Glucocorticoids and shock, what are we doing now? (Proceedings)

Shock

Shock can be classified into general categories: hypovolemic, maldistribution, and cardiogenic. Hypovolemic shock is due to a diminished volume of fluids and can occur in severe dehydration (Parvoviral gastroenteritis, hemorrhagic gastroenteritis) or hemorrhage. Maldistribution shock occurs when blood flow is shunted away from major organs and pools in the periphery. Examples of maldistribution shock are sepsis, endotoxemia, anaphylaxis, gastric dilatation with volvulus (GDV), neurogenic, and even due to severe pain. Cardiogenic shock occurs when cardiac output is markedly decreased in conditions such as myocardial disease, arrhythmias, pericardial tamponade, and pulmonary thromboembolism.

Glucocorticoids, mechanisms of action

GCs increase the circulating pool of mature neutrophils (PMNs) due to release of PMNs from the marginal pool which decreases migration into inflamed tissues. The effect is due to decreased expression of adhesion molecules, reduced adhesion to the vascular epithelium, and reduced movement through the vasculature into the tissues. Anti-inflammatory doses of GCs affect PMN trafficking more than function as minimal effects on phagocytosis and lysosomal stability occur. GCs decrease the circulating pool of lymphocytes, monocytes, eosinophils, and basophils primarily due to their movement from the vasculature to the lymphoid tissues. GCs alter the function of macrophages and other antigen presenting cells by reducing the cells ability to respond to antigens. The ability of macrophages to engulf and kill microorganisms is markedly inhibited. The production of cytokines such as TNF-α, interleukin-1 (IL-1), metalloproteinases, and plasminogen activator by macrophages are also markedly inhibited. GCs also decrease the production of IL-12 and interferon-γ by lymphocytes and macrophages which are important inducers of T-helper cell activity and cellular immunity. T-cells are more affected by GCs then B-cells with minimal affects on B-cell production of immunoglobulins at anti-inflammatory doses. However, high doses of GCs can decrease immunoglobulin production.

GCs also reduce the production of prostaglandins and leukotrienes by the arachidonic acid pathway. The primary effect on the arachidonic acid pathway is thought to be through inhibition of phospholipase A2, but some effects on cyclooxygenase-2 (COX-2) may also occur. GCs also have a variety of effects on blood vessels. GCs improve the microvascular integrity and circulation, and decrease vessel permeability. It is unclear as to the precise mechanisms by which these effects occur, but may be due to inhibition of vasoactive substances such as histamine, serotonin, and prostaglandins among others. The clinical benefits of the vascular effects have not been identified as a clinical benefit

Glucocorticoids, adverse effects

Adverse effects are expected with both short-term and long-term administration of GCs. The most common adverse effects with long-term administration include the polyuria, polydipsia, and polyphagia. Other effects with GC administration include osteoporosis, myoapthy, inhibition of fibroblast activity, decreased intestinal calcium absorption, pancreatitis, gastric ulceration / perforation, colonic ulceration / perforation, sodium retention, fluid retention, hyperlipidemia, lipolysis, protein catabolism, fatty infiltration of the liver, steroid hepatopathy, anti-insulin effects, decreased thyroid hormone production, increased parathyroid production, decreased host response to bacterial infections, and increased rates of cystitis. Case reports have been published detailing acute episodes of congestive heart failure after GC administration to animals with subclinical and undiagnosed cardiac disease which is probably due to fluid and sodium retention and hypertension. A study examining the effects of shock doses of methylprednisolone sodium succinate on animals presenting for spinal surgery resulted in 36/40 animals being identified as having GIT bleeding despite administration of cimetidine, sucralfate, or misoprostol. Therefore it is not unreasonable to expect GIT injury with administration of shock doses of GC for spinal injury. Shock doses of corticosteroids produce euphoria in human patients. The euphoric effect is probably the reason most animals "look better" after administration of shock doses of corticosteroids and typically is not an indication that the shock doses are beneficial. Opioid administration can also produce euphoric effects and make animals "look better" with less adverse effects than shock doses of GCs.

Glucocorticoids, dose-dependant effects

Glucocorticoid dosages depend on the condition that is being treated. Glucocorticoid dosages can be classified as physiologic replacement, anti-inflammatory, immunosuppressive, and shock doses. Physiologic dosages are designed to supplement or replace the amount of endogenous cortisol produced in a 24-hour period. Prednisone or prednisolone is administered at 0.2 mg/kg/d for replacement therapy. Anti-inflammatory dosages of glucocorticoids are commonly administered for conditions such as atopy, angioedema, and urticaria. The anti-inflammatory dosages of prednisone / prednisolone in dogs is 1-2 mg/kg/d and for dexamethasone 0.1-0.25 mg/kg/d. The anti-inflammatory dose in cats is approximately twice that of dogs. Immunosuppressive dosages are administered for conditions such as autoimmune hemolytic anemia and immune mediated thrombocytopenia. Prednisone administered at 2-6 mg/kg/d and dexamethasone 0.3-1 mg/kg/d are immunosuppressive dosages. The shock dosage of methylprednisolone sodium succinate is 30 mg/kg IV and for dexamethasone sodium phosphate the shock dose is 4 mg/kg IV. However there currently no indication for shock doses of dexamethasone in dogs or cats.

Efficacy of shock doses of glucocorticoids

Head trauma. A recent study in humans demonstrated an increased mortality rate in patients receiving shock doses of methylprednisolone sodium succinate as compared to groups that did not receive GCs. There are no large studies in animals assessing the effects of GCs on head trauma, but extrapolation from human data indicate GCs are NOT indicated in the acute management of head trauma in animals.

Spinal trauma. There are conflicting opinions on the benefit of shock doses and GC use in spinal trauma. A study in 1990 indicated a benefit to shock dose methylprednisolone sodium succinate (MPSS) in spinal trauma, but criticisms of the study soon followed as to its applicability and limitations. Experimental models have produced positive results for GC use in spinal trauma, but doses were administered prior to experimental injury or within a short period of time following injury. Clinical cases of IVDD in dogs, pre or postoperative administration of glucocorticoids provided no benefit compared to animals not treated with GC's, but increased adverse effects were seen in GC treated dogs. There is conflicting data supporting the use of GC in spinal trauma, although they are widely used. Currently, most people recommend shock doses of Solu Medrol only within 8 hours of spinal trauma.

Generalized trauma / Heat Stroke. There is no data supporting the use of GC in generalized trauma (i.e. hit by car, dog fights, etc.) or heat stroke. In fact GC may increase morbidity and mortality due to the numerous adverse effects. Supportive care such as crystalloids and colloids, pain management with opioids, and body temperature are the primary recommendations along with stabilization of blood loss and fractures. Antimicrobials may also be indicated.

Sepsis / endotoxemia. Most studies investigating the use of GC in sepsis and endotoxin models are poorly translated into clinical practice. Most of the models have administered GCs prior to exposure or immediately following exposure. Shock doses GCs may increase the morbidity and mortality in sepsis due to the immunosuppressive effects and beneficial effects have not been demonstrated clinically. Shock doses in endotoxemia also do not result in decreased mortality or morbidity, however physiologic doses may be beneficial (i.e. 0.2 mg/kg methylprednisolone), but there is not a consensus on their use.

Anaphylaxis. GCs are indicated for the treatment of anaphylactic reactions. However immunosuppressive doses are recommended (i.e. 2-6 mg/kg IV MPSS OR 0.3-1 mg/kg dexamethasone), not shock doses. If cardiovascular collapse is present administration of epinephrine (2.5-5 mcg/kg {0.0025-0.005 mg/kg} IV) will provide immediate cardiac stimulant and vasopressor effects.

Addison's Crisis. GCs are recommended for the treatment of animals in an Addison's (hypoadrenocorticism) crisis, although immunosuppressive dosages are recommended initially (2-6 mg/kg MPSS). The primary focus in stabilizing animals is to correct the hyperkalemia and hyponatremia. Normal saline is the fluid of choice for dehydrated animals with hyperkalemia and hyponatremia.

Fluid therapy, hypertonic saline

Hypertonic saline typically contains either a 5% or 7.2% concentration of sodium chloride. Hypertonic saline is administered relatively quickly, over 5 minutes, and results an increase in plasma osmolality. Advantages of hypertonic saline include the rapid administration of fluid, low volume, low cost, and efficacy. Studies in experimental dogs have indicated hypertonic saline, 4 mL/kg, induces a plasma volume change of 20 mL/kg. Other effects of hypertonic saline include improvements in cardiac output, arterial blood pressure, splachnic blood flow, and acid base status. Hypertonic saline does not appear to cause vasoconstriction or other changes in the mechanical properties of the circulatory system. The primary effects appear to be due to plasma volume expansion.

Administration of 7% hypertonic saline solution (4-5 mL/kg) results in increases in serum osmolality by approximately 28 mOsm/L within 10 minutes. The elevation remains approximately 12 mOsm/L above control values for 4-12 hours. As expected increases in serum sodium and chloride concentrations (~13 mEq/L) occur within 10 minutes of administration. No adverse effects have been noted with these changes in osmolality and sodium concentrations. Serum potassium values decrease following administration in a similar manner to administration of isotonic fluids. Serum potassium concentrations drop by approximate 0.8 mEq/L and no adverse effects have been reported.

Hypertonic saline has been studied in experimental models of hemorrhagic shock, endotoxic shock, and shock due to gastric dilatiation with volvulus. In each case hypertonic saline produced an equal or better effect to traditional resuscitation with isotonic fluids. Resuscitation with isotonic fluids or colloids results in increased intracranial pressure and, worsens cerebral edema. Hypertonic saline does not appear to increase intracranial pressure. Additionally, hypertonic saline does not increase lung water volume during resuscitative administration as compared to isotonic fluid administration. In models of GDV in dogs, hypertonic saline (in combination with dextran-60) 5 mL/kg, resulted in a more effective and sustained resuscitation than did lactated ringers solution, 60 mL/kg. Hypertonic saline treated dogs maintained a better cardiac output for the 3 hour monitoring period and experienced less hemodiltuion. However it is important to remember that experimental models do not always predict naturally occurring conditions.

Hypertonic saline has been assessed in human clinical trials in a variety of conditions resulting in shock. Hypertonic saline (7%) was administered to patients with a variety of conditions resulting in shock which were initially non-responsive to conventional resuscitation. No adverse effects were noted and 9/11 patients which were initially non-responsive, but responded to hypertonic saline. In a controlled study, hypertonic saline in combination with dextran-70 was compared in a blind fashion to isotonic fluid therapy in trauma patients. Patients treated with hypertonic saline had significantly higher mean arterial pressures on arrival to the hospital and a subsequent higher survival rate. Postoperative hypovolemia in surgical patients treated with hypertonic saline maintained increased systemic arterial blood pressures, atrial filling pressures, and cardiac output with less volume administration as compared to isotonic fluids.

Hypertonic saline is not an appropriate choice for resuscitation of a dehydrated animal. Dehydration requires replacement of fluid and electrolyte content of which isotonic solutions are better choices. Hypernatremia is also considered a contraindication to administration of hypertonic saline. Finally, cases of fluid overload (increases in intravascular fluid volume) are also considered a contraindication to hypertonic saline.

Fluid therapy, Hetastarch

Hetastarch is a commonly used colloid solution in veterinary medicine due to its ease of use and storage, and its relatively low cost. Hetastarch has a mean molecular weight of 70,000 (albumin is approximately 69,000 MW) with a colloid oncotic pressure of 30 mm Hg (albumin is approximately 18-20 mm Hg). Hetastarch ranges in size from 10,000 MW to 1,000,000 MW with sizes less than 50,000 MW eliminated by the kidneys, whereas large sized molecules are primarily cleared by the liver and spleen. Hetastarch is an effective volume expander with each mL capable of retaining approximately 30 mL of water. This property results in a volume expansion greater than the volume administered and may persist for up to 24 hours. Up to 50% of the administered hetastarch volume is retained in the vasculature for 48 hours. Hetastarch may increase the bleeding tendency due to a dilutional effect of clotting factors (fibrinogen and antithrombin III). A single case report in humans detailed a subclinical von Willebrand's patient that experienced increased bleeding following administration. Overall the adverse effect rate of hetastarch in humans is low, 0.085%.

Colloids are often used for shock resuscitation. Colloids provide rapid volume expansion with a low volume administration, which persists for long time periods. Hetastarch is often administered in conjunction with cystalloids to prolong the volume expansion provided by the crystalloids. A common dosing strategy for resuscitation is to administer 5 mL/kg of hypertonic saline (7.2%) followed by 5 mL/kg of hetastarch. As previously mentioned, colloids can increase intracranial pressure and cerebral edema, therefore should be used cautiously in patients with head trauma. Colloids can also be administered to hypoproteinemic animals to increase oncotic pressure and maintain proper fluid balance. A response to colloid administration is often noted within 12 hours including decreases in peripheral edema, increased urine production, and decreased lung volume. However it is important to note that hetastarch should not be used to treat cardiogenic pulmonary edema as it may worsen the condition due to increased pulmonary arterial pressures.

Management Of Pain

Pain is a common cause or contributing factor to shock in dogs, particularly trauma. Severe pain can result in a maldistribution shock, which is responsive to mu opioid agonists such as morphine, fentanyl, and hydromorphone. Morphine (0.5 mg/kg IV q 2-4 hours), fentanyl (5-10 mcg/kg IV q 1-3 hours), and hydromorphone (0.1 mg/kg IV q2-5 hours) can all be administered IV for the most rapid effect. Opioids are best administered IV over 30 – 90 seconds, as rapid injection can produce excitement. Fentanyl is expected to produce the most rapid analgesia (within 0.5-5 minutes), hydromorphone and morphine may take slightly longer to produce analgesic effects but clinically relevant analgesia often occurs within 5-10 minutes of IV injection. Opioids produce minimal cardiovascular effects (including IV morphine 0.5 mg/kg), therefore in a painful animal opioids should be administered even if clinical signs of shock are still present. In cases of chest trauma, where there is a respiratory compromise, or head trauma, opioids should be administered cautiously due to their respiratory depressant effects. The most efficient way to manage respiratory depressant effects is to administer opioids as a constant rate IV infusion, preceded by a loading dose equivalent to ½ of the recommended dose. The CRI avoids large fluctuations in the peaks and troughs and the respiratory depressant effect will be most pronounced at peak drug concentrations. The dose of the CRI can than be adjusted based on the clinical response of the patient. If clinical signs of pain occur during a CRI, a bolus dose of opioids equivalent to 1/4 of the recommended dose can be administered and the rate of the CRI increased.

Disclaimer: The information is accurate to the best of the author's knowledge. However recommendations change as new data become available and errors are possible. The author recommends double checking the accuracy of all information including dosages.