Corticosteroids are one of the most commonly used (and abused) drugs in veterinary medicine. Whilst there is no doubt that for some patients they are an essential part of therapy (especially feline asthma, immune mediated disease and some neoplasms), there are a number of other conditions especially in emergency and critically ill patients where their use is controversial. As with many things the evidence base in veterinary medicine is limited. During this lecture the evidence for and against use of corticosteroids in specific subgroups of critically ill patients will be presented and discussed.

Brief Overview of Pharmacology

Corticosteroids are steroid hormones produced primarily in the adrenal cortex from cholesterol; they exert their action by controlling the rate of synthesis of proteins. A number of corticosteroids are available for pharmacological use - their properties are summarised in the table below.

Corticosteroids have a large number of actions including influence on:

 Carbohydrate, protein and lipid metabolism

 Electrolyte and water balance

 Immune function

 Cardiovascular function and tissue perfusion

They can be administered at a variety of doses with different effects. A "physiological" dose is one that is necessary to maintain normal function in a non-stressed adrenalectomised animal whereas pharmacological doses are much larger and can give rise to typical effects of hypercortisolism if administered over prolonged periods.

The rationale for the use of corticosteroids in critically ill traumatised or septic patients is sometimes stated to be that many of the detrimental effects of sepsis/trauma are caused by over activation of the immune/inflammatory cascade and blocking this at an early stage may be beneficial. Some experimental studies show a survival benefit when corticosteroids are administered prior to the infectious/traumatic insult.

However corticosteroids may have a number of negative effects. The effects of corticosteroids on the immune system include:

 Inhibition of B and T lymphocytes, macrophages and neutrophils

 Decreased IL-1 and TNF-α production

 Suppression of IL-2 and lymphocyte proliferation

Other potential adverse effects include problems with wound healing, GI tract ulceration, sodium and water retention and promotion of hyperglycaemia (increasingly recognised as a negative prognostic indicator in critical patients).

There are concerns that in clinical patients the putative beneficial effects of corticosteroids in preventing excessive inflammation may be outweighed by the negative effects - what is the evidence?

Use of Corticosteroids in Sepsis and Septic Shock

The pathophysiology of sepsis and septic shock is complex but involves widespread uncontrolled release of inflammatory mediators with subsequent vasodilatation, changes in vascular permeability and the development of distributive shock. Septic shock has a high mortality rate even in human intensive care patients and there has long been a search for a single treatment that would lead to an improved outcome (the "magic bullet"). At one time it was hoped that corticosteroids, by blocking the over activation of the inflammatory response, may represent this treatment however clinical studies failed to show an improvement with high dose steroid therapy in this patient group and infectious complications were increased. In human medicine, steroids were considered to be contraindicated for this purpose.

Recently there has been renewed interest in corticosteroids for the treatment of septic patients with "relative adrenal insufficiency" (RAI) or CIRCI (critical illness related corticosteroid insufficiency). This is a syndrome of adrenal exhaustion where some critically ill patients, despite having normal-high circulating levels of cortisol, fail to respond to ACTH - they are thought to have exhausted their adrenal reserve. There is some evidence that in a subset of these patients supplementation of glucocorticoids at physiological doses may lead to a better outcome. There is still much discussion in the human critical care field as to the best way to identify this patient group and what dose/type of corticosteroid is most appropriate.

Does RAI/CIRCI exist in veterinary patients? A study published in 2007 suggests it does exist and may be associated with a worse prognosis. Randomised controlled treatment trials have not yet been performed, however although corticosteroids are not routinely recommended for septic patients, they may have a role to play in the management of canine patients with refractory hypotension and sepsis (septic shock).

Use of Corticosteroids in Neurological Disease

Corticosteroids have also been advocated for the treatment of patients with head or spinal trauma on the basis of experimental studies including ones where cats with spinal trauma that had been pretreated with high doses of steroids had a better functional outcome. Their use in human patients was promoted with publication of the NASCIS II trial in 1990 - this reported improved recovery when very high doses of corticosteroids (methylprednisolone - MP) were administered soon after the trauma. A follow-up study (NASCIS III) looked at different durations of therapy of MP and an alternative drug tirilazad (same effect on lipid peroxidation but no glucocorticoid effect). The NASCIS trials have been criticised on a number of counts and recent surveys of current practice in human trauma patients show that the MP protocol advocated is not routinely used.

The relevance of the results to veterinary patients has to be closely questioned. Is the improved outcome reported in human patients relevant to our patients? How many veterinary surgeons use the appropriate protocol? What about timing in our patients? MP has been used commonly for IVDD when time of onset of signs can be impossible to determine. A retrospective study in veterinary medicine showed a higher rate of GI complications and greater hospital costs when corticosteroids were used to treat patients with IVDD.

Head trauma is another area where corticosteroids are sometimes used. A large human study in the UK (CRASH trial) has recently been published and shows no benefit to the use of corticosteroids and potentially even a detrimental effect. The promotion of hyperglycaemia (associated with a worse outcome in head trauma in people) is one of the possible reasons why this may be so. There is no evidence base in veterinary medicine as yet but a retrospective study did show that hyperglycaemia was associated with more severe neurological signs in veterinary patients.

References

1.  Annane, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. Journal of the American Medical Association. 2002;288(7):862–871.

2.  Bone, et al. A controlled clinical trial of the use of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. New England Journal of Medicine. 1987;317:653–658.

3.  Bracken, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomised Controlled Trial. National Acute Spinal Cord Injury Study. Journal of the American Medical Association. 1997;277:1597–604.

4.  Bracken, et al. A randomised controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. Results of the Second National Acute Spinal Cord Injury Study. New England Journal of Medicine. 1990;322:1405–1411.

5.  Burkitt JM, et al. Relative adrenal insufficiency in dogs with sepsis. Journal of Veterinary Internal Medicine. 2007;21(2):226–231.

6.  Bush, et al. Functional outcome following hemilaminectomy without methylprednisolone sodium succinate for acute thoracolumbar disk disease in 51 non-ambulatory dogs. Journal of Veterinary Emergency and Critical Care. 2007;17:72–76.

7.  Edwards, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury outcomes at 6 months. Lancet. 2005;365:1957–1959.

8.  Marik, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Critical Care Medicine. 2008;36(6):1937–1949.

9.  Sayer, et al. Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature. Spine Journal. 2006;6;335–343.

10. Syring, et al. Hyperglycemia in dogs and cats with head trauma: 122 cases (1997–1999). Journal of the American Veterinary Medical Association. 2001;218:1124–1129.