Update on Current and New Treatments for Colic Patients
ACVIM 2008
Gayle D. Hallowell, MA, VetMB, CertVA, DACVIM, MRCVS
Leicestershire, England

Introduction

Only treatments for colic due to gastro-intestinal disease will be considered henceforth. There are a multitude of causes and all of these conditions are variably painful, may or may not have an infectious etiology, will have some degree of inflammation associated with them and the horse's may or may not have signs associated with endotoxemia and bacteremia which will include circulatory abnormalities including hypovolemia, clotting disorders and ileus. Drugs used to treat these clinical signs will be discussed below--some have more than one function and some are beyond the scope of this talk (e.g., antimicrobial agents). Surgery obviously is a very important treatment modality for colic patients but is beyond the scope of this talk.

Current Treatments Used in the Equine Colic Patient

Analgesics

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)

NSAID's are commonly used as part of a treatment regime for horses with colic, both for their analgesic and anti-inflammatory properties.1 Flunixin meglumine was shown 25 years ago in an experimental model to reduce the cardiovascular effects of endotoxin including prevention of hypotension, peripheral perfusion and vasodilatation when administered shortly after endotoxin.2 Semrad et al3 suggested that 0.25 mg/kg was a preferable dose for the treatment of endotoxaemia compared to the standard analgesic dose of 1.1 mg/kg, as at this dose toxicity would be reduced. Toxicity with NSAID's includes gastrointestinal ulceration, ileus and renal papillary necrosis. These are rare, but clinically important adverse effects of the use of these drugs.4 Phenylbutazone was shown to cause more of these adverse effects than flunixin meglumine, and thus the latter drug is probably preferable in endotoxaemic patients. However effectiveness against endotoxaemia induced clinical signs and analgesic properties has been shown to be dose-dependent.3 Currently no advantages to newer NSAID's have shown, e.g., firocoxib.

Alpha-2 Agonists

The alpha-2 agonists xylazine, detomidine and romifidine are used primarily as sedatives and are arranged in order of duration of action. All these drugs are excellent analgesics and the effects last just beyond the duration of sedation. However they can have severe cardiovascular side-effects so should be used with care in hypovolemic patients. They are well absorbed when administered intramuscularly and often this route provides a more 'plateaued' effect in terms of sedation and analgesia and helps to limit the changes in cardiovascular function compared to the intravenous route. In severely painful animals infusions of these drugs MAY be appropriate.

Opioids

Butorphanol is an excellent sedative at low doses (0.01mg/kg-0.5cc for 500Kg) horse, but has been shown to be a less efficacious analgesic at this dose. Its analgesic properties are improved at higher doses (0.1mg/kg-5cc for 500Kg/1100lb horse) as are its side effects. Pure mu-agonists such as pethidine, morphine, methadone, oxymorphone and hydromorphone are frequently not used in horses due to the reported excitatory effects. These do occur at high doses in normal horses but are extremely rare in painful animals. In addition, some worry about their use in colic patients due to their proposed effects on reducing gastro-intestinal motility. As ileus has a component linked to pain, it seems likely that improved analgesia may in fact improve rather than worsen ileus. Their biggest disadvantage is that they need to be administered frequently. These drugs can be given intramuscularly, intravenously or as an infusion, either on their own or with other drugs such as lidocaine and/ or ketamine. NB Pethidine can only be given IM.

Ketamine

This commonly used equine anesthetic agent is also an analgesic. Its effects are short-lived--probably 30-45 minutes and at low doses in painful animals can be an extremely useful analgesic (0.3 mg/kg IM) or administered as an infusion with other drugs such as lidocaine and morphine.

Anti-Inflammatory Agents

Corticosteroids

Corticosteroids reduce the production of inflammatory mediators produced in response to endotoxin or other factors.5 There has been widespread reluctance to the use of corticosteroids in the horse due to the risk of acute laminitis, worsening of inflammatory conditions that have an infectious component such as enterocolitis due to Salmonella spp. and also the potential effects on initial wound healing post-celiotomy. Endotoxemic horses are already predisposed to the development of laminitis and only triamcinolone has in fact been positively associated with development of this condition. However corticosteroids may be of benefit in enterocolitis cases to reduce the degree of inflammation in the gastrointestinal wall, particularly when inflammation is driving continued diarrhea. However there has been very little research on the use of this group of drugs in this situation regarding effectiveness and improvements in survival in horses.6 A study of experimentally induced endotoxemia in anaesthetized ponies showed some improvement in the hemodynamic changes seen with endotoxin when treated with dexamethasone, but this response was not as dramatic as the response seen with flunixin meglumine. In addition controlled trials in human patients with sepsis have failed to show any benefit from the use of corticosteroids.

Dimethyl Sulphoxide (DMSO)

Dimethyl sulphoxide is an inexpensive solvent that is a by-product of the chemical industry. It has been shown to be an anti-inflammatory agent with antithrombotic and have free radical scavenging properties. These properties should make this a potentially useful agent in the treatment of colic patients with endotoxaemia, is not without its side effects which include hemolysis and there is no evidence experimentally or in clinical patients that it has a beneficial effect. It is thought that to be efficacious in should be administered at a dose of up to 1g/kg as a 10-20% solution.

Lidocaine

Lidocaine is thought to have three key properties, all of which are useful for treating the colic patient: anti-endotoxic, analgesic and anti-ileus. As well as its' anti-inflammatory effects, it also directly stimulates smooth muscle. This drug has to be used as an infusion due to its very short half-life and recommended dose rates are a bolus of 1.4 mg/kg followed by an infusion rate of 0.03-0.05 mg/kg/min.

Anti-Endotoxic Agents

Polymyxin B

Polymyxin B is a polypeptide antibiotic, which is efficacious against gram-negative organisms. In addition to its bactericidal properties, at lower doses, polymyxin B also binds and neutralises endotoxin by binding to one region. Experiments in horses and clinical studies investigating its effects have shown that it can be effective even when given after endotoxin, making it useful clinically.7,8 Concerns have been raised regarding its neurotoxic and nephrotoxic effects. It is thought that these effects are more likely with repeated or high doses. Nephrotoxicity has not been demonstrated in experimental studies in horses even when large doses (up to 36,000 IU/kg) have been used. However reversible neurological signs including coughing and ataxia have been noted at doses of 18,000 and 36,000 IU/kg, although toxic effects of this drug are rarely seen in the horse at doses used in patients.9 The recommended dose for polymyxin B is 6,000 IU/kg IV every 8 to 12 hours. This drug is most likely to be effective when given early in the disease to gain most benefit from its properties.

Plasma Products

Plasma

Not only is a plasma a colloid and therefore useful for resuscitation in these patients, it also contains plasma proteins, primarily albumin, which can be used on their own or in conjunction with colloids to replace protein loss that may be seen in colitis cases, anterior enteritis and in post-operative colic patients (particularly those that presented with epiploic foramen entrapments and large colon torsions). In addition, plasma contains some immunoglobulins, obviously the proportion will be more if taken from immunized animals, which will increase the non-specific ability of the immune system to fight infection and also other products such as fibronectin, which are anti-endotoxic.

Lyophylized Immunoglobulin Products

Some commercial products available for horses contain anti-endotoxic antibodies. These are taken from horses vaccinated with the core regions of J5 Escherichia coli or Salmonella typhimurium. It should provide protection against other gram-negative bacteria. Use of similar products has been shown to improve the survival rate in humans with gram-negative septicaemia and septic shock.10 The studies investigating the efficacy of these products in clinical equine cases and experimentally induced models have however shown conflicting results.7,11,12 Some of the studies have demonstrated decreased mortality and fewer days in the hospital, whereas others have demonstrated no benefit. The different results may relate to the timing of treatment.

BiospongeTM

This orally administered product contains di-tri-octahedral smectitie, which has been shown in vitro at least to bind endotoxin from various Clostridial spp. at varying concentrations. No studies have been conducted investigating is efficacy in experimental horses or clinical cases. Anecdotally felt beneficial. Not available in Europe at the present time.

Drugs for Circulatory Abnormalities

Fluid Therapy

Covered in the previous session for the treatment of hypovolemia and dehydration.

Dobutamine and Norepinephrine

In the early (hyperdynamic) phase of endotoxic shock, blood vessels often dilate and constrict in an unpredictable manner. If they dilate significantly, forward flow of blood does not occur and it 'sits' within capillary beds preventing delivery of energy and oxygen and removal of waste products. Dobutamine is a positive inotrope (increases cardiac contractility) and norepinephrine primarily causes some vasoconstriction with some positive inotropic ability. These drugs can be used to improve perfusion to the gastro-intestinal tract in compromised and/or endotoxic patients. Care must be employed in hypovolemic patients as this can cause tachycardia and trigger dysrhythmias. Monitoring of blood pressure is desirable but not essential. Doses: start dobutamine at 0.5-1 µg/kg/min. Dobutamine can be combined with norepinephrine at starting dose of 0.05 µg/kg/min and may allow a lower dose of dobutamine to be used. Dopamine was once thought to have a selective effect of 'renal' and to a lesser extent GI blood flow at low doses; this has been disputed and its effects are most likely due to changes in the systemic circulation. The horse is quite insensitive to the effects of dopamine and thus more side effects are seen when compared to equipotent doses of dobutamine.

Pentoxifylline

Pentoxifylline is a methylxanthine derivative that has been shown to improve capillary blood flow by reducing blood viscosity and improving oxygen supply to the tissues. Pentoxifylline has been shown to improve survival in laboratory animals following endotoxic shock. Experimental studies in horses have demonstrated that pentoxifylline alone has limited benefits when given post-endotoxin administration,14 but that flunixin and pentoxifylline administered concurrently improve haemodynamic effects due to endotoxin more than if either drug is administered alone.15 Oral bioavailability of the drug is very variable, is poor in many patients and this may limit its clinical usefulness.16 Currently the recommended dose for pentoxifylline in the horse is 8 mg/kg every 8 hours orally. There is no commercially available IV preparation at the current time.

Drugs for the Treatment of Clotting Disorders

Heparin

Unfractionated heparin (UFH) has been widely used to treat clotting disorders seen with endotoxemia and sepsis both in animals and man. In addition UFH has been shown to prevent the development of carbohydrate overload-induced laminitis and intra-abdominal adhesions17 and for thrombophlebitis, venous thrombosis and disseminated intravascular coagulation, which can all be seen as a consequence of endotoxemia in colic patients.18 However UFH has some undesirable side effects including increased risk of hemorrhage, rapid and severe decreases in PCV, thrombocytopenia, reduction in RBC mass, reaction at the injection site and RBC agglutination with possible impairment to tissue blood flow when moderate to large doses are used.19 In addition it has been shown that there is marked individual variation to UFH therapy. This drug is however affordable and recommended doses are 100-150 IU/kg subcutaneously every 12 hours.

Low Molecular Weight Heparins (LMWH)

Due to the undesirable side effects of UFH, much interest has been aimed at the use of low molecular weight heparins. The LMWH have been widely used in humans as they appear to have similar antithrombotic properties as UFH but have fewer adverse effects, longer half-life, and dose-dependent coagulation effects. Fewer side effects have also been observed in horses when UFH and LMWH have been compared.20 Schwarzwald et al20 found similar pharmacokinetics in horses compared to people of two LMWH preparations (dalteparin and enoxaparin) so a recommendation of once daily subcutaneous administration was made. However more recent human pharmacokinetic data in critically ill human patients has shown that subcutaneous absorption is reduced and recommends that the first dose in a course be given intravenously at a higher dose followed by a lower subcutaneous dose 12 hours later and then every 24 hours subsequently. This regime can easily be applied to the equine critically ill patient and that used by the author is 100IU anti-Xa/kg IV followed by 50IU anti-Xa/kg SC 12 hours later and then 24 hours subsequently. These LMWH are affordable in Europe but are significantly more expensive in the USA; it seems likely that the cost of this drug will fall and then be accessible.

Other Drugs That May be of Benefit in the Future

Other human drugs currently licensed include antithrombin concentrate, direct thrombin inhibitors and activated protein C. All of these drugs affect the balance between pro- and anti-coagulation and may reduce the adverse clotting effects caused by endotoxin. Activated protein C has antithrombotic, anti-inflammatory and profibrinolytic properties. It has been shown to significantly reduce the mortality in septic human patients.21 At the current time these drugs are cost prohibitive for use in horses, but may prove promising for treatment of coagulopathic disorders for the future. One group of direct thrombin inhibitors, the hirudins are found in leech saliva and act here as the main anticoagulant. Pharmaceutically derived products are available. These drugs may have more predictable effects than the heparins on coagulation.

Platelet activating factor has been shown to be involved in many of the clinical signs seen with early endotoxemia, including hypotension, platelet aggregation, increased vascular permeability and ileus. In endotoxemia models in rats it has been shown that survival was improved when high doses of various PAF antagonists were administered. These drugs are currently expensive and being trialed in humans.......we'll have to wait and see if they will prove useful in horses.

Drugs for the Treatment of Ileus

It should be noted that in addition to the direct effects of endotoxin, and gut handling (at surgery), pain is associated as a major contributing factor to this condition therefore it is always worth investigating and changing the analgesic plan in addition to using the drugs listed below. These drugs should not be used in animals if GI obstruction is suspected. They are most likely to be effective if used prophylactically, rather than being started when ileus has already set-in.

Lidocaine--See Above

Erythromycin

This is an antibiotic that at lower doses acts on motilin receptors as a pro-motility drug. It is thought to be useful in improving gastric and small intestinal motility and perhaps for cecal impactions. Its main side effect at this dose is signs of colic. Diarrhea is not commonly seen in adult horses at this low dose. Dose recommended is 0.5-1 mg/kg administered slowly every 6-8 hours.

Metaclopramide

This acts on various receptors to increase gastro-intestinal motility and there is a reasonable amount of data available supporting its use. Its major drawback is that it can cause moderate to severe neurological disturbances making animals aggressive and unmanageable as well as other signs which include mild colic, sweating and restlessness. Doses recommended are 0.04 mg/kg/min administered as a continuous infusion. Cisapride has unfortunately been removed from the market due to adverse cardiac effects in humans; this had similar properties to metaclopramide, but without the neurological side effects and could be given orally.

(Bethanechol)

This drug has been shown to increase gastric and cecal motility in experimental (normal) ponies and acts as a muscarinic cholinergic antagonist. Its side effects include colic, diarrhea, salivation and gastric secretions). However it is currently unavailable.

(Neostigmine)

There is different data available regarding the actions of neostigmine on different components of the GI tract, which all come from normal, experimental animals. This drug may be beneficial for treatment of small intestinal ileus (2mg per 500 Kg adult horse) administered SC or IV every 30 to 60 minutes to a maximum dose of 10mg. Side effects include colic signs

Glucose Regulation - Insulin Therapy

There is some evidence in human medicine that regulating blood glucose between 4-7 mmol/L (75-132 mg/dl) improves survival and reduces morbidity. A recent study however contradicts this finding so the jury is out. Hyperglycemia is a common clinicopathological finding in colic patients, particular those with severe disease. This is due to various endocrine responses released as part of the stress response. Hyperglycemia can have many undesirable effects including polyuria, which is undesirable in a hypovolemic patient. Control with insulin infusions may be beneficial in these cases; it is necessary however to monitor blood glucose concentrations and/or administer with a glucose infusion to prevent severe hypoglycemia. Further studies are required in our patients as more data becomes available from human studies.

Conclusions

Treatment of colic patients is complex and variable, depending very much on findings in individual animals and their response to treatment. The key to appropriate therapy is to have a current problem list that is regularly updated and knowledge of available and possible 'treatments' that may be appropriate in that case rather than having recipes that are applied to all. New and novel treatments are proposed regularly, but assessment of the current data and evaluation in clinical cases, once identified as likely being safe is essential. Data on the efficacy of some of the treatments used on an everyday basis is colic patients are frequently based upon anecdotal information or experimental data from normal animals. This should be taken into account.

References

1.  Morris DD. J Vet Intern Med 1991;5:167-181.

2.  Bottoms GD, Fessler JF, Roesel OF, et al. Am J Vet Res 1981;42:1514-1518.

3.  Semrad SD, Hardee GE, Hardee MM, et al. Equine Vet J 1987;19:201-206.

4.  Moore JN, Barton MH. Treatment of endotoxemia. Vet Clin North Am Equine Pract 2003;19:681-695.

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9.  Southwood LL. Vet Clin North Am Equine Pract 2004;20:167-197.

10. Ziegler EJ, McCutchan JA, Fierer J, et al. N Engl J Med 1982;307:1225-1230.

11. Morris DD, Whitlock RH, Corbeil LB. Am J Vet Res 1986;47:544-550.

12. Spier SJ, Lavoie JP, Cullor JS, et al. Circ Shock 1989;28:235-248.

13. Lei MG, Qureshi N, Morrison DC. Immunol Lett 1993;36:245-250.

14. Barton MH, Moore JN, Norton N. Am J Vet Res 1997;58:1300-1307.

15. Baskett A, Barton MH, Norton N, et al. Am J Vet Res 1997;58:1291-1299.

16. Crisman MV, Wilcke JR, Correll LS, et al. J Vet Pharmacol Ther 1993;16:23-31.

17. Parker JE, Fibini SL, Car BD, et al. Vet Surg 1987;16:459-462.

18. Darien BJ, Sims PA, Stone WC, et al. Scanning Microsc 1993;7:1311-1319; discussion 1320.

19. Duncan SG, Meyers KM, Reed SM. Am J Vet Res 1983;44:2271-2276.

20. Schwarzwald CC, Feige K, Wunderli-Allenspach H, et al. Am J Vet Res 2002;63:868-873.

21. Bernard GR, Vincent JL, Laterre PF, et al. N Engl J Med 2001;344:699-709.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Gayle Hallowell, MA, VetMB, CertVA, DACVIM, MRCVS
Shepshed, Leicestershire, United Kingdom


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