kappa
B) at several levels, which regulates the expression of many proinflammatory mediators (e.g.,
cytokines, chemokines) and other effectors of the innate immune response system. (Singer & others
2008) In addition, recent research has revealed that free EPA and DHA also inhibit the activation of
Toll-like receptor 4 by endotoxin and thereby further inhibit the inflammatory response. (Lee & others
2006) Finally, recent discoveries have identified that EPA and DHA are also substrates of two novel
classes of mediators called resolvins and protectins, which are involved in the inhibition and resolution
of the inflammatory process, which now appears to be a well orchestrated, complex, active process
involving these mediators. (Singer & others 2008, Willoughby & others 2000) Therefore, in the context
of disease modulation, omega-3 fatty acids help reduce the production of inflammatory mediators
and are incorporated in the synthesis of anti-inflammatory and "pro-resolution" factors, which serve
to attenuate the inflammatory response and the innate immune response.

In regards to the clinical use of omega-3 fatty acids in critically ill populations, the evidence is exclusively from human medicine. Enteral supplementation of EPA/DHA with concurrent antioxidants has been well established in ventilated patients with acute lung injury (Pontes-Arruda & others 2008) and more recently, it has been shown to improve outcome in patients with early sepsis. (Pontes-Arruda & others 2011) However, the data is not entirely conclusive, especially when omega-3 fatty acids are administered intravenously via parenteral nutrition. In a recent meta-analysis of studies evaluating supplemental omega-3 fatty acids in parenteral nutrition, no statistically significant benefits were identified in regards to mortality, infection or ICU stay and only weak evidence that such supplementation may shorten overall hospitalization. (Palmer & others 2013) However, the analysis should be considered preliminary as there fewer than 10 trials included in the analysis and 6 of these trials contained fewer than 50 patients and therefore the conclusions regarding the utility of parenteral omega-3 fatty acids should be reserved until more data is available. (Palmer & others 2013) It is worth noting that the analysis did possibly uncover that timing of supplementation (i.e., early versus late in the disease process) may have a large impact in results. Many of the trials included in the analysis recruited patients in septic shock and therefore the ability to demonstrate treatment benefit would be extremely difficult. (Palmer & others 2013) The recent results of the INTERSEPT Study (Pontes-Arruda & others 2011) using enteral EPA/DHA would support this hypothesis as they recruited patients with early sepsis without organ dysfunction and were able to demonstrate various improvements in outcome. Currently, no data is available on the use of omega-3 fatty acids in critically ill veterinary populations. Given the number of potential benefits in modulation inflammation and patient outcome, further research in this area is warranted.

Antioxidants

Similar to inflammation, oxidative stress is also recognized to be a prominent and common feature of
many disease processes, including neoplasia, cardiac disease, trauma, burns, severe pancreatitis,
sepsis, and critical illness. During various pathophysiological states, particularly those typified by an
inflammatory response, cells of the immune system such as neutrophils, macrophages, and
eosinophils substantially contribute to the production of reactive oxygen species (ROS) and reactive
nitrogen species (RNS). With the depletion of normal antioxidant defenses, the host is more
vulnerable to free radical species and prone to cellular and subcellular damage (e.g., DNA,
mitochondrial damage). (Manzanares & others 2012) The degree of antioxidant depletion appears to reflect severity of illness in human patient populations. (Alonso de Vega & others 2002) Oxidative stress is believed to be not only a promoter of inflammation but also a key factor leading to multiple organ failure. (Manzanares & others 2012).

Replenishment of antioxidant defenses attempts to lessen the intensity of the injury caused by ROS and RNS. Antioxidants can be classified in three different systems: 1) Antioxidant proteins such as albumin, haptoglobin and ceruloplasmin, 2) Enzymatic antioxidants such as superoxide dismutase, glutathione peroxidase, and catalase and 3) Non-enzymatic or small molecule antioxidants such as ascorbate (vitamin C), alpha-tocopherol (vitamin E), glutathione, selenium, lycopene and beta-carotene. N-acetylcysteine is a powerful progenitor of glutathione and has been associated with some positive results in several patient populations. Treatment with N-acetylcysteine not only scavenges ROS but also enables continual production of glutathione and even blocks transcription of inflammatory cytokines. (Manzanares & others 2012).

In regards to clinical evidence in critically ill people, a number of meta-analyses have indicated that the administration of antioxidant micronutrients (both as monotherapy or in combination therapy or antioxidant cocktails) is associated with a mortality risk reduction, reduced mechanical ventilator dependence but only a trend for reduced infectious complications. (Manzanares & others 2012, Heyland & others 2005, Visse & others 2011) It is interesting to note that the effect on mortality reduction was most apparent in populations with expected highest mortality rates but a difference could not be detected when the mortality rate between the critically ill population and control population was less than 10%. (Manzanares & others 2012) However not all of the data regarding the use of antioxidants in the critically ill is positive. In a recent Cochrane review (Szakmany & others 2012) of the use of N-acetylcysteine for sepsis and systemic inflammatory responses syndrome (SIRS) in adult human patients, the authors concluded that their analysis casts "doubt on the safety and utility of intravenous N-acetylcysteine as an adjuvant therapy in SIRS and sepsis. (Szakmany & others 2012) At best, N-acetylcysteine is ineffective in reducing mortality and complications in this patient population." (Szakmany & others 2012) The analysis also highlighted concern that administration of N-acetylcysteine after 24 hours of onset of symptoms could lead to cardiovascular depression. (Szakmany & others 2012) Typically, Cochrane reviews are very conservative in their analytical methods and seldom support novel interventions in critically ill populations. It is clear that further research is required to identify the most appropriate approach in modulating oxidative stress in the critically ill patients.

Despite the clear importance of oxidative stress in various diseases in veterinary species, investigations evaluating the effect of antioxidants on disease processes are limited. Positive results have been demonstrated in experimental models of oxidative stress including in conditions such as congestive heart failure, (Amado & others 2005) acute pancreatitis, (Marks & others 1998) gastric dilatation-volvulus, (Badylak & others 1990) renal transplantation, (Lee & others 2006) gentamicin-induced nephrotoxicity, (Varzi & others 2007) and paracetamol (acetaminophen) toxicity. (Webb & others 2003, Hill & others 2005) Supplementation of vitamin E alone did not prevent oxidative injury (i.e., development of Heinz body anaemia), in cats fed onion powder or propylene glycol but the same group of investigators later showed that supplementation of vitamin E with cysteine in cats decreased
the production of methaemoglobinaemia following paracetamol (acetaminophen) challenge. (Hill & others 2005).

In naturally-occurring disease such as chronic valvular disease (Freeman & others 1998) and renal insufficiency (Plevraki & others 2006) there have also been some positive results that support the need for further evaluation. Unfortunately, the use of antioxidants in the setting of critically ill veterinary patients has not been published.

## Immune-Modulating Nutrients

Amino acids fulfill a vast array of functions in the body. They primarily serve as building blocks for protein synthesis and participate in various chemical reactions. Certain amino acids have immune-modulating properties and they help maintain the functional integrity of immune cells, aid in wound healing and tissue repair. They may also serve as an energy source for certain cells; perhaps the most pertinent example being glutamine which is the preferred fuel source for enterocytes and cells of the immune system. During disease states, the body undergoes marked alterations in substrate metabolism that could lead to a deficiency in these amino acids. In the response to stress there may be a dramatic increase in demand by the host of particular amino acids such as arginine and glutamine. In health these amino acids are adequately synthesized by the host. However, during periods following severe trauma, infection or inflammation, the demand for these amino acids cannot be met by the host, and they become "conditionally essential," and must be obtained from the diet. Given the importance of these amino acids, the sudden depletion in these important substrates led to the hypothesis that dietary supplementation of these amino acids during disease would improve outcome. In addition, in times of injury and tissue repair and rapid cellular proliferation, nucleotide availability may become depleted and rate-limiting for the synthesis of nucleotide-derived compounds. (Hegazi & others 2011).

## Arginine

Arginine is a conditionally essential amino acid that is required for polyamine synthesis (for cell growth and proliferation), proline synthesis (for wound healing) and is a precursor for nitric oxide (signaling molecule for immune cells). Following extensive injury or surgery, immature cells of myeloid origin produce arginase-1, an enzyme that breaks down arginine. The ensuing arginine deficiency is associated with suppression of T-lymphocyte function. (Popovic & others 2011) When steps are taken to replenish arginine along with omega-3 fatty acids, T cell number and function improves. There is also data that demonstrates a significant treatment benefit following supplementation after major surgery. Clinical benefits included fewer infectious complication rates and decreased overall length of stay when compared with standard nutritional support. (Hegazi & others 2011).

The one population where arginine therapy is likely to be contraindicated is patients with severe sepsis. (Hegazi & others 2011) Likely causes of this detrimental effect relate to promotion of excessive nitric oxide synthesis, worsening of cardiovascular tone and decreasing organ perfusion. (Hegazi & others 2011).

## Glutamine

Glutamine, another conditionally-essential amino acid, is the most abundant free amino acid in circulation, however, stores are rapidly depleted during critical illness in people. A deficiency in
glutamine has been documented to impair several important defense mechanisms of the host. Supplementation of glutamine during critical illness is well accepted to confer beneficial effects on patient outcomes. The evidence had been so strong that nutritional guidelines for critically ill people recommended supplemental glutamine to any patient receiving parenteral nutrition. (Wernerman 2011, McClave & others 2009, Kreymann & others 2006). The proposed mechanisms by which glutamine improves outcomes involve: 1) Tissue protection (e.g., heat shock protein expression, maintenance of gut barrier integrity and function, and decreased apoptosis), 2) Anti-inflammatory and immune-modulation (e.g., decreased cytokine production, inhibition of NF-kB), 3) Preservation of metabolic function (e.g., improved insulin sensitivity, ATP synthesis), and 4) Anti-oxidant effects (i.e., enhance glutathione generation) and 5) Attenuation of inducible nitric oxide synthase activity. (Wischmeyer & Heyland 2010).

The evidence supporting the use of glutamine in critically ill human patients had been overwhelmingly positive, until the publication of the largest randomized placebo-controlled, double blinded clinical trial evaluating high dose glutamine and antioxidants in severely ill patients. (Heyland and others 2013) In this seminal study, over 1200 critically ill patients, with at least 2 failing organ systems and requiring mechanical ventilation were randomly allocated to glutamine vs placebo treatment and antioxidants vs placebo treatment. Unexpectantly, there was a trend for increased mortality associated with glutamine use. (Heyland and others 2013) There was no effect of glutamine on rates of organ failure or infectious complications, and antioxidants had no effects discernable. (Heyland and others 2013) The exact reasons for the observed trend in increased mortality was not identified, but it is worth noting that the dose of glutamine used in this study was much higher than any previous study to date and also, that this study population included patients in shock being treated with nutritional support prior to achieving haemodynamic stability. Most recommendations for nutrition support (both enteral and parenteral) in the critically ill patient, stipulate that cardiovascular stability must be achieved before commencing nutritional support. (McClave and others 2009).

Despite ample evidence guiding treatment recommendations in people, there are no equivalent recommendations in the veterinary literature pertaining to glutamine use. This is likely due to the lack of supporting data and limited availability of parenteral glutamine. To date, there are only a few published veterinary trials that have evaluated the use of glutamine (enteral or parenteral) in dogs and cats. In a trial of cats treated with methotrexate, enteral glutamine offered no intestinal protection in terms of reducing intestinal permeability or improving severity of clinical signs. (Marks & others 1999) Another trial evaluating the effects of enteral glutamine on plasma glutamine concentrations and prostaglandin E₂ concentrations in radiation-induced mucositis showed no measurable benefit. (Lana & others 2003) Possible reasons for the apparent failures in both of these trials could be attributed to inadequate doses used or because of the form used, enteral, was not effective in these conditions. In contrast, a recent experimental canine model of post-operative ileus (Ohno & others 2009) evaluated the effects of glutamine on restoration of interdigestive migrating contraction in the intestines and they were able to demonstrate a statistically significant reduction in the time to restore contractions in the glutamine treated group. The authors hypothesized that the benefit was derived from glutamine's ability to maintain glutathione concentration and thereby counteract the deleterious effects from surgical injury, inflammation and oxidative stress. They concluded that administration of glutamine following gastrectomy could shorten the duration of ileus (a major problem post-operatively in critically ill people) and may protect against surgical stress in
general. (Ohno & others 2009) Given these positive results, further studies should evaluate the
possible beneficial effects of glutamine supplementation in treating ileus and other gastrointestinal
motility disorders in dogs with natural-occurring disease.

Most recently Kang et al demonstrated that the immune suppression induced by high-dose
methylprednisolone sodium succinate therapy can be ameliorated by parenteral administration of L-
alanyl-L-glutamine. (Kang & others 2011) The study was designed to address a common concern
associated with high dose glucocorticoid therapy, namely, immune-suppression. The model employed
did demonstrate that such high doses of glucocorticoid can suppress oxidative burst activity and
phagocytic capacity of neutrophils. Although the study used an experimental model, it suggests that
parenteral glutamine does have immunomodulatory effects in dogs, and that in the future, more
clinically applicable uses should be explored. Unfortunately, parenteral glutamine is not routinely
available in North America and the majority of studies evaluating parenteral glutamine are performed
in Europe and Asia.

Nucleotides

These low molecular weight intracellular compounds (i.e., pyrimidine and purine) are the basic
building blocks for the synthesis of DNA, RNA, ATP and key coenzymes involved in essential metabolic
reactions. Similarly to amino acids, nucleotides can be synthesized de novo or can be salvaged and
recycled from other molecules. The reason nucleotides are included in this discussion of therapeutic
nutrition is that during disease states and injury, the rapid cell proliferation required for tissue healing
leads to nucleotide depletion. (Hegazi & others 2011) Dietary supplementation can compensate for
such depletions and support cell proliferation and differentiation. As the cell types most affected by
shortfall in nucleotides are cells of the immune systems and of the gastrointestinal tract, nucleotide
supplementation is often included in 'immune-enhancing diets.' The evidence for the beneficial
effects of dietary nucleotides is mostly from pre-clinical trials and rodent models, therefore further
research is still warranted. (Hess & Greenberg 2012) From the pathophysiological point of view,
supplementation of dietary nucleotides may be particularly important in animals with prolonged
anorexia as supplementation in rodent models enhance intestinal repair, restore brush-border
enzyme activity and improve gut barrier function. (Hess & Greenberg 2012) Additional benefits of
dietary nucleotides include positive effects on gut flora, gastrointestinal microcirculation, immune
function and inflammation. (Hess & Greenberg 2012) Given the plethora of potential beneficial effects
without clear detrimental effects, it is not surprising that nucleotides have been included in some
immune-enhancing diet cocktails despite the lack of definitive results. Although results of trials using
these immune-enhancing cocktails are encouraging and mostly positive, it is unknown if these effects
are synergistic or whether they result from the summation of the individual components. To date, no
veterinary studies have evaluated the potential utility of supplementing nucleotides to critically ill
patients.

Probiotics

Probiotics are live microorganisms that, when ingested in sufficient amounts, have a positive effect
on the health of the host. Some of the benefits purportedly related to probiotics include reduced
production of toxic bacterial metabolites, increased production of certain vitamins, enhanced
resistance to bacterial colonization, and reinforcing host natural defenses. Probiotics are also believed
to shorten duration of infections or decrease host susceptibility to pathogens. (Morrow & others 2012)
The proposed mechanisms underlying the positive effects include restoration of gastrointestinal
barrier function, modification of the gut flora by inducing host cell antimicrobial peptides (i.e., defensins, cathelicidins) or releasing probiotic antimicrobial factors (e.g., bacteriocins, microsins), competing for epithelial adherence and immunomodulation. (Morrow & others 2012) Probiotics are therefore believed to have a role in balancing gut microflora and increasing host resistance to pathogenic bacteria. It is worth bearing in mind that the effects of probiotics are not only dose-dependent but also both strain and species-specific. (Petrof & others 2012) In people, probiotics used include various species of *Lactobacillus*, *Bifidobacterium*, and *Streptococcus*. (Morrow & others 2012) Microorganisms approved for use in animal feeds include strains belonging to the *Bacillus*, *Enterococcus*, and *Lactobacillus* bacterial groups.

The mechanism by which probiotics enhance gut barrier function may involve how certain bacteria e.g., *Lactobacillus*, stimulate mucin production and thereby inhibit pathogenic bacteria from invading and attaching to the gut epithelium. (Morrow & others 2012) One of the concerns with the use of probiotics is that there is a risk that certain microorganisms, such as enterococci, may harbor transmissible antimicrobial resistance determinants (i.e., plasmids), thus contributing to the problem of antimicrobial resistance. The use of probiotics in the critically ill is controversial and guidelines recommend further safety trials before further use in critically ill patients. (Petrof & others 2012).

In human critical care, probiotics have been used to combat antimicrobial-associated diarrhoea, *Clostridium difficile* infections, and ventilator-associated pneumonia. (Morrow & others 2012) The probiotic yeast *Saccharomyces boulardii* apparently produces a protease which degrades *C. difficile* toxins and may also stimulate IgA secretions against *C. difficile* toxins. (Petrof & others 2012) The only meta-analysis evaluating probiotics to prevent ventilator-associated pneumonia demonstrated a significant reduction in incidence of ventilator-associated pneumonia and length of ICU stay. (Siempos & others 2010) Thus far, trials evaluating probiotics in critically ill patients have only demonstrated a trend towards reduced ICU mortality. (Petrof & others 2012).

Probiotics have the theoretical risk of transferring antibiotic resistance genes, translocating from intestine to other areas or developing adverse reactions via interactions with host's microflora. While bacteraemia has not been documented with probiotic use in critically ill people, there are single case reports detailing infections with probiotic strains in patients that are immune-suppressed. (Boyle and others 2006).

In veterinary medicine, there are no trials evaluating the use of probiotics in a critically ill patient population. However, there have been trials in dogs with gastrointestinal signs. A prospective placebo controlled probiotic trial using a canine-specific probiotic cocktail containing 3 different *Lactobacillus spp* strains in addition to novel protein diet was able to demonstrate a dramatic improvement in clinical signs after dietary change but no additional benefit attributed to the additional of a probiotic. (Sauter & others 2006) Other studies have documented some positive effects such as improvements in immunological markers or desirable changes in microbiota, however, these trials have mostly been performed on healthy dogs. It is uncertain whether these benefits would improve clinical signs in dogs with critical illness.
**Summary**

Despite the many pitfalls discussed, nutritional modulation of diseases appears to be a potentially useful strategy for companion animals. However, until trials can elucidate which specific nutrients and what dosages confer beneficial effects to particular patient populations, a certain degree of caution is advised. Of particular concern is the distinct possibility that significant species differences may reduce the usefulness of some of these approaches in veterinary patients. Before general recommendations for the use of immunomodulating nutrients in veterinary patients can be made, many questions must be answered. Central issues of safety, purity and efficacy must be addressed. However, as our understanding of the interactions between nutrients and disease processes grows, we may yet identify specific nutrients that could modulate serious diseases. Based on the progress being made in the area of clinical nutrition, it is quite evident that there should be a greater appreciation for the role nutrients play in ameliorating diseases, and how treatment strategies for certain conditions in companion animals may one day heavily depend on nutritional therapies.

**References available upon request**
# REFEEDING SYNDROME – PHANTOM MENACE?

Daniel L. Chan, DVM, DACVECC, DECVECC, DACVN, FHEA, MRCVS
The Royal Veterinary College, North Mymms, Hertfordshire, UK

## Introduction

Refeeding syndrome refers to a potentially fatal constellation of metabolic derangements that occur following refeeding a patient after an extended period of anorexia or severe malnutrition. These metabolic derangements include severe hypophosphataemia, hypomagnesaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hyperglycaemia and vitamin deficiencies. Clinical manifestations of these abnormalities include peripheral oedema, haemolytic anaemia, cardiac failure, neurological dysfunction and respiratory failure. These patients often have an intracellular depletion of electrolytes that may not be identified on evaluation of serum electrolytes.

Upon refeeding, there is increased utilization of phosphorus and magnesium to drive metabolic pathways as substrate and co-factors for adenosine triphosphate (ATP) synthesis. This increased intracellular need, in conjunction with cotransport of potassium into the cell with insulin-driven glucose uptake, results in the depletion of these electrolytes. Many of these metabolic changes are believed to result from sudden release of insulin (stimulated by carbohydrate intake) in the presence of total body nutrient depletion. Hypophosphataemia is the most common and consistent abnormality seen in refeeding syndrome and also results in many of the complications seen. Moreover, depletion of magnesium and potassium further contribute to development of complications. The successful management and refeeding of a patient with a history of prolonged starvation, therefore, involves careful use of fluid therapy, nutritional replacement, and support of cardiac and respiratory function.

## Pathophysiology

This syndrome is believed to result when enteral or parenteral nutrition, are fed to starved or severely malnourished patients leading to changes and redistribution of fluid and electrolytes that cannot be accommodated by the weakened cardiovascular system. The ensuing depletion in phosphate results in neuromuscular, cardiovascular and respiratory compromise (e.g., diaphragmatic muscle fatigue, respiratory failure). Arrhythmias could be induced by hypokalaemia in combination with hypocalcaemia and hypomagnesaemia. Upregulation of carbohydrate metabolism may explain increased demand for magnesium and thiamine, which then leads to neurological and neuromuscular complications. Typically, refeeding syndrome occurs within the first 2 to 5 days after initiation of feeding, but signs can be detected within hours of refeeding or delayed up to 10 days.

Systemic responses to prolonged starvation reported in people with severe weight loss secondary to anorexia nervosa include severe bradycardia, hypothermia, and hypoventilation. These changes reflect a decrease in resting metabolic rate that occurs within a few days of cessation of nutrition. Decreased metabolism results from decreased insulin activity, reduction of glucose utilization, and loss of metabolically active lean body mass. Skeletal muscle wasting and reduction in respiratory muscle function leads to poor shivering ability and further compromises ventilatory function and body temperature regulation. Eventually, decreased myocardial mass and ventricular contractility occur, leading to decreased cardiac output. The reported incidence of cardiovascular related complications
in anorexia nervosa is high (up to 95%), and these include bradycardia, postural hypotension, fluid overload and cardiac arrhythmias, and result in a high incidence of cardiovascular-related mortality. During starvation, depletion of electrolytes such as potassium and magnesium, occur because of decreased dietary intake. Catabolism of fat and muscle also contributes to further electrolyte losses. Adjustments in renal electrolyte excretion maintain serum concentrations and clinical signs of electrolyte depletion may not be seen initially. During refeeding, intake of carbohydrate stimulates insulin release, resulting in conversion from a catabolic to an anabolic state, which increases cellular demand for phosphorus, potassium, and water. Newly synthesized cells require potassium for maintenance of electrical gradients and translocate serum potassium and phosphorus intracellularly. Stimulated processes such as glycolysis and protein synthesis also require cellular uptake of phosphate and magnesium. The increase in cellular activity resulting from insulin release therefore rapidly increases cellular requirement for magnesium, depleting serum magnesium concentration. As starvation leads to whole-body depletion of these electrolytes, cellular translocation can cause severe serum depletion and life-threatening complications. Inorganic phosphate is required for generation of high-energy substrates such as adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG). Protein phosphorylation is also required for many intracellular enzymatic processes. Hypophosphataemia decreases ATP synthesis causing an energy deficit that is responsible for many of the clinical signs associated with refeeding syndrome. Refeeding-associated hypophosphataemia has been reported previously in cats when it resulted in haemolytic anaemia. Thiamine deficiency is an important component of refeeding syndrome in people and has also been reported in cats. Signs of thiamine deficiency include ataxia, vestibular dysfunction, and visual disturbances. Thiamine is a cofactor in many enzymatic reactions involved in carbohydrate metabolism and clinical deficiencies may develop as refeeding of carbohydrates dramatically increase cellular thiamine utilization.

## Nutritional management strategies

The risk of developing refeeding syndrome may be related to the degree of prior malnutrition, although it has been reported to occur in critically ill patients after a brief period of starvation (48 hours). Proposed guidelines for identification of patients at high risk for developing refeeding syndrome in people include decreased body mass index (BMI), unintentional weight loss >10% in previous 3 to 6 months, complete lack of food intake, decreased serum concentrations of potassium, phosphorus or magnesium before initiation of feeding.

General guidelines for the prevention of refeeding syndrome state that nutritional support should not be initiated prior to correction of fluid and electrolyte imbalances. Once stabilization is achieved, nutrition should be administered gradually and only increased incrementally. Recommendations for prevention of refeeding complications in people suggest that initial refeeding should not exceed 20 kcal/kg/day. Refeeding syndrome has been reported to occur in cats fed only approximately 6 kcal/kg/day; it is therefore possible that refeeding complications in cats may be triggered at a lower level of caloric intake than is typically seen with people. A loading dose of thiamine, followed by daily injections until day 3 of therapy is also recommended before initiation of feeding.

Although there is insufficient information available from dogs and cats at risk for developing refeeding syndrome, protocols for reducing the risk for this disorder are available in people. In a protocol proposed by Hofer and others (2014), which have been adopted by the European Society of Clinical Nutrition and Metabolism (ESPEN), there should be careful patient assessment of patients at risk for
developing refeeding syndrome, restoration of fluid balance without overloading the cardiovascular system, initiation empirical supplementation of phosphate, potassium and magnesium (unless serum concentrations of these electrolytes are increased), initiation of thiamine and other B vitamins and trace mineral with the exception of iron. The caloric intake is gradually increased from 10 kcal/kg to 30 kcal/kg over the course of 10 days with daily monitoring of potassium, phosphate, magnesium and glucose.

Extrapolating from recommendations in people and recommended supplementation regimens in animals, a sensible approach would be to empirically supplement high risk patients with phosphate at 0.01-0.03 mmol/kg/hr, potassium at 0.05 mmol/kg/hr, and magnesium at 0.01 to 0.02 mmol/kg/hr for first 24 hours of therapy, provided the patient does not have any of these electrolytes above the reference interval for the first 3 days. Thiamine should be administered prior to feeding at 25 mg total dose (cats) or 100 mg total dose (dogs) either subcutaneously or intramuscularly daily until signs resolve. When nutritional support is instituted, no greater than 20% of RER should be provided in first day and nutritional support should be increased gradually over 4-10 days.

## Monitoring

Patients considered at risk for developing refeeding syndrome should be monitored daily as successful treatment may be dependent in identifying this condition in the early stages. Body weight, urine output, serum electrolytes, electrocardiography, serum glucose, cardiovascular and respiratory function should also be monitored closely. The specific electrolytes that should be monitored closely include potassium, phosphate, magnesium, and calcium.

## Summary

Refeeding syndrome is an uncommon but potential fatal complication associated with the initiation of nutritional support in severely malnourished animals, particularly cats. Typical metabolic derangements include severe hypophosphataemia, hypomagnesaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hyperglycaemia and vitamin deficiencies. Clinical manifestations of these abnormalities include peripheral oedema, haemolytic anaemia, cardiac failure, neurological dysfunction and respiratory failure. The successful management and refeeding of a patient with a history of prolonged starvation, involves careful use of fluid therapy, nutritional replacement, and support of cardiac and respiratory function. Before initiation of feeding, patients should be supplemented with thiamine as well as phosphorus, potassium and magnesium. Energy targets should be very conservative (e.g., 20 to 30% of RER on first day) and only gradually increased over the next several days. With careful management of cases at risk for developing refeeding syndrome, nutritional support can play a key role in the recovery of these patients.

References available upon request
# PROBIOTICS IN THE ICU WITH REFERENCE TO THEIR USE IN INFLAMMATORY BOWEL DISEASE

Silke Salavati, Dr.med.vet., PhD, DECVIM-CA, MRCVS
R(D)SVS, University of Edinburgh, Scotland

**Probiotics** are live microorganisms that, when ingested in adequate amounts, confer a health benefit to the "host" (WHO definition). In contrast, **prebiotics** are substances (often carbohydrates, dietary fibres) that promote growth of probiotics. When probiotics and prebiotics are combined, the resulting product is called a **synbiotic**.

Unfortunately, few studies have demonstrated any health benefit of alleged probiotics in small animals at all (negating the definition of a probiotic) and no trial has evaluated their use in critically ill small animals. However, there have been trials in dogs with both acute and chronic gastrointestinal (GI) conditions, which might be useful for some dogs or cats seen by emergency services.

Inference of treatment recommendations from the use of probiotics in critically ill people to dogs or cats is problematic. The most commonly used probiotics are different (mostly Lactobacillus, Bifidobacterium, Streptococcus in people) to what is used in small animals (Enterococcus, Saccharomyces). Effects of probiotics have not only been demonstrated to be dose dependent, but crucially both strain and species specific. This makes sense, as probiotics are supposedly mimicking or strengthening the "friendly" microbiota already present in the gut, but the composition and abundance of this commensal microbiome is somewhat different in small animals, especially cats.

Broadly speaking, probiotics likely need to be characterised by the overall immunological response (mucosally or systemically) they induce. **Immunostimulatory probiotics** are characterised by the ability to promote activation of natural killer cells and the development of a T helper (Th)1 adaptive immune response, resulting in augmentation of the immune defense against infection. **Immunoregulatory probiotics** are characterised by the ability to induce development of regulatory T cells (Tregs) and control inflammatory responses, resulting in an increase in allergy, inflammatory bowel disease (IBD) and autoimmune disease (see figure 1). It is largely unknown which probiotics exert these or more flexible responses in small animals. The type of immune response elicited might also depend on the responding cell types and simultaneous stimuli (**multifunctional probiotics**), which explains how the same probiotic has been successfully used in different conditions in people.