Download 2009 CE Proceeding Notes - Seattle Veterinary Specialists

SEATTLE VETERINARY
SPECIALISTS
2009 Continuing Education Symposium
DVM Program
Technician Sessions
0800 - 0845 Registration/Coffee Registration/Coffee
0850 - 0900 Introduction - Sean Sanders, DVM, PhD, Dipl. ACVIM (Neurology)
0900 – 0950 Piecing the Puzzle Back Together: Basic Reconstructive Skin Surgery
Michael Mison, DVM, Dipl. ACVS
0950 - 1000 Break
1000 - 1050 Electrolyte Disturbances in the Emergency Setting
Janelle Wierenga, DVM, Dipl. ACVECC
1050 - 1100 Break
1100 - 1150 Parathyroid Disorders
Dana Brooks, DVM, Dipl. ACVIM (Internal Medicine)
1200 - 1300 Lunch
1300 - 1350 Coils, Balloons, Pacemakers, Oh My!: Intravascular Cardiac
Procedures
Adonia Hsu, VMD Resident III (Cardiology) - UC Davis
1350 - 1400 Break
1400 - 1450 Update on Urinary Incontinence
Matt Vaughan, DVM, Dipl. ACVIM (Internal Medicine)
1450 - 1500 Break
1500 - 1550 Neurosurgical Treatment for Intracranial & Spinal Neoplasia
Sean Sanders, DVM, PhD, Dipl. ACVIM (Neurology)
1550 - 1600 Meeting Adjournment - Sean Sanders, DVM, PhD, Dipl. ACVIM
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Notes 2
Piecing the Puzzle Back Together: Wound management & basic reconstructive skin surgery Michael B. Mison, DVM, Diplomate ACVS Surgeon – Seattle Veterinary Specialists Affiliate Assistant Professor – University of Washington School of Medicine Principles of Traditional Wound Management: The principles of wound management have not significantly varied from those advocated by Esmarch and Halsted several years ago. In managing any skin wound, thorough understanding of normal wound healing and factors that may adversely affect wound healing are necessary in considering treatment options. Proper assessment and management of wounds have a significant impact on the outcome. When presented with a wounded patient, life‐threatening injuries should be addressed and the animal’s condition stabilized before further wound management is undertaken. Wounds should be assessed and classified in order to determine appropriate therapy. Wounds are classified as clean, clean‐
contaminated, contaminated, or dirty/infected. The type of treatment chosen is determined by the patient’s status, estimated degree of wound contamination, amount of soft tissue damage, and amount of adjacent tissue available for closure. Primary closure is usually performed when the wound is classified as clean or clean contaminated, whereas contaminated or grossly exudative wounds are treated as open wounds. Improper evaluation and closure of an unsuitable wound may result in significant morbidity. Most wounds in animals can be treated adequately by prevention of further wound contamination, practice of aseptic technique, débridement of devitalized and necrotic tissue, removal of foreign debris and contaminants, provision of adequate drainage, obliteration of dead space, promotion of a viable vascular bed, and selection of appropriate wound closure or bandage type. The objective of open wound care is to convert the open contaminated wound into a surgically clean wound that can be closed. After initial inspection, cultures should be obtained from contaminated or infected wounds. A wide area surrounding the wound should be clipped and prepared with an effective surgical scrub solution. Care is taken to prevent hair and scrub solution coming into contact with the open wound tissues. Bacterial counts can be effectively reduced from the wound surface by surgical débridement, wound lavage, and 3
antibiotic therapy. Pressure irrigation of a wound with sufficient volume of fluid (Table 1) is effective in decreasing bacterial numbers. Table 1: Lavage Fluid Advantages Disadvantages Tap water – Readily available – Hypotonic – Inexpensive – Contains trace – Not associated with elements that are increased infection in cytotoxic contaminated – No antimicrobial wounds properties Lactated Ringer’s – Isotonic – No antimicrobial solution – Effective lavage fluid properties Normal (0.9%) saline – Isotonic – Slightly more acidic – Effective lavage fluid compared to LRS – No antimicrobial properties 0.05% Chlorhexidine – Wide spectrum of – Precipitate in diacetate antimicrobial activity electrolyte solutions – Good residual activity – More potent solutions – Activity in the may slow formation presence of organic of granulation tissue matter 1% povidone‐iodine – Wide spectrum of – Inactivated by organic antimicrobial activity matter – Limited residual activity – Cytotoxic effects Irrigants are delivered at a pressure of 8 psi (35‐mL syringe and 19‐gauge needle) to be maximally effective. The use of a higher pressure lavage may be more effective in reducing bacterial numbers and removing foreign debris and necrotic tissue. However, such pressures may result in dissemination of bacteria and debris into deeper tissues, damage underlying tissues, and reduce resistance to infection. Commercial lavage units such as Surgilav (Stryker Co.) are available for clinical use. This disposable pressure lavage unit connects to an intravenous fluid bag and is effective for aggressive lavage of contaminated wounds. 4
Devitalized tissue may be removed by surgical excision, enzymes, or wet‐
dry bandages. The extent of surgical débridement varies with the type of wound and the degree of contamination. Devitalized tissue should be surgically excised in layers beginning at the surface and progressing to the depths of the wound. Evaluation of skin viability in the acute period may be difficult due to vasospasm and edema. Skin débridement may be delayed 48 to 72 hours to allow the tissues to declare their viability. Staged débridement allows for selectivity, and tissues that are initially questionable may recover and can be spared for facilitate wound closure. Alternatively, the entire wound can be excised en‐bloc if sufficient healthy tissue surrounds the wound and vital structures can be preserved. Enzymatic débridement (trypsin and chymotrypsin) has a minor role in treatment of wounds in small animals. They may be beneficial in patients that are poor anesthetic risk or when surgical débridement may damage healthy tissue. These agents are generally not a substitute for surgical débridement of larger areas of necrosis. The benefits of topical antimicrobial agents in the treatment of superficial wounds outweigh their potential cytotoxic effects. Clean or mildly contaminated wounds do not benefit from topical antimicrobials. However, combined systemic and local therapy is advantageous in heavily contaminated wounds. Antibiotics applied within 1 to 3 hours of contamination often are effective in preventing infection. Once infection is established, topical antibiotics have no beneficial effect in preventing suppuration of wounds. Commonly used topical antimicrobials in small animals include triple‐antibiotic ointment (bacitracin‐
neomycin‐polymyxin), silver sulfadiazine, nitrofurazone, and gentamicin sulfate. Systemic antibiotics may be used prophylactically or therapeutically. Selection of systemic antibiotics should be targeted against the microorganism most likely to cause wound infection or based on culture sensitivity. Provision of adequate drainage is important in the management of wounds. Leaving the wound open provides optimal drainage for the patient’s injury. At the time of closure, drains may be used to minimize dead space and provide an outlet for removal of debris and tissue fluids. Drains can be divided into two types: passive and active drain systems. The most commonly used passive drain is the Penrose drain. This is a flat drain that functions through capillary action and gravity. Other types of drains include tube drains and multilumen drains. Active drainage is provided by closed suction drains, in which a vacuum created within the wound facilitates continuous drainage. A vacuum of 80 mmHg is ideal. Closed suction drains allow dressings to remain dry, prevent ascending infection, and enable quantitative assessment of drainage. 5
Wound healing stimulants have application on chronic wounds, as well as severe acute wounds. Wound healing stimulants are topical preparations that stimulate wound healing cells to produce cytokines and growth factors which enhance wound healing. These stimulants do not have antimicrobial activity. Such medications available for clinical use include macrophage activators (Acemannan), hydrophilic agents (copolymer flakes, dextranomer, maltodextrin, and hydrolyzed bovine collagen), and tripeptide‐copper complex medication (Iamin‐Vet Skin Care Gel®). It has been found that these medications have their greatest effect during the first 7 days of use. Porcine collagen (Vet BioSISt®) has also been used for wound management. It has been reported that there is rapid incorporation of the Vet BioSISt® into full‐thickness wounds. Studies have shown that there is an earlier appearance of granulation tissue over exposed bone in wound treated with porcine collagen as compared to control wounds treated with only bandage. Experimentally, pulsed electromagnetic field treatment of open wounds has been shown to enhance wound epithelialization and possibly early wound contraction. There is also evidence that both ultrasonography and phototherapy (low‐powered laser) shorten the inflammatory phase of healing and enhance the release of factors that stimulate the proliferative stage of repair. The use of a controlled sub‐atmospheric pressure dressing (Vacuum Assisted Closure™) has also been shown to help remove interstitial fluid allowing tissue decompression, help remove tissue debris, and promote wound healing Bandages provide wound cleanliness, control the wound environment, reduce edema and hemorrhage, eliminate dead space, immobilize injured tissue, and minimize scar tissue. They also provide comfort and absorb and allow for characterization of wound secretions. Bandages keep wounds warm, which improves wound healing and facilitates oxygen dissociation. Absorbent/adherent bandages are indicated for open contaminated and infected wounds. These assist in microdébridement with each dressing change, usually performed daily or more often if strike‐through occurs. Absorbent/adherent bandages should be replaced by non‐adherent bandages when drainage becomes serosanguenous and granulation tissue forms on the wound. Wounds may be closed immediately (primary wound closure), within 1‐3 days after injury when they are free of infection but before granulation tissue formation (delayed primary wound closure, after the formation of granulation tissue (secondary closure), or they may be allowed to contract and epithelialize (second intention healing). Factors that affect the decision to close wounds include the amount of time elapsed since the injury, degree of contamination, amount of tissue damage, completeness of débridement, status of the wound’s blood supply, animal’s health, extent of tension or dead space, and location of 6
the wound. Delayed primary closure is indicated for mildly contaminated, minimally traumatized wounds. Wounds are first lavaged and débrided, and treated with bandages after injury before closure. Grossly contaminated or infected wounds or wounds with considerable tissue loss should not be closed primarily and should be treated as open wounds. Again, the goal is to convert the open contaminated wound into a surgically clean wound. They should be thoroughly explored and lavaged to remove debris and reduce bacterial numbers. The wounds will initially heal by contraction and epithelialization and may be allowed to heal completely. Alternatively, healthy wounds may be repaired by secondary closure or by use of a flap or graft. Postoperative wound care should optimize healing. Wounds should be evaluated frequently for infection, tension, seroma formation, dehiscence, and necrosis. Sutures should be removed from wounds in 7 to 14 days. Scarring and suture associated infection is greater when sutures are left for longer periods. Although many of the wounds seen in clinical practice are not life‐
threatening, delays in early effective management can have devastating consequences. Successful results require practice, careful attention to detail, and adherence to the basic principles of wound management. Introduction to Reconstructive Surgery: Indications for reconstructive surgery include: Anatomical Review: The skin is composed of stratified squamous epithelium. The dermis, located under the epidermis is composed of connective tissue with an extensive vascular and nervous network. The subcutaneous tissue lies deep to the dermis. The glands of the skin (apocrine sweat glands and sebaceous sweat glands, perianal glands, and merocirne sweat glands) extend through the dermis into the subcutaneous tissue. The cutaneous trunci muscle is found under the subcutaneous tissue and allows for skin movement. Innervation to the skin is by the cutaneous branches of the ventral branch of the 8th cervical nerve and the 1st thoracic nerve. The blood supply to the skin is provided by direct cutaneous arteries. Three plexuses develop from the direct cutaneous artery and include: deep or subdermal plexus, middle or cutaneous plexus, and superficial or subpappilary plexus). The subdermal plexus provides the major blood supply to the skin and preservation of this vascular network is essential to skin flap survival. Since this plexus is located in the subcutaneous connective tissues, it is very important to undermine skin flaps such that the subcutaneous layer remains attached to the dermis. In areas where panniculus or cutaneous trunci 7
muscles are under the skin, elevation of skin by dissecting under the muscle preserves the plexus. Remember that the skin is an organ. It provides a barrier to infectious disease, and to chemical or gaseous exchange, as well as insulation against thermal changes. Like many other tissues, as an organ, it does not regenerate when excised. Epithelial and connective tissue structural repair occurs but adnexal structures do not regenerate. Skin Defects: Sources of skin injury could be due to: • Trauma • Abrasion • Secondary skin defects • Extensive surgical dissection Surgical closure of cutaneous defect requires proper timing and planning. Infected wounds are generally treated and managed as on open wound so multiple debriding procedures can be done to allow formation of healthy granulation tissue. The location of the defect is also a factor that contributes to skin repair. The trunk of small animals is blessed with very mobile skin. In general, region of good skin mobility include the trunk, cervical region, and upper extremities, whereas skin around the eyes, ears, anogenital region, and distal extremities has limited mobility. Tension lines resulting from gravitational pull and muscle pull influence closure of cutaneous wounds. Incisions made across tension lines tend to separate. Incisions made parallel to tension lines gape less. Thus, when planning an incision, it is helpful to make your incision parallel to the tension lines. There are a few basic principles to remember when suturing skin flaps. Suture placement must be done with care when securing skin flaps to the recipient area. Few sutures, if any, should be placed under the flap for dead space control. Place too many sutures under the flap may compromise blood supply. Sutures should be placed atraumatically at the periphery (subcuticular pattern) of flaps and then simple interrupted skin sutures are placed. And remember to limit tension. Cutaneous Reconstructive Surgery: Walking sutures: The purpose of “walking sutures” is to take advantage of the normal elasticity of the skin when stretching skin over a cutaneous defect. The skin is undermined deep to the subdermal plexus to facilitate movement of skin. Using an absorbable monofilament suture material, the “walking suture” is placed 8
through the dermis away from the proposed line of closure, and then subsequently through fascia closer to the proposed line of closure. The technique effectively disperses tension over the entire surface area of the flap, closes dead space, and advances surrounding skin over the defect to be covered. Closure by local skin mobilization: In the following procedures described, the skin defect is closed by utilizing tissue in the area of the defect. Examples of techniques include: • Undermining – Dissecting under each edge of a defect to allow the skin to be stretched over the defect without tension. • Relaxing incision – After an incision is made in juxtaposition to the defect, the intervening skin is undermined and moved over the defect. The resulting new defect is closed by an alternative technique or allowed to heal by second intention. • Local skin flaps – These are full thickness flaps that are incised, undermined, and transposed over a cutaneous defect. They are based on the subdermal plexus blood supply. Examples include: o Rotational flaps o Transposition flaps o Advancement flaps • Closure by distant skin mobilization – These techniques often require multiple procedures. The additional procedures are required to allow the blood supply within a flap to increase and allow collateral circulation to develop. Techniques involving distant skin transposition are based on redirection of blood flow or incorporation of direct cutaneous arteries into the flap. Examples include: o Axial pattern flap – Based on direct cutaneous arteries. Since these flaps contain an arterial supply, then can be made in long lengths, and subsequently mobilized to cover large distant trunk or extremity defects. o Island arterial flap – This flap is dissected completely free of surrounding skin but the direct cutaneous artery and vein that supplies the flap is left intact. The technique results in increased flap mobility. o Tube flaps – Based on the subdermal plexus. After parallel incisions, the skin is tubed on itself and the skin defect remaining is closed under the tube. After 14 days, the blood supply in the tubed skin is redirected in a longitudinal flow and one end of the tube can be safely excised and moved to a distant cutaneous defect. After 9
adequate collateral circulation develops within the transferred pedicle, the tubed portion can be excised. o Pouch flaps – These are flaps located on the lateral aspect of the trunk and based on the subdermal plexus. Used to cover defects on distal extremities. The extremity is immobilized to the flap by bandaging for 14 days. The base of the flap is excised at that time and sutured to the remaining defect. The cutaneous defect on the trunk is then closed primarily. Free skin grafts: Skin grafts are free avascular tissue that are transferred to a distant site that has a healthy granulation bed. Free grafts depend on tissue fluid from the graft recipient bed (plasmatic imbibition) for nutrition during the first 48 hours after transposition. During this period, capillary anastamosis or ingrowth (inosculation) form the granulation bed to the donor skin occurs. Movement, hematomas, seromas, or infection all decrease the likelihood of “graft take”. Several methods of free skin grafts are possible and include: • Full thickness skin graft – Full thickness skin that is transferred to a recipient bed of granulation tissue. This graft results in complete hair growth is it is important to note the direction of hair growth prior to transfer. Strict immobilization is required. • Split thickness skin graft – The skin is split with a dermatome or a scalpel blade creating a thin graft. The split thickness skin graft can be placed over more undulating areas than the full thickness grafts. This graft is devoid of adnexal structures. • Split thickness meshed skin graft – A split thickness graft that is meshed by scalpel or by a skin mesher to allow an accordion‐like expansion of the graft. Doing so allows coverage of greater area with a smaller piece of skin. It can be placed over mobile, undulating defects and the meshed areas provide a route for escape of blood and serum. • Sieve graft – A full thickness graft with holes punched in the center to allow drainage of serum and blood in hopes of better graft‐granulation tissue contact. • Strip graft – Strips of full thickness skin placed parallel to each other to cover a skin defect. • Seed or Punch grafts – Circular areas of full thickness skin removed with a biopsy punch and set into holes of like diameter made in granulation tissue. 10
Notes 11
Electrolyte Disturbances in the Emergency Setting Janelle Wierenga, DVM, DACVECC Electrolyte disturbances are a common and life‐threatening condition in small animal patients. It is important to evaluate electrolytes in patients that present in a condition of illness. Measurement of electrolytes in life‐threatening situations needs to be performed rapidly and at the scene. These situations include evaluation of the potassium levels in feline urethral obstructions, calcium levels in patients that are having clinical signs consistent with tremors or sodium levels in a patient with possible Addison’s disease. Patients with critical illnesses can have alterations in many different electrolytes and it is important to re‐
evaluate the electrolyte levels in any patient that is on fluids for more than 24 hours and not eating. Alterations in electrolytes can result in critical conditions and severe clinical signs though it is also important to remember that treatment of disease conditions can also result in electrolyte disturbances that can be life‐
threatening (Addison’s disease, diabetes ketoacidosis). Some electrolyte disturbances can be immediately life‐threatening such as hyperkalemia, while others can result in a life‐threatening condition in a few days such as rapid correction of a hyponatremia. To understand the importance of electrolytes in the body, there needs to be a short review of cellular physiology. The cell membrane in mammalian systems is a bipolar lipid membrane made of lipids and free fatty acids and protein channels. The membrane is semi‐permeable which means that it allows for some substances to pass freely such as water but other substances, such as electrolyte molecules, must pass through channels. Because the membrane is not freely permeable to cations and anions, a chemical gradient is created with some electrolytes at a higher concentration inside the cell (potassium, magnesium, phosphorus, calcium) and others outside the cell (sodium, chloride). An electrical gradient is a result of the chemical gradient with a resulting negative charge across the cell membrane (charge quantity is dependent on the cell type). The electrochemical gradient across a cell membrane may create a draw for an electrolyte based on both the charge of the electrolyte and also the concentration gradient of the electrolyte. This may result in competing gradients for the different electrolytes. Electrolytes mainly move across the cell membrane in two ways: either through channels that open and the electrolytes will move based on the electrochemical gradients or electrolytes will be pumped through channels which is usually against the electrochemical gradients and may involve energy 12
use in the form of ATP. The electrochemical gradient is important for many reasons, for example, changes in the gradient allow for contraction of muscle in smooth, cardiac and skeletal muscle cells and the changes also create the conduction of signals in both central and peripheral nervous cells. The gradient also allows for the cell to maintain its size and integrity subjective to changes in osmolality inside and outside the cell. Alterations in osmolality may result in cell death as the cells may shrink or swell. If the integrity of the cell membrane is compromised, cations and anions will leak out and into the cell resulting in a loss of the electrochemical gradient and subsequent cell death. There is not enough time to evaluate all the aspects of electrolyte disturbances so we will concentrate on the two electrolytes that can be extremely important in the emergent setting, potassium and sodium. The other electrolytes can result in emergency situations, though less commonly than potassium or sodium. Calcium, Phosphorus and Magnesium: Calcium, both hypocalcemia and hypercalcemia, can result in emergent situations. Some of the underlying causes and therapy for calcium disturbances will be reviewed in the lecture by Dr. Dana Brooks. Life‐threatening or severe hypocalcemia can occur if the total calcium is less than 5 to 6.5mg/dL or if the onset is acute. Situations when severe hypocalcemia can occur include eclampsia, hypoparathyroidism (especially if the parathyroid glands are damaged or removed in thyroidectomy surgery), and less likely acute renal failure, acute pancreatitis and ethylene glycol intoxication. It is important to note that when dealing with hypocalcemia, regardless of the underlying cause, IV calcium supplementation with calcium gluconate or calcium chloride should be performed when the patient can be evaluated with an ECG for any dysrhythmias. Patients with clinically significant hypocalcemia, those that are clinical for the hypocalcemia, should be critically monitored in a 24‐hour facility if possible. Hypercalcemia can result in clinical signs along with mineralization of soft tissues in the body. Life‐threatening hypercalcemia is dependent on both the value and chronicity of the calcium with a total calcium of greater than 18 to 20mg/dL. The most common therapy includes IV fluid diuresis +/‐ diuretics such as furosemide in order to excrete the excess calcium and identifying the underlying cause of the hypercalcemia and treatment of the cause if possible. Causes likely to be associated with severe hypercalcemia include, but are not limited to, hypercalcemia of malignancy, hypervitaminosis D (secondary to ingestion of cholecalciferol‐containing rodenticides, plants containing calcitriol or iatrogenic), and less likely granulomatous disease. 13
Phosphorus does not commonly result in emergent conditions. Severe hypophosphatemia can result in detrimental effects to the red blood cells and weakness and severe hyperphosphatemia can result in mineralization of soft tissue and multi‐organ failure. The most common reason for severe hypophosphatemia is secondary to the treatment of DKA though severe hypophosphatemia can also occur with refeeding syndrome. Severe hypophosphatemia can result in hemolysis when the phosphorus is less than 1.0 to 1.5mg/dL and also has been reported to result in metabolic encephalopathy and decreased cardiac contractility in experimental dogs. Respiratory depression from muscle weakness can also occur in severe hypophosphatemia. Therapy for severe hypophosphatemia includes IV administration of potassium phosphate. In DKA patients that routinely become hypophosphatemic with treatment, it is recommended to use ½ potassium phosphate and ½ potassium chloride for the potassium supplementation to prevent severe hypophosphatemia. Severe hyperphosphatemia can result in significant mineralization of tissues that can lead to organ failure. Therapy for hyperphosphatemia is similar to therapy for hypercalcemia with the administration of IV fluids and subsequent diuresis. Insulin and dextrose can also be administered which shifts phosphorus into the cell and transiently treats hyperphosphatemia. Causes of severe hyperphosphatemia include acute tumor lysis syndrome, crush injury and rhabdomyolysis and acute renal failure. For most cases of severe hyperphosphatemia, IV fluid therapy is sufficient for treatment because mineralization is a chronic process. Magnesium is an electrolyte that is gaining widespread fame and notoriety recently in the literature for critically ill patients. Magnesium is essential for most enzymatic reactions including reactions with ATP and it is also important in nerve conduction and muscular contraction along with platelet adhesion. Magnesium is a co‐enzyme in the most abundant ATPase pumps, the sodium‐potassium ATPase pumps, and is also important in oxidative phosphorylation. Hypomagnesemia is more common in patients with any illness and hypermagnesemia is relatively uncommon. Life‐threatening decreases in magnesium are not common. Usually decreased magnesium is caused by decreased intake, IV fluid support without supplementation and/or increased losses. Increased loss of magnesium can occur with diuretic administration, DKA, renal disease, third spacing of fluid and gastrointestinal losses. It is difficult to diagnose decreased levels of magnesium because 99% of the magnesium is intracellular. Total magnesium levels do not commonly diagnose a decrease in total body magnesium though if the total magnesium is low, the total body magnesium is low. Ionized magnesium will diagnose decreased 14
levels of magnesium more commonly than total magnesium though it needs to be measured with an ion‐selective electrode. Clinical signs associated with decreased levels of magnesium include dysrhythmias, peripheral vasoconstriction and hypercoagulability. The most common reason magnesium is measured in critically ill patients is due to refractory hypokalemia. In approximately ½ of critically ill patients, potassium levels will not increase or only increase slightly if there is concurrent decreased magnesium. Concurrent decreased magnesium will cause the cell to be unable to maintain the potassium gradient between the intracellular and extracellular fluid spaces and there will also be increased loss of potassium via the kidneys and GI tract. Patients can also have neurological clinical signs associated with decreased levels of magnesium due to decreased influx of calcium into the cells. The current treatment recommendations are to supplement the magnesium if the ionized magnesium is low or if total magnesium is less than 1.2mg/dL. Magnesium can be supplemented in IV fluids in the form of magnesium sulfate (more common) or magnesium chloride. It needs to be diluted if not given via IV fluids by 20% or more at a dose of 0.75 to 1mEq/kg/day. Magnesium is not compatible in fluids containing calcium (LRS, Norm R or P148) or with sodium bicarbonate. Magnesium supplementation also needs to be given slowly, as the side effects can be hypotension, AV block or bundle branch block. Potassium: Potassium is an intracellular cation that is the major electrolyte for creating cell excitability. The normal potassium inside the cell is approximately 150mEq/L while the normal potassium outside the cell is approximately 5mEq/L. The potassium inside the cell compared to the potassium outside the cell results in the resting membrane potential (RMP) of the cell and excitability of the cell. The excitability of the cell is based on the difference between the resting membrane potential and the threshold potential (TP). Alterations in potassium can increase (more negative) or decrease (less negative) the RMP. The change in the RMP will either result in a hyperexcitable cell (when the RMP is less negative and closer to the TP), a hypoexcitable cell (when the RMP is more negative than normal and farther from the TP), or a cell that is unable to generate an action potential (if the RMP is greater than the TP). The calcium ion concentration difference results in the TP of the cell. An increase in calcium extracellularly results in an increase in the TP and will normalize the difference between the TP and the RMP in a hyperkalemic patient while a decrease in the calcium extracellularly will decrease the TP and create a greater difference between the RMP and TP in a hyperkalemic patient. Due to the change in the potentials across the cell membrane, hyperkalemia and even marked hypokalemia, can be 15
extremely detrimental to select cells in the body, primarily the muscle cells and will result in inability of the muscle cells to contract that can be life‐threatening in cardiac musculature. Hyperkalemia can be caused by many different factors but it can be broken down to increased intake, decreased loss or a transcellular shift of potassium. There are also pseudo‐increases that can occur resulting in a measurable but not clinically significant increase in the potassium. Increased intake of potassium that can result in hyperkalemia is secondary to iatrogenic intravenous (IV) administration of potassium supplementation. The most common condition in which this occurs is from overzealous administration or bolus administration of intravenous fluids that contain additional potassium supplementation, usually in the form of potassium chloride and/or potassium phosphate. This is the reason for the maximum rule of potassium supplementation to not exceed greater than 0.5mEq/kg/hr to attempt to prevent iatrogenic hyperkalemia. Iatrogenic hyperkalemic may also occur, though less frequently, with intravenous potassium supplementation and specific drugs used in cardiomyopathies such as beta‐blockers, angiotensin‐converting enzyme inhibitors or potassium‐sparing diuretics. Transcellular shifts of potassium can result in hyperkalemia from conditions such as tumor lysis syndrome, crush injury, reperfusion injury, hyperkalemic periodic paralysis (also called periodic familial hyperkalemia) that has been reported in Pit Bulls and digitalis toxicity. Transcellular shifting of potassium can also occur in acute metabolic acidosis as hydrogen ions shift into the cells to be buffered and potassium ions shift out of the cells. Usually this results in a small change in potassium levels in the blood secondary to metabolic acidosis. Decreased loss of potassium is the most common mechanism by which hyperkalemia occurs in small animal patients. Potassium is excreted through the kidneys and the potassium levels in the blood are regulated closely by the kidneys and adrenal glands. Aldosterone from the adrenal glands regulates the excretion of potassium at the level of the kidneys. If the kidneys or the remainder of the urinary system are unable to excrete potassium (urethral obstruction, ureteral obstruction, oliguric or anuric renal failure, or uroabdomen) or the adrenal glands are unable to secrete aldosterone and/or respond to factors that result in aldosterone secretion (direct response to hyperkalemia and angiotensin II along with other factors that are less substantial causes of aldosterone secretion), hyperkalemia results. Gastrointestinal disease, specifically parasitic disease such as trichuriasis, has also been associated with hyperkalemia. Other gastrointestinal diseases such as perforated duodenal ulcers or other infectious gastrointestinal diseases such as salmonellosis and 16
pleural space diseases such as chylothorax have also resulted in hyperkalemia though this is uncommon and not typical in these diseases. Pseudohyperkalemia has been reported in some diseases reported above along with other conditions and is not usually clinically significant. Marked thrombocytosis and leukocytosis (>100,000 WBC) has been associated with pseudohyperkalemia. Hemolysis can result in hyperkalemia in Japanese breeds such as Akitas and Shiba Inu although it has been reported in other dog breeds such as a Chinese Shar Pei and it does occur in humans and other mammals such as pigs, horses, and cattle. Pseudohyperkalemia can also occur secondary to contamination of blood or plasma with potassium EDTA or heparin in tubes. Clinical signs associated with hyperkalemia are secondary to the affects on the cell membrane excitability. These effects are most apparent in cardiac muscle cells. Hyperkalemia can cause decrease conduction through the AV node, abnormally rapid repolarization or overall impaired conduction through the cardiac muscle. The effect on the action potential will be based on the acute or chronic nature of the increase in the RMP and also where the RMP is compared to the TP. The effects on the ECG are a combination of the initial effects on the RMP which are potassium‐related, and also the subsequent affects on the opening of the other electrolyte channels such as the fast sodium channels and calcium channels secondary to changes in the electrochemical gradients. The onset of changes on the ECG is tented T waves, increased R‐R interval, decreased P wave height and widened P wave, increased QRS, bradycardia, absent P waves, ventricular fibrillation, ventricular asystole and atrial standstill. Some studies have shown an association between the severity of the hyperkalemia and the ECG changes that will be noted, but it is variable and not predictable. The patient may also have neuromuscular weakness secondary to decreased conduction through nervous cells and skeletal muscle. The treatment for hyperkalemia involves first stabilizing the cardiac muscle cells along with treating the underlying cause of the hyperkalemia. Intravenous fluids are recommended to diurese the patient and attempt to excrete potassium through the kidneys. IV fluids are recommended in the patient with urethral obstruction as the next step in therapy is unobstructing the patient. In situations such as oliguric or anuric renal failure, one needs to be cautious with IV fluid administration as fluid overload can occur quickly. In these patients, hemodialysis is the best treatment if there is no response of the urine output to fluid challenges +/‐ diuretics. Isotonic crystalloids are the IV fluids recommended. Any isotonic crystalloid is beneficial for the purpose of diuresis of the patient though some may choose to use 0.9% NaCl due to the absence of potassium in the fluids. A study performed on urethral obstruction in felines did not show a difference in the hyperkalemia, clinical signs or outcome 17
of the patients that were treated with saline versus isotonic crystalloids with potassium such as lactated ringers solution. Calcium gluconate is recommended to stabilize the cardiac muscle cells by increasing the TP and re‐establishing the difference between the RMP and TP. The dose is 0.5‐1.5mL/kg IV of a 10% solution and it should be given over 10‐15 minutes with monitoring of the ECG since IV calcium administration can cause dysrhythmias. Administration of calcium will not change the potassium levels and the duration of effect is usually between 20 to 60 minutes or less. Dextrose +/‐ insulin is used to shift potassium into the cells. The dose is 0.5‐1U/kg IV regular insulin and 0.25‐0.5g/kg IV 50% dextrose which can be diluted 1:1 or more to decrease the osmolality of the solution. Sodium bicarbonate will also work to decrease the hyperkalemia by shifting the potassium into the cell. Sodium bicarb should be used in patients that have a metabolic acidosis and are not hypernatremic. The dose of sodium bicarb is 1‐3mEq/kg IV and given over 10‐15 minutes as rapid administration can cause hypotension. Multiple doses of sodium bicarbonate can result in hypernatremia. Due to the transcellular shift of potassium into cells, both sodium bicarbonate and dextrose and insulin will decrease the potassium levels transiently. The second step involves treating the underlying cause of the hyperkalemia if indicated such as urethral catheterization, hemodialysis, surgery to repair an uroabdomen and continued IV fluid therapy. Hypokalemia is usually not as immediately life‐threatening as hyperkalemia though severe hypokalemia can result in life‐threatening consequences. Hypokalemia is caused by decreased intake which is very common, transcellular shifting of potassium or increased loss of potassium. Decreased intake is common from prolonged anorexia or inappetance and/or IV fluid administration without potassium supplementation. Transcellular shifting of potassium resulting in hypokalemia can result from catecholamine administration such as patients on vasopressor support or post‐cardiopulmonary resuscitation or from insulin and/or dextrose administration, especially in DKA patients. It also has been reported secondary to rattlesnake envenomation. Hypokalemia can result from increased loss of potassium through the gastrointestinal tract or through the urinary system. Vomiting and diarrhea commonly result in hypokalemia if they are prolonged or severe. Renal insufficiency, usually chronic renal failure, renal tubular acidosis, hyperthyroidism or a post‐obstructive diuresis will result in hypokalemia. Cushing’s disease, hyperaldosteronism, and the administration of diuretics has been associated with hypokalemia. Administration of other drugs such as amphotericin B and penicillins has also been associated with hypokalemia. Clinical signs associated with hypokalemia are dependent on the severity of the hypokalemia. Usually patients will not show any clinical signs until the 18
potassium levels are less than 2.5mEq/L. If the hypokalemia is severe, weakness can be observed, ileus, dysrhythmias and cervical ventroflexion in cats. Polyuria and polydypsia can also been associated with hypokalemia. Severe muscle weakness leading to hypoventilation has been reported in a cat, resulting in the need for mechanical ventilation. The treatment for hypokalemia is potassium supplementation. A patient that is in the hospital and receiving IV fluids should be supplemented with potassium in the IV fluids. In most cases, potassium is administered with chloride, KCl, because most patients with hypokalemia will have a chloride deficiency also though potassium can also be administered as potassium phosphate, KPhos. A combination of KCl and KPhos is recommended for DKA patients, as they will likely become both hypokalemic and hypophosphatemic with IV fluid and insulin therapy. The recommendation is to not exceed greater than 0.5mEq/kg/hr to avoid iatrogenic hyperkalemia. In some cases of severe hypokalemia and/or refractory hypokalemia, a CRI of greater than >0.5mEq/kg/hr is indicated but the potassium should be checked routinely (every 4‐6 hours). Potassium supplementation is usually administered in the IV fluids as follows, as long as the patients are not fluid intolerant: Serum [K+] Amount of K+ (mEq/L) <2.0 80mEq/L 2.1‐2.5
60 2.6‐3.0
40 3.1‐3.5
30 3.6‐5.0
20 or none For patients with a chronic hypokalemia in which the underlying cause of the hypokalemia cannot be treated, potassium can be administered orally in the form of Tumil K. Sodium: Alterations of sodium are usually the result of imbalances of water within the body rather than changes in total body sodium. Some cases do exist and have been reported in veterinary medicine and human medicine related to increased levels of ingested sodium rather than a loss of water resulting in hypernatremia. Ingestion of homemade play dough, beef jerky, saltwater and hot dogs can result in clinically significant hypernatremia. Also, some diseases cause a direct effect at the level of the adrenal gland which can result in decreased mineralocorticoid levels and hyponatremia though in most of these 19
patients there also may be an increase in water secondary to a decreased effective circulating volume. The two important factors in sodium changes, or water changes, are the rate of change and the severity of the change. In some instances the rate of the change is even more important than the actual sodium level that is measured. The sodium level, though, is important in order to decipher the severity and likelihood of clinical signs from the hyponatremia or hypernatremia and/or the treatment of the sodium imbalance. The reason why it is important to attempt to determine the rate of change of the sodium is due to osmolality. Osmolality is the number of solutes per kilogram or gram of body weight. On the other hand, osmolarity is the number of solutes per liter of volume. The osmolality in the body determines cell swelling or shrinkage that can result in cell death. Osmolality is determined by 2(Na + K) + BUN/2.8 + Glucose/18. Normal osmolality is 290‐310mOsm/L. Potassium is negligible in the equation, even when elevated, and BUN and glucose are divided by a denominator and they do not cause a dramatic enough change in the osmolality unless they are severely elevated. Sodium is, therefore, the major determining factor in osmolality. Situations when BUN can cause a dramatic change in osmolality that can be clinically significant include treatment of severe acute renal failure called dialysis disequilibrium because it usually more likely to be associated with hemodialysis treatment and is difficult, though possible, to attain a dramatic decrease in BUN with IV fluid therapy. Severe diabetes when the glucose is greater than 500‐
600mg/dL and the initiation of fluid therapy and regular insulin administration can result in clinically significant dramatic decreases in the osmolality with hyperglycemia, though this is uncommon. Osmoreceptors located in the hypothalamus sense small changes in osmolality within the body (2‐3mOsm/kg). This change in osmolality will send signals via afferent neurons to the posterior pituitary for release, or not, of ADH. Also the baroreceptor response can also trigger the release of ADH to retain water if hypotension is noted. ADH travels to the renal tubular cells and attaches to the V2 receptors. This then reabsorbs water. It is also important to note that the thirst center will be stimulated in conditions of hyperosmolality and/or hypotension. The three important factors in sodium imbalances are the starting value of the sodium, acute versus chronic onset of the sodium imbalance if it can be determined and the rate of change of the sodium in the therapy. Acute onset sodium changes are known to occur in less than 24 hours. It is rare that sodium changes are acute unless a large volume of sodium is ingested or an underlying central diabetes insipidus is uncovered. Situations when the onset may also be determined to be acute is when the sodium was measured to be normal in the 20
hospital and then documented to change acutely within 12‐24 hours or less. Most situations resulting in sodium changes are chronic or cannot be determined to be acute in onset. The other possibility is that the onset is likely acute in onset but the patient did not present to the hospital during that time period. Chronic onset is determined to be greater than 24 to 48 hours. The importance of determining the onset of change of the sodium is due to the physiologic response of the cell to changes in osmolality. In the brain cell, it is known to take 24‐48 hours for the cell to complete the production of substances called idiogenic osmoles or to get rid of osmoles intracellularly with changes in extracellular osmolality. If the extracellular osmolality is corrected too quickly for the cell and the cell has begun to equilibrate, water will leave or go into the cell without hesitation, resulting in significant cell shrinkage or swelling. In the brain, this could result in cerebral edema or cell death. This is why it is important to attempt to determine the acute versus chronic nature of the onset. If the acute nature of the sodium imbalance cannot be determined, it is recommended to treat it as if it was more chronic in onset. Sodium imbalances do not equate to hydration imbalances clinically in patients. Hydration status does not indicate sodium levels. Patients can be hypernatremic and be dehydrated, euhydrated or overhydrated. On the other hand, patients can be hyponatremic and be dehydrated, euhydrated or overhydrated. Hypernatremia is usually due to a water loss rather than a salt gain. Most patients will become hypernatremic due to free water loss and/or decreased intake of free water. In most patients, it is a combination of the two that causes the hypernatremia. Situations such as denial of access to free water, hypotonic losses in vomiting and diarrhea or diabetes insipidus (DI) can lead to hypernatremia. DI can be nephrogenic or central and can be unmasked with decreased free water intake. Central DI can occur in patients with traumatic brain injury or head trauma or can occur secondary to other intracranial diseases. These diseases include congenital diseases like hypodypsic hypernatremia in Schnauzers and holoprosencephalopathy, hydrocephalus or acquired diseases such as hypothalamic granulomatous meningoencephalitis or CNS lymphoma. There are situations when increased salt intake can result in hypernatremia. In‐
hospital conditions include iatrogenic hypernatremia from sodium bicarbonate therapy, hypertonic saline administration or sodium‐phosphate‐containing enemas. Out‐of‐hospital situations that can result in clinical hypernatremia include ingestion of beef jerky, sea or salt water or salt‐flour dough mixtures. The clinical signs associated with hypernatremia are usually vague to none, but can include CNS signs. The patient may be seen drinking a large amount of water and sometimes the water can be in excess. The CNS signs that 21
can be associated with hypernatremia will usually occur if the hypernatremia occurs rapidly and usually it is measured to be greater than 170‐180mEq/L. The signs include obtundation, seizures, head pressing, coma and death. These signs occur due to shrinkage of cells of which the CNS cells are least tolerant of these cellular changes. As mentioned above, the cells create idiogenic osmoles to increase the intracellular osmolality. This starts immediately when there is an extracellular change in osmolality but it takes 24‐48 hours for completion. Treatment of hypernatremia should always occur. If the sodium is less than 180mEq/L, the sodium should be decreased by 1mEq/L/hr; if the sodium is greater than 180mEq/L, the sodium should be decreased by 0.5mEq/L/hr. The rules for decreasing the sodium are to prevent cerebral edema secondary to the production of the idiogenic osmoles in the cell. Free water can be administered orally if the patient is drinking and there is no vomiting or risk for aspiration pneumonia with decreased mentation. The water amount needs to be monitored and should be given in 4‐6 hour increments. Free water can also be administered intravenously in three forms. 5% dextrose in water, D5W, is the easiest fluid to administer because it has 250mOsm/L (isotonic) but becomes free water in vivo. Sterile water can also be administered IV, but it needs to be given into a central line and piggy‐backed into isotonic fluids due to the hemolysis that will occur if given directly into a peripheral vein. Maintenance fluids such as 0.45% NaCl, Norm M or Plasmalyte 56 can be given but the amount of free water that is administered needs to be calculated. In the acute setting, less than 12‐24 hours, the free water can be given back rapidly but it is uncommon that the acute onset is documented. Some patients with central DI and subsequent polyuria may need to be bolused free water and this should be performed in a critical care facility if feasible due to the complications that can occur and close monitoring that is needed. If the onset is chronic or not documented to be acute, the sodium should be increased by 0.5‐1mEq/L/hr. First, the free water deficit is calculated. The free water deficit = [(current Na/normal Na) – 1] x body weight in kg. The free water deficit amount is given by the number of hours to decrease the sodium by approximately 1mEq/hr or less. A shortcut can be created for the amount of free water that is needed to decrease the sodium by approximately 1mEq/hr. The shortcut is to administer 3.7mL/kg/hr of water. This amount is a place to start and may need to be increased if there are ongoing free water losses. It is important to monitor the sodium every 4‐6 hours initially to monitor your therapy and monitor for any CNS signs. If the patient has concurrent volume depletion or dehydration, use IV fluids within 6‐10mEq/L of the patient’s current sodium to give back the deficit or to bolus. These fluids can be made using a 23.4% NaCl solution (4mEq/mL) added to isotonic crystalloids. It is also 22
important to note that when administering free water, only 1/3 of the volume will remain extracellularly and the rest will go into the cell. Complications that can occur from treatment of hypernatremia include cerebral edema. Clinical signs include head pressing, obtundation, coma, or seizures. If these signs are observed during the therapy, stop the free water administration and recheck the sodium level. If cerebral edema is suspected, mannitol can be administered (0.5‐1g/kg IV). Mannitol will affect the sodium excretion and sodium levels may need to be checked more frequently. Hyponatremia can occur directly from various disease processes, from administration of hypotonic fluids or from increased water reabsorption from hormonal diseases or hypovolemia. The most common reason for hyponatremia is a decreased effective circulating volume (ECV). The decreased ECV causes release of ADH and also stimulates thirst which results in hyponatremia. Diuretic administration can also result in hyponatremia either through a decreased ECV and/or the sodium goes intracellularly as the potassium comes out of the cells. Addison’s disease results in sodium retention, increased drinking and also a decreased ECV and hyponatremia. Another disease that can result in hyponatremia is SIADH (syndrome of inappropriate ADH secretion) which results in water retention in response to improperly increased levels of circulating ADH. SIADH can occur in humans secondary to administration of many pharmaceuticals including opioids, antibiotics and chemotherapy. The clinical signs associated with hyponatremia are usually vague to none, but can include CNS signs. CNS signs will occur if the onset was rapid and is usually associated with sodium levels less than 120mEq/L. The signs are head pressing, obtundation, seizures, coma or death. This is due to cell swelling from water initially going into the cell and the expulsion of intracellular ions which is initially rapid but the loss of intracellular osmolytes is longer and may take hours to days. With hyponatremia, it is recommended to increase the sodium by no more than 0.5‐1mEq/L/hr. If the patient is symptomatic for the hyponatremia, the sodium may need to be increased more quickly. If there is concurrent decreased ECV, it is recommended to use LRS, which has a sodium level of 130mEq/L or maintenance fluids with sodium added to be within 6‐10mEq/L sodium as the patient. For most patients with a decreased ECV, the LRS will be the fluid of choice. For Addisonian patients, the sodium may be lower than 120mEq/L and then fluids will have to be made up for deficit/bolus administration. It is difficult to change the sodium in congestive heart failure patients and since most of them cannot tolerate fluids, it is recommended to monitor the hyponatremia (which is usually mild) and consult with a cardiologist. If the hyponatremia is moderate to severe (less than 120‐130mEq/L) and the patient is edematous with an adequate 23
ECV, the patient should be water restricted. If it is moderate to severe and the patient is euhydrated to dehydrated, the sodium in the IV fluids should be made to be 6‐10mEq/L more than the patient. The sodium will need to be rechecked every 4‐6 hours and new fluids created as the sodium levels increase. Drugs can be used to increase the free water excretion such as mannitol or furosemide. These should only be used if IV fluid therapy is ineffective or the patient is symptomatic. Complications that can occur with treatment of hyponatremia can be severe and life‐threatenting. Central pontine myelinolysis can occur which is neuronal shrinkage away from the myelin sheath. This usually occurs in the thalamus in small animals though in humans it occurs in the pons. This condition can be reversible but it also can be irreversible. The clinical signs usually occur 3‐5 days after therapy and intervention rather than immediately and can include paresis, ataxia, dysphagia or obtundation. Usually these patients will present with a sodium less than 110‐120mEq/L initially and have an increase in the sodium that was greater than 0.5mEq/L/hr with administration of therapy. Intensive supportive care is recommended for these patients and they may or may not recover. Usually clinical signs are not noted during therapy for hyponatremia, but if they are, the fluids should be discontinued and the sodium level rechecked. Free water may need to be administered if the sodium level has increased too rapidly. Pseudohyponatremia can occur in diabetic patients and is secondary to the hyperglycemia and increased plasmas osmolality. It is also called hyperglycemic hyperosmolar syndrome. For each 100mg/dL increase in blood glucose, the sodium will decrease by 1.6mEq/L. These patients usually have a mild hyponatremia and the hyponatremia will resolve with insulin and fluid therapy. If the hyponatremia is moderate, LRS can be administered or IV fluids with decreased sodium amount. References: 1) Small Animal Critical Care Medicine, eds. Silverstein DC and Hopper K. 2009, St. Louis, MO. Saunders and Elsevier. 2) Fluid Therapy in Small Animal Practice, ed. DiBartola SP. 2000, Philadelphia, PA. Saunders. 24
Notes 25
Parathyroid Disorders Dana Brooks, DVM, Diplomate ACVIM (Internal Medicine) The parathyroid glands are responsible for calcium and phosphorus homeostasis. The internal parathyroid glands are located within the thyroid gland parenchyma. The external parathyroid glands are attached to the thyroid capsule, and although they can be located anywhere, they are most commonly at the cranial pole. Adjustments of parathyroid hormone (PTH) are based on negative and positive feedback mechanisms. The control of ionized calcium (iCa) levels is regulated very tightly and only minor fluctuations will cause a change in PTH levels. When looking at parathyroid disorders it is helpful to remember that iCa and PTH should always have an inverse relationship. Therefore if iCa goes down, PTH will be secreted, if iCa goes up, PTH levels will decrease. Anytime this inverse relationship is disturbed, the parathyroid glands are acting inappropriately and a primary parathyroid disorder can be assumed. PTH exerts its activity in three ways. It helps to accelerate bone reabsorption of calcium by activating osteoclasts, stimulates intestinal absorption of calcium through vitamin D production, and stimulates renal tubular reabsorption of calcium. The total serum calcium we measure on most chemistry analyzers is a combination of ionized calcium, protein bound calcium and complexed calcium. Ionized and bound make up 95% or more of the total calcium. Although we routinely measure total calcium, it is ionized calcium that is the active form. If calcium is borderline high or low, measurement of ionized calcium may be necessary to determine if a true problem exists. It is common practice to correct calcium with albumin by using 3.5 as a standard albumin level and either adding or subtracting the difference of measured albumin and 3.5 to the total calcium depending on if albumin was low or high respectively. (if albumin is 2.0, subtract that from 3.5 = 1.5. Add 1.5 to the calcium) This is certainly helpful to a degree, but it is by no means precise. Take into account that only about half of calcium is bound to albumin, and when hypoalbuminemia is present, there will be a shift to more ionized calcium. Acidosis or alkalosis can affect ionized calcium levels by increasing or decreasing them respectively. If thereis more complexed calcium present, such as calcium oxalate or calcium phosphate, ionized calcium levels may be lower. There are also a number of things that can cause laboratory error in the measurement of total calcium. Lipemia can exert a tremendous effect on the measurement of calcium, causing measurements as high as 20mg/dl. Other factors that can falsely elevate measured calcium include postprandial measurements, hemoconcentration and administration of calcium based 26
phosphate binders. Young animals tend to have slightly higher calcium levels than adults. Hypoparathyroidism: Hypoparathyroidism is defined as the failure of the parathyroid glands to secrete parathyroid hormone, usually secondary to lymphocytic parathyroiditis or surgical removal. It can occur at any age and toy poodles, miniature Schnauzers, Labrador retrievers, German Shepherd dogs and terriers appear to be predisposed. In dogs it appears more common in females whereas in cats it is more prevalent in males. Clinical signs can vary depending on the severity of the hypocalcemia, but most commonly involve muscle tremors or twitches, nervousness, facial rubbing or sneezing, muscle cramps, pain, stiff gait, or seizures. Gastrointestinal signs such as inappetence, vomiting and diarrhea may occur as well as tachycardia in the dog (probably from pain) and bradycardia in the cat. Clinical signs usually do not occur until the total calcium is less than 6.5mg/dl, but the average at presentation is about 4.8mg/dl. Phosphorus is either normal or increased and is often higher than the calcium. A PTH profile will show a decreased PTH along with decreased ionized calcium. Emergency management involves intravenous administration of calcium gluconate as a 10% solution. Typically 5‐15mg/kg (roughly equal to 0.5‐1.5ml/kg) is given over 10‐30 minutes while monitoring for bradycardia. If bradycardia occurs, the infusion should be stopped until the heart rate returns to normal, and then restarted at a slower rate if the calcium is still low. Always save serum for the PTH assay PRIOR to treating ‐ PTH can only be interpreted in light of the ionized calcium at the time it was taken. Once the patient is stabilized, short term maintenance is begun. This may be accomplished with calcium gluconate as repeated IV boluses, a CRI (60‐90ml/kg/day) or diluted SQ infusions. Even with a 1:10 dilution I have had dogs form firm masses under the skin in the area of the infusion. Oral calcium will NOT work in dogs with hypoparathyroidism because there is no PTH to activate Vitamin D which is responsible for calcium absorption. Therefore, it is important to begin long term maintenance therapy when there is a reasonable expectation that the dog or cat is hypoparathyroid. Other potential causes of hypocalcemia may include eclampsia, malabsorption syndromes (lymphangectasia), ethylene glycol toxicity, phosphate containing enemas, chronic renal failure, over dosage of biphosphonates, administration of a transfusion with too much CPDA, or laboratory error (EDTA chelates calcium). Most of these causes of hypocalcemia should be relatively easy to recognize. Dogs with clinical hypocalcemia from lymphangectasia will also be hypoalbuminemic and hypocholesterolemic. 27
Long term maintenance therapy involves either calcitriol or dihydrotachysterol (DHT). Calcitriol is a very powerful synthetic version of Vitamin D which can reportedly raise the calcium in as little as 1‐4 days although 1‐2 weeks may be more common. The starting dose is 0.03‐0.06mcg/kg/day. In all but large dogs this will have to be compounded. Be very careful in your instructions to the pharmacist – calcitriol is supplied in nanograms while the dose is in micrograms – be careful in the conversion! If overdose occurs, it can take anywhere from 1 day to 2 weeks for hypercalcemia to resolve. In my experience it is preferable to (DHT) in cats. I have also had situations where the compounded product from one pharmacy produced no appreciable effect after several increases in dosage, while a compounded product from another company produced the desired results at the normal or less than the normal calculated dose. If there has been no response in 2 weeks, I would double check the dosage (mcg vs. ng) and if correct would consider using a different pharmacy for compounding. Dihydrotachysterol (DHT) is an older form of vitamin D that comes in tablet form. It usually takes longer to increase the calcium, and longer hypercalcemia to subside if an overdose occurs. It can also be difficult to dose in small animals without compounding. The starting dose is 0.02mg/kg/day, and is usually reduced to 0.01mg/kg once daily or once every other day. I have not had success using this drug in hypoparathyroid cats. Hyperparathyroidism: Primary hyperparathyroidism is caused by excessive secretion of parathyroid hormone by abnormal, autonomously functioning PTH chief cells. This can occur with parathyroid hyperplasia, solitary or multiple adenomas or carcinomas. It typically occurs in older dogs (>7yrs) and has no gender predilection. Keeshonds and Siamese cats seem predisposed. The most common presenting clinical sign is PU/PD. Some dogs also present for lethargy, exercise intolerance, anorexia or vomiting, but many dogs may be asymptomatic until they present for urinary calculi related signs. The physical examination is usually unremarkable, but on occasion a parathyroid nodule can be palpated. The physical examination is most important for ruling out other potential causes of hypercalcemia such as neoplasia, hypoadrenocorticism, granulomatous disease and renal failure. Dogs with hyperparathyroidism tend to have total calcium levels around 15‐16mg/dl. The phosphorus is low to normal and many dogs are isosthenuric because of PU/PD. If the hypercalcemia has been prolonged and renal damage has occurred, azotemia may be present.. Hematuria and crystalluria occur with urolithiasis. On the PTH assay both the PTH and iCa will be elevated. 28
There are several methods of lowering calcium in the short term. Saline diuresis alone is often effective because sodium competes with calcium for tubular reabsorption. Furosemide inhibits calcium reabsorption from the tubules and is usually dosed initially as 5mg/kg IV followed by a 5mg/kg/hr constant rate infusion if hypercalcemia is severe. Glucocorticoids (prednisone 2mg/kg divided BID will decrease bone and intestinal absorption and promote tubular excretion of calcium. If saline diuresis, glucocorticoids and furosemide do not bring the calcium down to normal, biphosphonates such as pamidronate which inhibit osteoclast activity can be used. Pamidronate is given as an IV bolus of 1.3‐
2mg/kg in 150ml of saline over 2 hours. This infusion can be repeated in 1‐4 weeks as needed. Hemodialysis is another option. Treatment involves removal or destruction of the abnormal parathyroid gland. Surgical removal is the treatment of choice because affected tissue can be visualized and a histopathologic diagnosis can be obtained. Ultrasound or heat ablation can be attempted if the abnormal gland can be identified sonographically. A single treatment is not always successful and multiple treatments may be required, each requiring general anesthesia. Potential complications involve secondary damage to the recurrent laryngeal nerve or other nearby structures. As stated before, the physical examination is more helpful to rule out other causes of hypercalcemia than it is to definitively diagnose hyperparathyroidism. It is important to rule out these other causes since many are life threatening. Hypercalcemia of malignancy is the most common cause of significant hypercalcemia. Hematopoietic tumors such as lymphoma or multiple myeloma are more likely to cause hypercalcemia than other types due to their propensity to secrete parathyroid hormone related protein. Solid tumors with bone metastasis can cause hypercalcemia via increased osteoclast activity. Other solitary tumors which can cause hypercalcemia include anal sac adenocarcinomas, thyroid carcinoma and thymomas. Hypervitaminosis D is most commonly caused by cholecalciferol rodenticide toxicity. Other possibilities would be overdose or accidental ingestion of calcitriol or DHT, or ingestion of cholecaliferol containing psoriasis creams such as Dovonex. Hypervitaminosis D typically results in severe elevations of calcium levels. Weakness, lethargy and anorexia can occur within 48 hours and can progress to gastric hemorrhage, renal failure and mineralization in the GI, heart, kidneys and blood vessels. Prompt identification and treatment (usually with biphosphonates) is necessary to prevent death. Day‐blooming Jessamine is also reported to cause hypercalcemia due to similar mechanisms. Hypoadrenocorticism can cause hypercalcemia although it is typically mild and iCa is normal. This is uncommon and seems to correspond to the 29
degree of hyperkalemia. Chronic renal failure may lead to renal secondary hyperparathyroidism and mild hypercalcemia. Ionized calcium levels are variable, and phosphorus will be elevated. Other much less common causes of hypercalcemia include systemic mycosis or granulomatous disease, septic bone disease and schistosomiasis. The PTH Assay: In order to definitively diagnose hyper or hypoparathyroidism, a PTH assay needs to be performed. The most basic PTH profile includes PTH and ionized calcium. Based on the degree of suspicion for other diseases, parathyroid hormone related protein and cholecalciferol can be added to the profile. Remembering that PTH and ionized calcium have an inverse relationship will help interpretation of the assay. Evaluate the ionized calcium first – if normal, the patient is not truly hyper or hypocalcemic and the total calcium could have been affected by a change in complexed calcium, or by laboratory error. If ionized calcium is low, a normal parathyroid gland should be secreting PTH in attempt to raise it. If ionized calcium is low, a normal parathyroid gland should have stopped secretion of PTH or at least only be producing a very low level. Therefore, hypoparathyroidism will be associated with low ionized calcium, and low parathyroid hormone. PTHrp should be negative and vitamin D levels will be reduced. Hyperparathyroidism will cause increased ionized calcium with increased PTH levels. Vitamin D levels may be mildly elevated and PTH‐rp should be negative. Hypercalcemia of malignancy will have elevated ionized calcium, low PTH (appropriate response) and low vitamin D levels. Depending on the type of neoplasia, PTH‐rp may or may not be elevated. However, if the PTH response is appropriate for the ionized calcium, you have ruled out parathyroid disease and malignancy becomes a more likely cause. Vitamin D toxicosis will result in severely elevated ionized calcium, very low PTH levels (the appropriate response), normal PTHrp, and significantly elevated vitamin D levels. 30
Expected PTH profile results for different causes: Hyper PTH Hypo PTH HCOM Vit D Tox iCa PTH PTHrp Vit D 31
Notes 32
Coils, Balloons, Pacemakers, Oh My! Intravascular Cardiac Procedures Adonia Hsu, VMD Resident III (Cardiology) ‐ UC Davis Interventional cardiovascular therapies have become part of the high level of veterinary care afforded to pets with eager reception from pet owners given the reduced risk, pain, and recovery time compared to surgical procedures. These minimally invasive procedures provide palliation and/or cure of diseases only surgically managed previously. A brief introduction to the most common procedures offered is described below. Transvascular Occlusion: Patent Ductus Arteriosis (PDA): If left untreated, puppies with a left to right shunting patent ductus arteriosis (PDA) will decompensate within months to a few years after birth. Patients most often present asymptomatic unless they are in congestive heart failure (CHF). Once a PDA is clinically recognized in a patient, ligation or transvascular occlusion is advised. Delay to pursue treatment is not recommended as the chronic left heart volume overload leads to congestive heart failure. In rare cases, the PDA can reverse and shunt right to left. Ligation or occlusion of right to left shunting PDA often results in death and is not recommended. Surgical ligation or transvascular occlusion of the left to right shunting PDA is curative. Procedural risks associated with transvascular occlusion include hemorrhage, arrhythmias, and pulmonary or systemic embolization. Mortality rate has been reported to be less than 3% with coil embolization. Currently, three types of occlusion devices are available including coils, vascular plugs, and the Amplatzer Canine Ductal Occluder (ACDO). Ideally, the ACDO is preferred; however, this is dependent on patient size. At this time, coil occlusion is mostly limited to smaller patients (<3 kg). Occasionally, the very small patient with a larger PDA will be advised to pursue surgical ligation as these patient are more difficult to place a large enough transvascular device for occlusion. Residual flow is common, however, most often considered minimal and therefore insignificant. In rare instances, a second procedure, whether transvascular or surgical is recommended to address the residual flow. Most often, occlusion is considered curative. In many instances, patients may have persistent mild systolic dysfunction; however, it appears to be well tolerated and clinically insignificant. Using a small incision, the approach is most often from the femoral artery, however, a carotid or a venous approach may be pursued in certain patients. Post‐procedural recovery time is minimal 33
and patients often do not require pain management. A three month cardiology follow up is recommended to ensure device placement, otherwise no other follow‐up is necessary unless the continuous murmur returns. Balloon Valvuloplasty: Pulmonic Stenosis (PS): Severe pulmonic stenosis (PS), defined by a pressure gradient across the valve of >80mmHg diagnosed by Doppler echocardiography, leads to sudden death or decompensation to right sided congestive heart failure within a few years of life. Often patients present with no clinical symptoms, however, may present with lethargy, syncope, or exercise intolerance. These at‐risk patients are advised to pursue balloon valvuloplasty (BV), the current standard of care treatment for severe valvular pulmonic stenosis. BV often palliates, if not cures patients. A small incision is used with a jugular vein approach. Procedural risks include hemorrhage, arrhythmias, and damage to the tricuspid valve resulting in significant tricuspid regurgitation. Mortality rate has been reported to be less than 10%. Commonly, BV will result in a right bundle branch block (RBBB) which may be temporary or persistent, however inconsequential to the patient. Success is defined by a reduction in pressure gradient of 50% or more. Only valvular PS is considered amenable to BV, while supravalvular or subvalvular lesions usually do not result in a successful procedure. The most successful BVs rely on a thin, “doming” valve in which the cusps are tethered. A dysplastic pulmonic valve and/or hypoplastic pulmonary artery is less amenable to BV, however all patients with severe valvular PS are advised to pursue BV. Depending on the success of the procedure, recheck is recommended 3 months after BV and then every 1‐2 years as long as the patient is asymptomatic. Post‐
procedural recovery time is minimal, and patients rarely require pain management. Other less common lesions including cor triatriatum dexter, tricuspid stenosis, and mitral stenosis may also be amenable to BV. Transvenous Pacemaker Placement: Bradyarrhythmias resulting in clinical symptoms of syncope or lethargy such as sick sinus syndrome (SSS), high grade second degree AV block, third degree AV block, and persistent atrial standstill can be treated by transvenous pacemaker placement affording these patients a near normal life. Full systemic work up is commonly recommended pre‐procedure as many of these patients are middle aged to geriatric at the time of presentation. It is imperative to ensure there is no evidence of infection (urinary, skin, etc.) as these may be a nidus for infection and a pre‐operative urinalysis +/‐ culture is ideal. The transvenous lead 34
is placed via the right jugular vein with the lead tip ideally within the trabeculae of the right ventricular apex. The generator is placed in the subcutaneous space either on the right lateral neck or behind the scapula with 2 small skin incisions at the jugular vein site and the generator placement site. The jugular vein used to place the lead is no longer usable for phlebotomy. Complications include hemorrhage, arrhythmias, displacement of the lead or infection of the lead requiring another procedure, and seroma formation at the site of the generator. Mortality rate has been reported to be 4‐10%. Post‐operative care includes restricted exercise for 1 month post pacemaker placement to discourage displacement of the lead. A body or head harness (Halti or Gentle Leader) is recommended once the pacemaker has been placed. Using a neck collar for leash walking is strongly discouraged since pulling on the collar may result in displacement of the pacemaker lead which is tunneled through the subcutaneous space in the neck. Recheck with cardiology 3 months post placement is recommended to optimize generator/battery life and then once yearly thereafter to monitor battery life. Generators are procured from the CanPacers program which receives generators that have past the shelf life for human use. Generally these generators have an average of 5 years of life and rarely require replacement. However, replacement can be performed easily under general anesthesia, utilizing the original lead and replacing the subcutaneous generator only. Currently, the more commonly placed transvenous lead is a single chamber lead in which only the right ventricular pacing lead is placed (VVI pacemaker). Certain candidates may benefit from a duel chamber pacemaker (VDD) in which an additional atrial lead is placed to allow sensing of intrinsic atrial activity with appropriately timed and paced ventricular activity to allow atrio‐ventricular (AV) association. The VDD system requires substantially more management as compared to the VVI system; however it affords a more physiologically natural system with improved hemodynamic activity over single chamber pacing. VDD pacing may be recommended in more active patients who may benefit from the more physiologic pacing. The chronic benefits of VDD pacing as compared to VVI pacing have yet to be shown and therefore only select patients are advised to have a VDD system placed. 35
Notes 36
Update on Urinary Incontinence Matt Vaughan DVM, DACVIM (Internal Medicine) Seattle Veterinary Specialists, Kirkland, WA Physiology: The two components of normal micturition include a storage phase and a voiding phase. Control of micturition takes place largely in the lumbosacral spinal cord, with coordination from higher neurologic centers in the brainstem (pontine micturition center). The forebrain is not essential for micturition but can determine the onset of the urination process. Afferent signals from bladder stretch receptors travel via the pelvic nerve to the sacral spinal cord and on to the brainstem and cerebral cortex. The storage phase is under control of the sympathetic and somatic nervous system. Sympathetic input is via the hypogastric nerve from the lumbar spine (L1‐L4). Norepinephrine release stimulates beta‐adrenergic receptors in the bladder wall, causing bladder relaxation as well as suppressing pelvic nerve stimulation. Norepinephrine also stimulates alpha‐1 receptors in the internal urethral sphincter (IUS) resulting in contraction of the IUS. In addition, somatic input via the pudendal nerve (S1‐3) causes contraction of striated muscle in the external urethral sphincter (EUS) which aids in urine retention. The alpha‐1 receptors are found primarily in the urethral muscle and trigone region of the bladder and stimulation of them causes contraction of smooth muscle. Three subtypes (a,b,d) exist, with the alpha‐1a being the primary subtype found in the bladder and alpha‐1b and 1d primarily in the cardiovascular system. Alpha‐2 adrenoreceptors are found in the urethral mucosa and submucosa (not in the muscle) and regulate blood flow and urethral lubrication. They are not involved in muscle contraction. (There is evidence of a down‐regulation of these receptors in cats with interstitial cystitis) The voiding phase of micturition consists of detrusor contraction and simultaneous urethral relaxation. Voiding is under control of the parasympathetic nervous system via the pelvic nerve (S1‐3). Acetylcholine is released and acts upon the muscarinic receptors of the detrusor muscle within the bladder wall, resulting in contraction. At the same time there is inhibition of sympathetic and somatic input, resulting in urethral relaxation and voiding occurs. M2 and M3 muscarinic receptor subtypes are found in the bladder. The M3 receptors mediate contraction (via acetylcholine). M2 receptors may enhance the M3 response. M1 receptors are pre‐junctional and facilitate acetylcholine release and bladder emptying. Detrol (tolerodine) is a muscarinic antagonist 37
that is used for “hyperactive bladder” or “detrusor hyperreflexia” and results in bladder relaxation. It has better affinity for the M3 subtype in the bladder than M3 receptors in the salivary gland, resulting in lower side effects (dry mouth). It also blocks M2 receptors more effectively than oxybutinin, which is another muscarinic antagonist. Urinary Incontinence: Urinary incontinence is defined as the lack of voluntary control over the passage of urine. This may be due to a disorder in the storage or voiding phases of micturition. Disorders in the storage phase are more common than voiding phase disorders. Causes of urinary incontinence can be divided into four broad categories; anatomic abnormalities, decreased urethral closure pressure, increased urethral closure pressure and increased bladder contractility. It is very important to differentiate urinary incontinence from pollakiuria and PU/PD. It is quite common for a complaint of “urinary incontinence” to really mean “my dog is peeing in the house” which may be a result of PU/PD and not related to urinary incontinence. Obviously the differential diagnoses and resulting diagnostic plan would differ accordingly. It is also possible that PU/PD can exacerbate incontinence, especially in the case of urethral sphincter mechanism incontinence (USMI). In these cases, successful treatment of urinary incontinence relies just as much on improving the PU/PD (if possible) as improving urethral sphincter tone. Baseline diagnostics for any patient with urinary incontinence would include a complete physical, neurologic and orthopedic exam, urinalysis and urine culture. A CBC and chemistry panel should be considered in any patient exhibiting signs of systemic disease. I. Anatomic Abnormalities: Anatomic abnormalities would include conditions such as ectopic ureters, ureterocoeles, pelvic bladder, and bladder or urethral hypoplasia. A. Ectopic Ureters Ectopic ureters are the most common cause of urinary incontinence in a young dog and are defined by a ureteral termination point anywhere except for the normal trigone position (ectopic). This results in urine flow that bypasses the bladder and therefore the storage phase of micturition. Ectopic ureters may be unilateral or bilateral and often terminate in the urethra or vagina/vestibule. These can be intramural, meaning that they reach the bladder in the normal 38
region, but tunnel through the wall distally until opening in the urethra or vagina. Intramural ectopic ureters are due to a failure of migration or absorption of the ureteral bud and common excretory duct. Extramural ectopic ureters are less common and do not tunnel through the wall but attach directly to an ectopic site (usually vaginal). These are a result of the mesonephric duct failing to contact the urogenital sinus. Ectopic ureters are commonly associated with concurrent abnormalities of the urogenital tract such as USMI, hydroureter, hydronephrosis, renal agenesis or hypoplasia, ureteroceles, pelvic bladder and urachal remnants. Ectopic ureters are typically diagnosed in young dogs and breeds that are over‐represented include Siberian Huskies, Labrador Retrievers, Golden Retrievers, Newfoundlands and English Bulldogs. Ectopic ureters are diagnosed more frequently in female dogs, which may be partly due to the fact that the length of the male urethra may provide increased resistance and therefore less symptomatic urinary incontinence with ectopic ureters. Bilateral ectopic ureters are more frequent than unilateral, however there are conflicting reports regarding this. Clinical signs include constant urine dribbling since birth which may worsen in a recumbent position. Dogs often will have urine scald or be constantly urine soaked. Diagnosis is made via contrast radiography (intravenous pyelogram, retrograde ureterogram, vestibulovaginogram), cystoscopy or helical contrast CT. Abdominal ultrasound may find evidence of a hydroureter, which increases the suspicion of an ectopic ureter. Cystoscopy and helical contrast CT have been shown to be the most sensitive diagnostic tests for ectopic ureters. Advantages of cystoscopy include full visual evaluation of the vestibule, mucosa and fenestrations of the ectopic ureters can be more easily detected. Disadvantages of cystoscopy include a lack of evaluation of the upper urinary tract and the trigone region and the vesiculourethral junction can be difficult to characterize. Evaluation of the upper urinary tract to look for evidence of hydronephrosis, a ureterocele or renal agenesis should be performed in all dogs with suspected ectopic ureters via a contrast study or abdominal ultrasound. Urodynamic testing can be performed to evaluate for concurrent USMI and/or increased bladder contractility. This may offer prognostic information in regards to gaining urinary continence with surgical correction of the ectopic ureters but equipment for urodynamic testing is often limited to the university setting and may not be available. Treatment for ectopic ureters is surgical either by a nephrectomy/ureterectomy (if the associated kidney is hydronephrotic or agenic) or by ureteral reimplantation. Continued urinary incontinence is common 39
following surgery (reported in 40‐71% of dogs). Smaller dogs (<20kg) may have a better surgical outcome. Reasons for lack of surgical success are likely due to a component of USMI or pelvic bladder, although unidentified bilateral ectopic ureters or recannulization of a surgically ligated ureter are also possibilities. A relatively new technique that has been developed for treatment of intramural ectopic ureters involves cystoscopic‐guided LASAR ablation. This is a quick, minimally invasive procedure that can be performed at the time of cystoscopic diagnosis. Preliminary reports have found a success rate that equals or surpasses that of surgical correction (continence achieved in 60‐80%). However, this procedure has only been performed in a small number of dogs to date and long term follow‐up, as well as studies involving large numbers of dogs, are lacking. II. Decreased Urethral Closures Pressure: A decreased urethral closure pressure may be due to USMI (urethral sphincter mechanism incontinence) or neurologic disorders (lower motor neuron bladder) including discospondylitis, lumbosacral disease, malformations (Manx), disc disease and German Shepherd myelopathy. A. USMI This is the most common cause of urinary incontinence in the dog which is seen predominantly in middle to older, female spayed medium to large breed dogs. Contributing causes of USMI would include a decrease in estrogen resulting in decreased intrinsic tone, abnormal bladder morphology, a decrease or lack of responsiveness in alpha‐1 adrenergic receptors or other hormonal disorders. A diagnostic workup if you are suspicious for USMI should include a thorough neurologic exam to rule out a lower motor neuron disease, urinalysis, urine culture and the confidence that PU/PD has been ruled out. The gold standard test for diagnosing USMI is a urethral pressure profile. This involves placement of a urinary catheter that is slowly removed at a constant rate as a vesicular pressure tracing is measured via a pressure transducer. This is ideally done awake as sedation and anesthesia alter the urethral closure pressure. A graph is generated from which the maximal urethral closure pressure (MUCP) as well as the functional profile length (FPL) can be calculated. As this requires specialized equipment, it is not routinely performed in the initial diagnostic workup for USMI but can be helpful in dogs that are not responding to medication or if the diagnosis is in doubt. In a dog with a compatible 40
signalment and clinical signs, the most commonly utilized diagnostic test is a pharmacologic trial of medication aimed at increasing urethral tone. Therapy of USMI includes treatment with alpha‐1 agonists (PPA, pseudoephedrine), estrogen supplementation (diethylstilbestrol, Premarin), GnRH analogue depot injections, submucosal urethral collagen injections or surgical management. Phenylpropanolamine (PPA) is an alpha adrenergic agonist and causes an increase in urethral tone. It is an effective treatment for USMI in approximately 85‐90% of female dogs. Male dogs have a lower response rate (less than 50%). It is given at 1‐2 mg/kg PO BID‐TID. The most common adverse side effects include a decreased appetite and restlessness. Hypertension is reported but changes in blood pressure have not been frequently documented in the literature. An extended release formulation is available in a 75mg tablet (which can be split once in half without losing sustained release). The author has found that there is often an improvement in dogs when switched from a non‐sustained release formulation (such as Proin) to the sustained release. The sustained release is given at a dose of 1‐2 mg/kg PO BID. Other alpha adrenergic agonists such as psuedoephedrine are not as efficacious as PPA and may result in more side effects. Estrogen therapy with diethylstilbestrol or Premarin (conjugated estrogen) is effective in approximately 50‐65% of female dogs with USMI. The author uses diethylstilbestrol, given as a daily loading dose at 1mg/dog for 5‐7 days and then given at 1mg once to three times weekly (lowest effective dose). Estrogen therapy is thought to result in increased numbers and increased responsiveness of alpha adrenergic receptors to norepinephrine. It can also enhance urethral mucosal maturation, submucosal blood flow and periurethral collagen synthesis. In post‐menopausal women, estrogens improves bladder capacity and genitourinary reflexes. Estrogen therapy and PPA are theoretically synergistic, however a recent study did not find increased urethral closure pressures in dogs given PPA that were already being treated with estradiol. The author usually starts with PPA and if there is a lack of response I add in estrogen therapy while continuing PPA (due to possible synergistic effect). Bone marrow suppression has been reported with older generation depot injections and high doses of DES. Estrogens are not recommended in male dogs. Testosterone in can be used in male dogs but may result in prostatic disease (hypertrophy, cysts) and behavior changes. Gonadotropin releasing hormone (GnRH) analogues have been recently investigated in the role of treatment for USMI. It has been hypothesized that a decrease in urethral closure pressure may be a result of increased LH and FSH levels that follow ovariohysterectomy. Treatment with GnRH analogues 41
decrease LH and FSH levels by down‐regulating production and secretion. A recent study found that GnRH analogues resulted in improvement in urinary incontinence (71%) but were not as efficacious as PPA (92%). The dogs that improved did not have significant increased in urethral closure pressures and there was no correlation between LH/FSH levels and those dogs that responded to treatment or didn’t. It is not entirely clear why some dogs respond to GnRH analogues but it appears that there may be a direct effect upon the bladder via local receptors. The author has used deslorelin depot injection, at a dose of 4.7 mg/dog subcutaneously (two separate injections of this dose for dogs >30kg). If effective, this dose is repeated once signs of incontinence recur (mean reported duration is 120 days). It can be difficult to obtain (Wycliff Pharmacy in Kentucky is one source). Side effects are rare and it can be used in addition to PPA therapy. A more recent therapy for treatment of USMI is endoscopically guided submucosal urethral collagen injections. Collagen is injected circumferentially in 3‐4 regions, 1‐2 cms distal to the trigone via cystoscopy. In one study, 68% of dogs became continent following this procedure with injection alone and a total of 83% were continent with the addition of medical therapy. One third of the dogs that improved were reclassified as incontinent by one year, which is likely due to flattening of the collagen bulges. Retreatment is possible and many dogs will still need additional medical therapy for incontinence following this procedure. The author typically recommends this procedure after all other medical treatment options are exhausted. Surgical management of USMI includes procedures such as culposuspension or cystourethropexy. Reported success rates vary (50‐60%) and the duration of continence post‐operatively drops over time. III. Increased Urethral Closure Pressure: An increased urethral closure pressure causes urinary incontinence due to an “overflow bladder” and may be due to functional or mechanical obstructions. Functional obstructions may be due to an upper motor neuron disorder, urethral spasms or reflex dyssynergy. Mechanical obstructions may be due to urethroliths, bladder or urethral neoplasia, severe urethritis, proliferative urethritis, prostatic diseases (benign prostatic hypertrophy, neoplasia, prostatic cysts or abscesses), urethral foreign bodies and extraluminal compression. Animals with urinary incontinence due to an increased urethral pressure should have an increased residual urine volume and will typically have an enlarged bladder that is evident on physical exam. Visualization of urination is a critical part of the physical exam, as these patients often have an altered or intermittent stream. Measurement of the residual urine volume can be done 42
after urination (normal residual urine volume is <0.4 ml/kg). Other initial diagnostics should include a complete neurologic and orthopedic exam as well as a urinalysis and urine culture. A rectal exam with careful attention to the prostatic and urethral palpation is also important. The next diagnostic step is to rule out a mechanical obstruction via radiographs, cystourethrogram, cystoscopy and/or abdominal ultrasound. Placement of a urinary catheter can also be helpful in determining if a mechanical obstruction exists. If there is no evidence of a mechanical obstruction, then a functional obstruction may be suspected in a patient with an elevated residual urine volume. An increased urethral closing pressure may be confirmed via urodynamic testing (urethral pressure profile). Treatment for a functional urethral obstruction would include an alpha‐
adrenergic antagonist such as phenoxybenzamine (0.25 mg/kg PO BID) or prazosin (1mg/15 kg BW PO TID). Prazosin is a more selective alpha‐1 antagonist and is also more affordable than phenoxybenzamine, especially for large dogs. Weakness, lethargy and hypotension are side effects with either medication, and a blood pressure should be checked in patients exhibiting any signs of lethargy or weakness. Skeletal muscle relaxants (diazepam) to decrease the external urethral tone may also be helpful. A parasympathomimetic, such as bethanechol, may be used for detrusor atony. A mechanical obstruction MUST be ruled out prior to treatment with a parasympathomimetic and increased urethral tone should be diminished first with an alpha antagonist. Side effects include salivation, diarrhea and vomiting. Close monitoring of voiding and residual volume is recommended when instituting treatment. Mechanical obstructions are treated by removing the obstruction if possible. If not possible, pharmacologic treatment may be of some benefit. Other palliative treatments include urethral stent placement (using video fluoroscopy) or placement of a cystostomy tube. Transitional Cell Carcinoma: Transitional cell carcinoma (TCC) is the most common urinary bladder and urethral tumor in the dog. TCC is more common in female dogs and Scottish Terriers, Shelties, Beagles, West Highland Whit Terriers and Wirehaired Fox Terriers are over‐represented. TCC most often involves the trigone region of the bladder but can also commonly involve the urethra and prostate. Clinical signs include hematuria, pollakiuria, stranguria and urinary obstruction. Physical exam findings may find an enlarged urinary bladder and a rectal exam may find urethral swelling or lymphadenopathy. Imaging via 43
abdominal ultrasonography can be used to visualize the bladder and proximal urethra. Distal urethral masses may be missed and cystoscopy or advanced imaging may be necessary. Differentials for a urethral or bladder mass would include granulomatous cystits/urethritis, polypoid cystitis or other neoplastic conditions. Diagnosis of TCC is ideally done by histopathology. Neoplastic cells may be seen on a urine sediment but may be hard to distinguish from reactive epithelial cells. A free catch voided sample, using centrifugation to concentrate a large volume of urine may increase the diagnostic yield for urethral tumors. Traumatic catheterization can be performed and is relatively easy, especially in the male dog. The tip of a polypropolyne catheter is passed to the region of the mass (verified by concurrent rectal palpation) and a small amount of saline is instilled and then aspirated while the catheter is rapidly moved back and forth. Roughening the edges of the catheter tip or cutting extra holes can be done but has not been necessary in the authors experience. Sedation is usually necessary and care must be taken not to pass the catheter through the diseased bladder or urethral wall. A urine tumor antigen test is available and is sensitive, however there are many false positive tests (low specificity). The specificity is improved if there is no evidence of hematuria or an inflammatory sediment (which is rarely the case in dogs with TCC). Fine needle aspirates can be performed via ultrasound guidance, however seeding the needle tract with neoplastic cells has been reported. Because of this, the author will avoid needle aspirations unless a diagnosis via catheterization is not possible and the owner is not interested in pursuing cystoscopic biopsies. Most dogs typically have problems with local growth (urinary obstruction) before abdominal seeding and metastases would be a problem, which may make seeding of the needle tract clinically irrelevant. Tumors that appear surgically resectable (located in the apical region) should not be aspirated due to the risk of seeding the abdomen. Metastasis to lymph nodes is present in about 15% of dogs at the time of diagnosis and about 50% of dogs at the time of death. Thoracic radiographs and an abdominal ultrasound to evaluate sublumbar lymph nodes are recommended for staging. TCC can metastasize to bone rarely and pelvic and lumbar radiographs should be considered in any dog with a TCC exhibiting lameness. Treatment options for TCC involve surgery, radiation, chemotherapy and palliation. Complete surgical resection is rarely possible due to the location of most TCCs (trigone, urethra). Tumors located in the apex may be resectable, however margins can be difficult to obtain and recurrence elsewhere in the 44
bladder is common. Cystoscopy is recommended prior to surgical attempts to further evaluate the extent of disease. Medical therapy of TCC includes chemotherapy and treatment with cyclooxygenase (COX) inhibitors. Piroxicam has been the COX inhibitor most frequently used in canine studies. Treatment with piroxicam alone (0.3 mg/kg PO SID) has resulted in >50% reduction of tumor burden in 18% of dogs and a median survival time in all dogs treated of 6 months. Mitoxantrone along with piroxicam has resulted in a >50% reduction in 35% of dogs and a median survival time of 9 months. Carboplatin has also been used instead of mitoxantrone but with a shorter reported median survival time. Treatment with at least piroxicam in the obstructed dog is encouraged as many obstructed dogs may regain the ability to urinate within 24‐48 hours after starting therapy. Palliative care includes cystostomy tube placement (low‐profile tubes are a possibility) or urethral stent placement. Placement of self expanding metallic stents can be performed in male or female dogs and have had a good to excellent palliative outcome in 86% of dogs. IV. Increased Bladder Contractility: Increased bladder contractility (“overactive bladder”) is most commonly secondary to an underlying cause such as cystitis (sterile or bacterial), cystic calculi, neoplasia, polyps or drugs. Pollakiuria is more frequently a complaint than urinary incontinence in these cases. Behavioral or submissive urination should also be considered as differentials. Idiopathic detrusor hyperreflexia is occasionally observed and diagnosis is made by first ruling out the above mentioned underlying causes and then ideally documenting hyperreflexia with urodynamic testing (cystometrogram). A cystometrogram is performed by placing a urinary catheter into the urinary bladder and slowly filling the bladder as the vesicular pressure is measured. Bladder wall compliance can be assessed and contractions or pressure spikes are seen with hyperreflexia. Anticholinergics (tolterodine, oxybutinin) are used in the treatment of idiopathic detruser hyperreflexia and act by blocking the muscarinic receptors in the bladder. Tolterodine (Detrol) blocks the M2 receptors more effectively than oxybutinin and blocks the urinary M3 receptors more than salivary M3 receptors. Some tricyclic antidepressants such as amitryptalline, imipramine and clompiramine have anticholinergic effects and have been used for treating overactive bladder. There are newer generation antimuscarinic agents that are more specific for M2 and M3 receptor subtypes although as far as the author is aware, evaluation of these in veterinary medicine is limited. 45
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Hamaide AJ, Grand JG, Farnir F, et al. Urodynamic and morphologic changes in the lower portion of the urogenital tract after administration of estriol alone and in combination with phenylpropanolamine in sexually intact and spayed female dogs. Am J Vet Res 2006;67:901‐908. Augsburger HR, Cruz‐Orive LM. Influence of ovariectomy on the canine striated external urethral sphincter (M. urethralis): a stereological analysis of slow and fast twitch fibres. Urol Res 1998;26:417‐422. Byron JK, March PA, Chew DJ, et al. Effect of phenylpropanolamine and pseudoephedrine on the urethral pressure profile and continence scores of incontinent female dogs. J Vet Intern Med 2007;21:47‐53. Carofiglio F, Hamaide AJ, Farnir F, et al. Evaluation of the urodynamic and hemodynamic effects of orally administered phenylpropanolamine and ephedrine in female dogs. Am J Vet Res 2006;67:723‐730. Reichler IM, Jochle W, Piche CA, et al. Effect of a long acting GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles and clinical signs of urinary incontinence due to Sphincter mechanism incompetence in bitches. Theriogenology 2006;66:1227‐1236. Barth A, Reichler IM, Hubler M, et al. Evaluation of long‐term effects of endoscopic injection of collagen into the urethral submucosa for treatment of urethral sphincter incompetence in female dogs: 40 cases (1993‐2000). JAVMA 2005; 226: 73. Glickman LT, Raghavan M, Knapp DW et al. Herbicide exposure and the risk of transitional cell carcinoma of teh urinary bladder in Scottish terrier dogs, JAVMA 2004; 224: 1290‐1297. Raghavan M, Knapp DW, Bonney PL et al. Evaluation of the effect of dietary vegetable consumption on reducing risk of transitional cell carcinoma of the urinary bladder in Scottish terriers. JAVMA 2005; 227: 94‐100. References (cont.): Knapp DW, Richardson RC, Chan TCK et al. Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder. JVIM 1994; 8: 273‐278. 47
Henry CJ, McCaw DL, Turnquist SE et al. Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma. Clin Cancer Res 2003; 9: 906‐911. Boria PA, Glickman NW, Schmidt BR et al. Carboplatin and piroxicam in 31 dogs with transitional cell carcinoma of the urinary bladder. Vet Comp Oncol 2005; 3: 73‐78. Weisse C, Berent A, Solomon J, et al. Evaluation of palliative stenting for management of malignant urethral obstructions in dogs. JAVMA 2006; 229:226‐
234. 48
Notes 49
Surgical Treatment of Spinal and Intracranial Neoplasia Sean Sanders DVM, Ph.D, DACVIM (Neurology) Introduction: Neoplasia and the nervous system are two terms that typically do not conjure up the idea of a “successful outcome”. Truth be told, most of our experiences associated with cancer of the nervous system are not favorable. Over the years, new surgical procedures, advances in microsurgery and adjunctive treatment modalities have contributed significantly to increased survival times in companion animals with neoplasia of the brain and spinal cord. Setting aside the above mentioned advances that lead to increased survival times, diagnostic imaging which allows us to discover the disease process earlier in its course, allows the clinician to provide treatment choices while they still exist. Our understanding of how the nervous system works combined with a complete neurological exam leads us to a neuroanatomical localization. The importance of the descriptive history provided by the client cannot be understated. The client spends the majority of the time with the patient and their observations often provide important insights to what might be going on with the patient when they are not in the exam room. Being able to correctly localize the lesion will provide a more precise plan for diagnostic imaging of the nervous system. The brain and spinal cord are very well suited for cross sectional imaging which includes magnetic resonance imaging (MRI) and computed tomography (CT). MRI is considered the “gold standard” of imaging the nervous system, however CT scan are occasionally used in combination with MRI to provide a more distinct representation of how bone is affected by a disease. In addition to allowing for more early intervention, making a diagnosis also allows a client to make the best decisions for their pet and their lifestyle. Knowing what the disease is, where it is and how bad it is gives the clinician the best ability to prognosticate which then gives the owner of the pet the most options for dealing with the disease. Options include conservative management, surgery, radiation therapy, chemotherapy and combinations of the above. Neoplasia of the Spinal Column: The difference between a successful and an unsuccessful outcome after spinal surgery often has little to do with the technique employed or the disease 50
process that is affecting the patient. Rather, it is often the amount of time that takes place between the initial injury to the spine and the point where the spine is either decompressed or stabilized. While decompression is often the main purpose for spinal surgery, stabilization and obtaining a definitive diagnosis are also common goals of spinal surgery. The decision to pursue spinal surgery or continue with conservative management will depend on several variables. The variables we must consider include: the injury to the spine, the stability of the patient, the goals of the owner, the clinical status and signalment of the patient and the owner’s finances relative to the cost of the diagnostics, treatment and aftercare. Certain disease processes warrant rapid spinal decompression while in other cases a more conservative approach is desired, always in an attempt to either prepare the patient for the best possible outcome of surgery or in some cases to avoid surgery altogether. Surgery should be considered a last resort. It should be employed when there is continual pain that is unresponsive to reasonable analgesics, deteriorating neurological status, failure for conservative management to resolve the problem and to obtain a definitive diagnosis. In all cases where spinal surgery is a consideration, some form of advanced imaging technique has often provided a reasonable diagnosis of the problem or at least directed the surgeon toward a reasonable plan. Advanced imaging techniques utilizing MRI are considered the gold standard of imaging the nervous system. However, with certain disease processes, MRI is often combined with or potentially replaced by CT scanning. Radiographs are often considered part of the minimal database prior to advanced imaging. Radiographs of the spine will rarely be definitive as to a disease process. The radiographs often show “footprints” of the disease process, however, in a few cases they can provide a definitive diagnosis (diskospondylitis and fracture). When a neoplastic process is suspected based on radiographic findings, advanced cross sectional imaging is employed to further characterize the disease. Time, above all is the one variable that we have the most control over. Once an owner is committed to surgery, it is up to us to direct the patient toward the most appropriate diagnostic technique in the right amount of time. Knowing when to procede to spinal surgery is quite often the pivotal point in the healing process. Situations where surgery should occur include: 1. If a patient’s clinical status is deteriorating 2. Pain that cannot be adequately controlled. 3. Instability of the spine 4. Paresis with the inability to walk 5. Paralysis 6. To obtain a definitive diagnosis 51
Neoplasia: Intramedullary neoplastic lesions of the spinal cord typically present with a history of gradual weakness in a progressive manner. Since there are no pain receptors inside the spinal cord, these patients do not often show pain at least early on in the disease. Pain will be present once the meninges are stretched, as this is the location of pain receptors in the spinal cord. The most common Intramedullary spinal cord tumors include oligodendrogliomas, neuromas and tumors that have metastasized to the spinal cord. Spinal cord metastasis is not common. Tumors of the choroids plexus, in the brain, can spread to lower levels of the central nervous system and “seed” themselves distal from the primary lesion. These are referred to as “drop mets”. Since neoplasia in this region of the spine is generally gradually progressive, emergency surgery is often not warranted. Many patients will present with a sudden worsening of clinical signs and lose the ability to walk as the functional threshold of the spine is passed. In these cases, surgery should be performed in a timely manner if not only to lessen the complications associated with a recumbent patient. Because of the anatomical organization of the descending tracts of the spinal cord, Intramedullary lesions in the C1 – T2 segments of the spine will commonly present with clinical signs that are worse in the forelimbs or began in the forelimbs when compared to the rear limbs. Descending spinal cord tracts destined for the forelimbs are located more centrally within the spinal cord, where those on their way to the pelvic limbs are located more superficially in the spinal cord. Extradural neoplasia and intradural extramedullary lesions tend to behave in the same manner as intramedullary lesions, with the exceptions that the patient often presents with asymmetrical signs and pain is usually a very prominent clinical finding. As the meninges are either compressed or infiltrated with neoplastic cells, pain receptors in the meninges will begin firing. In cases where the compression is extradural, there is the potential that clinical signs may present very acutely. If you think of the spinal cord as a rope made up of thousands of strands, the damage to the spine from a growing or expanding compression is like cutting one strand of a rope at a time. Eventually the rope will snap and it will no longer function as it is meant to. The spinal cord behaves much in the same way. The central nervous system can compensate for compression and loss of function only to a point. Eventually the clinical signs manifest and sometimes the manifestation is very acute. Tumors either originating from bone or causing boney destruction may weaken the bones of the spine to the point where a pathological fracture develops. The most common example of these tumors are osteosarcoma, chondrosarcoma, multiple myeloma, plasmacytoma and hemangiosarcoma. The 52
spinal column can withstand a large amount of insult and weakening of its structure due to tumors that destroy bone. A sudden abnormal force directed to the spine can often lead to acute clinical signs of weakness to paraplegia. As with any other disease that compresses the spine, the time to perform decompressive surgery will depend on the clinical status of the patient.
The diagnostic tests that are commonly used in cases of neoplasia of the spine typically start with survey radiographs and may also include CT scan and MRI. Survey radiographs will show you foot prints of certain disease process such as collapsed disk spaces and proliferation of articular facets commonly seen in patients with cervical vertebral malformation / malarticulation. Survey radiographs are only conclusive in cases of diskospondylitis and tumors that either destroy or produce bone. A three view metastasis check of the thorax is always recommended in patients greater than 6 years old and earlier in breeds that have a higher incidence of neoplasia of the nervous system such as golden retrievers and brachycephalic dogs. Even then, metastatic lesion in the pulmonary parenchyma can occur at any age. As in most cases of disease of the nervous system, an MRI scan is used to rule in or out structural disease of the spine. MRI allows visualization of soft tissues and bone. Additionally, it allows for multiplanar scans so better surgical planning can be performed. As with any compressive disease of the nervous system, the scan should include the entire localized area of interest. In cases where a L4 – S1 localization is made, the scan should include T3 – S1, as not all cases follow the rules completely. Cases of C6 – T2 localization should have C1 – T2 scanned. A recent study in JAVMA looked at the accuracy of localizing a lesion based on reduced withdrawal reflexes in the forelimbs. The study showed that decreased withdrawal reflexes were only associated with C6 – T2 lesions 65.8% of the time (JAVMA, Vol 232, No. 4, page 559 – 563). Additionally, the higher up the lesion in the cervical spine, the less likely the localization was to be accurate. CT scans are often useful when compared with MRI scans to help with neoplasia that is destroying bone. CT scans can also be helpful when surgical planning may involve the use of implants or bone grafts. Deformities of the spine secondary to benign neoplasia can often create conditions of scoliosis, kyphosis or lordosis making MRI scans difficult due to poor positioning of the patient. CT scans with advanced 3D software can create a virtual picture of the spine that can be manipulated via computer to give the surgeon the best possible assessment of the disease process and allow for better surgical planning. Most of the same approaches and techniques for other spinal surgeries are used with neoplastic conditions. Often a myelotomy is necessary in order to remove intramedullary tumors. The client should be well informed that with 53
myelotomy, there is greater chance of a negative outcome following the surgery. Myelotomy of the cervical spine can be associated with death due to the disruption of the descending sympathetic pathways in the lateral tectotegmental tract (Acute Sympathetic Cervical Blockade) of the spine and disruption of the cell bodies that give rise to the phrenic nerve in the C3 spinal cord segment. With myelotomy, the goal is to find a plane of dissection between the tumor and the normal spine. This is sometimes facilitated with ultrasonic surgical tools such as a CUSA ultrasonic aspirator. A durotomy or durectomy is used to approach the intramedullary portion of the spine and to remove tumors that are intradural. With this procedure, the dura is either excised and reflected or removed entirely with the tumor. Oftentimes, both sides of the spine are approached in order to create avenues for implant placement and to provide for more complete dissection of neoplastic tissue. Vertebral body replacement has been performed and utilizes bone graft tissue that is banked by a local supplier. Because of the natural limitation of surgery involving the nervous system, margins are usually not possible. Because the neoplastic tissue is usually involving the structure itself, the structure often needs to be removed in its entirety. Rhizectomy is the severing of a spinal nerve root and is performed when nerve root tumors are removed. I will try to dissect out as much of the nerve as possible. Occasionally amputation of a limb is combined with surgical removal of nerve root tumors. If performed early prior to involvement of the tumor with the spine, a clinical cure of the cancer is possible. Prognosis is of course dependent on the location of the lesion, the type of cancer and the treatment options. It is very important to remember that even with surgery alone, survival times for certain types of cancer can be years. Some are curable with surgery and others will benefit from adjunctive therapy such as chemotherapy or radiation therapy. Tumors such as multiple myeloma and plasmacytoma can be controlled with chemotherapy such as prednisone and melphalen with cases often going into clinical remission for years. Surgery, however is necessary in order to obtain a definitive diagnosis. In cases where surgery is not possible, a trial with prednisone followed by significant improvement makes me think plasmacytoma or multiple myeloma. These cases can be further confirmed by the presence of lytic bone lesions of the vertebral column or long appendicular bones and by the presence of Bence – Jones proteins in the urine. Surgery for spinal tumors has two goals; one goal is to decompress the spine in order to improve clinical status and relieve pain, while a second goal is to identify the neoplastic tissue in order to provide for possible adjunctive therapy and to help in prognostication. 54
Steroid Use: Much controversy surrounds the use of steroids in dogs and cats suspected to or confirmed to have spinal cord disease. Over the years many protocols and therapies have been promoted for the most part based on empirical evidence. Very little scientific evidence is available to support the use of steroids in this manner. It is important to differentiate between the times when steroids may or may not be applicable. We should always remember to “do no harm”. As clinicians, we have all seen the benefits of steroids and there is no doubt that they can improve clinical status. However, sometimes too much of a good thing can be bad. Side effects secondary to steroids usually preclude their chronic use in patients with neoplasia of the spine, however, when faced with a deteriorating clinical status, they are often the patient’s last chance. A recent study (JAVMA, Vol 232, No.3, page 411 – 417) confirmed what many of us have always known; the fact that treatment with dexamethasone resulted in more adverse side effects when compared to dogs treated with other steroids or no steroids at all. Additionally, there was no difference in clinical outcome between the groups that were given steroids (dexamethasone or prednisone) or not given steroids and there was no difference in clinical outcome between the steroid treated groups. It has been well demonstrated that high doses of methylprednisolone sodium succinate will cause gastric hemorrhage (AJVR, Vol 60, No.8; 977 – 981). The only steroid I use is prednisone in cases where I think there is a potential for spinal cord inflammation or edema. We all have seen the benefit of dogs that receive steroids and as long as we use appropriate doses, it is unlikely we are going to see negative side effects. In cases of acute worsening of clinical signs from pathological fracture, I recommend using 0.5 mg/kg of prednisone every 12 hours for two weeks, then once a day for two weeks, then every other day for two weeks. This also corresponds to the time we employ conservative management (6 weeks of rest and confinement). Conservative therapy is an option when the patient still has voluntary movement. I do not recommend conservative management in cases where the patient cannot walk on their own. I give it as an “option”, but stress that surgery is the treatment of choice if they want the best chance of return to mobility. In cases of chronic neoplastic disease, I use the same protocol but try to find the lowest possible dose that still results in a benefit. In cases of spinal cord neoplasia, steroids not only help to reduce inflammation and edema but they might also be directly cytotoxic to certain form of neoplasia. The recommended treatment of choice for spinal cord compression is surgical decompression. 55
Non – steroidal anti – inflammatory medications are usually not beneficial because the lack the lipophillic properties of steroids which are necessary to “get into” the fatty tissue of the nervous system. Steroids induce ulcers at the anti – mesenteric side of the junction between the transverse and descending colon, so there is little chance that common GI protectants such as acid reducers and sucralfate will be of benefit. Still, we should use them if not only to “cover our bases” in today’s litigious society. Misoprostal, a synthetic prostaglandin probably provides the most benefit by helping to replace that which steroids prevent the body from producing. Using steroids is not wrong, in fact it is a very important factor in managing these cases, just remember to use the appropriate steroid (prednisone) at the appropriate dose (see above) and watch closely for side effects. Surgical Treatment of Brain Tumors Introduction: The approach to intracranial neoplasia should combine an accurate evaluation of the patient via neurological exam, appropriate diagnostic imaging and the possible outcome of therapy (prognosis). An accurate neuroanatomic localization is essential to ensure that the area suspected to have the disease process is evaluated completely. Inaccurate localization usually involves a lack of specific clinical signs that lend evidence to the portion of the nervous system that is affected. While most clinicians are confident in the ability to recognize when an intracranial structure is altered, there are common presentations that can be confusing. Severe cervical pain can often be mistaken for a seizure disorder. Conversely, seizure disorders are sometimes mistaken for cervical pain. Syncope and collapse secondary to cardiac disease may be mistaken for a seizure disorder. Systemic metabolic dysfunction such as renal or hepatic encephalopathy can present with clinical signs associated with lethargy, depression, altered states of mentation and seizures. Seizures secondary to hypoglycemia are difficult to diagnose. An insulinoma may be present in middle aged or older animals, have transient secretion of insulin and therefore sporadic collapse and seizures. When routine blood work is performed, blood glucose levels may be normal. Being able to recognize a specific clinical syndrome is beneficial to clinical practice, however, also being aware of disease entities that might be responsible for the particular clinical signs you are observing is also equally important. The successful outcome of case management begins with a complete history and a thorough physical and neurological exam. A minimal database consisting of a CBC, biochemical profile and urinalysis is the next step. Additional testing such as fasting and fed bile acids evaluation, serum insulin levels or specific neurotoxin screening should follow. Finally, diagnostic 56
imaging evaluating the thoracic cavity for possible metastatic disease, abdominal ultrasound (if indicated) and advanced imaging such as magnetic resonance imaging (MRI) or computed tomography (CT) is performed. Treatments for intracranial neoplasia may include conservative therapy, chemotherapy, surgical intervention and/or radiation therapy. Often times, multiple treatment modalities are employed in order to achieve the best outcome. It is important to tailor recommendations to the desires and realistic expectations of the client. It is up to the practitioner to be able to provide the client the best information as far as prognosis so they can make the most informed decision for their pet. Common Clinical Entities Associated with Intracranial Neoplasia: Seizures: There are three general categories that seizures can be classified into; primary epilepsy, metabolic disease and structural disease of the brain. Intracranial disease may cause seizures if the disease process involves the forebrain. Any patient that develops seizures secondary to intracranial disease should be treated with anticonvulsants. These may include phenobarbital, potassium bromide, zonisamide, levetiracetam, gabapentin and others. Even if the intracranial disease is removed, seizures may be a persistent clinical sign. Increased intracranial pressure: The Monro – Kellie doctrine states that within a confined space (the cranial cavity), there is only room for brain, blood and spinal fluid. If anything else is introduced into that space, something has to move or the pressure in that space will increase. For instance, if a brain tumor is present resulting in an addition of mass to the cranial cavity, in order for the space to accept more tissue something has to move. Blood flow to the brain will decrease and normal brain tissue will tend to move down a pressure gradient, which in this case is caudal to the foramen magnum. As the pressure increases brain tissue starts to get pushed under the tentorium cerebelli, the falx cerebri and out the foramen magnum. The Cushing reflex may ensue which results in a decreased heart rate (bradycardia) in order to try to reduce the pressure in the cranial cavity by reducing the amount of blood in the confined space. The most common clinical sign of increased intracranial pressure is altered mentation. As pressure in the cranial cavity increases, metabolic process of the brain slow down due to alterations in blood flow, disruption of neural pathways and alterations and destruction of neurons and their supporting glia. Typically, following an altered state of mentation, pupil changes will be the next indication of a pressure change. As intracranial pressure increases and pressure is placed on the occumotor nucleus 57
pupil size will change. The first pupillary indication of increased intracranial pressure will be anisocoria followed typically by bilateral miosis. As pressure increases and the area around the hypothalamus is compressed, pressure on the origination of the descending sympathetic fibers will result in bilateral mydriasis. Finally, as the pressure continues to increase the brainstem starts to feel the results of compression as the diencephalon starts to move toward the foramen magnum. The ascending reticular activating system (thought to keep us awake) is affected and quickly followed by cardiac and respiratory pathways. The patient may suddenly die from cardiac or respiratory arrest. Mannitol is recognized as the most effective diuretic available to decrease intracranial pressure. Most of the beneficial effects of mannitol are thought to arise from its ability to decrease blood viscosity thereby increasing cerebral perfusion pressure. It is also well recognized as a free radical scavenger and osmotic diuretic. By increasing cerebral perfusion pressure to reflect that of systemic blood pressure, vasoconstriction results in a lower intracranial pressure. mannitol is given as a bolus over 10 minutes at a dose of 0.5 – 1 gram/kg. The author routinely uses the 1 gram/kg dose. With this dose and a 20% solution of Mannitol, the calculation is simply 5 ml/kg. Although mannitol will not hurt a patient without increased intracranial pressure it is simply known to not be effective in further decreasing intracranial pressure. Contraindications to the use of mannitol include hypovolemia, and current cerebral or intracranial hemorrhage. The latter complication is difficult to be able to assess in veterinary patients. It is safe to assume that when in doubt of the existence of current hemorrhage, give the mannitol regardless. You will save more animals with the use of mannitol that you would hurt if they were concurrently bleeding in the cranial cavity. Furosemide should be used in combination with mannitol to achieve the maximal effect of reducing intracranial pressure. When to give furosemide in relation to the mannitol is a debatable question. Some feel that furosemide should be given prior to the mannitol in order to decrease the possibility of an initial spike in intracranial pressure that is often associated with mannitol administration. Others feel that giving furosemide after the mannitol has the greatest effect on decreasing intracranial pressure. The author gives furosemide 15 minutes after administration of mannitol at a dose of 1 mg/kg IV. In situations where the effects of mannitol and furosemide do not appear to be decreasing intracranial pressure, hypertonic saline may effectively decrease intracranial pressure further. A dose of 0.3 ‐ 0.6 ml/kg of 24% saline may be beneficial. This dose is extrapolated from a human study so it must be emphasized that this is anecdotal evidence for the use of hypertonic saline in this extra label manner. In studies looking at the use of “ultra” hypertonic saline 58
(24% solution) in humans a decrease in intracranial pressure was commonly associated with a concurrent increase in serum sodium concentration by approximately 5 mmol. There is a direct relationship between cerebral perfusion pressure (CPP), intracranial pressure (ICP) and mean arterial blood pressure (MAP) that can be expressed by the equation: CPP = MAP – ICP This relationship basically states that as intracranial pressure increases, cerebral perfusion pressure decreases. Additionally, if mean arterial pressure increases or decreases, there may be a negative effect on cerebral perfusion pressure and intracranial pressure. The maintenance of normal blood pressure through adequate and appropriate fluid resuscitation is extremely important in managing intracranial pressure. Over hydration, however, may be detrimental by increasing intracranial pressure. Therefore, critical evaluation of systemic blood pressure should be a major tenet to supportive care in patients that are suspected to have or may develop increased intracranial pressure. Studies have demonstrated that intracranial surgery and specifically a craniectomy (the surgical removal of a portion of the skull without replacement) combined with a durectomy (the removal of the overlying dura) was very effective in decreasing intracranial pressure. Unfortunately, once the craniectomy defect was repaired during closure, intracranial pressure again increased. Subsequently, we assume that removal or biopsy of the disease process, combined with the craniectomy and durectomy may be the most effective way of decreasing intracranial pressure via surgery. Supportive care: A significant portion of the success associated with treatment of intracranial disease is associated with proper supportive care. As in all neurological patients, thick, clean and dry bedding, maintenance of adequate hydration, elevated head and neck (30 degrees), routine passive range of motion exercises, rotation and massage of down muscles, nutritional support and general stimulation are all essential for a successful outcome. Patients that have received intracranial trauma or had surgery (another form of trauma) are typically some of the most critical patients we see. They demand 24‐hour care at a hospital facility, preferably under the watchful eye of multiple specialists such as neurology, internal medicine and critical care. Veterinary technicians that are trained in a particular specialty are also important components to the operative and post‐operative team. 59
Steroids: The use of steroids in the treatment of intracranial neoplasia is considered essential both prior to and after surgery. Prior to surgery, steroids can decrease intracranial pressure through reduction of cerebral spinal fluid production and increasing the absorption of spinal fluid. This reduces the chance of brain herniation once the patient is under anesthesia which has been shown in many cases to double intracranial pressure. The use of steroids prior to surgery, therefore, is thought mainly of as a prophylaxis to prevent potential life threatening increases in intracranial pressure. Following surgery, steroids are used to help reduce intracranial edema by reducing inflammation. It is well recognized that corticosteroids through their anti – inflammatory actions are beneficial in reducing edema and inflammation. However, corticosteroids potentiate ischemic injury to damaged neurons. It has also been demonstrated that humans with elevated blood glucose levels have a poorer prognosis than those with normoglycemia. This is thought to be due to increased cerebral metabolism at the time of the head injury. Because corticosteroids result in a transient increase in blood glucose levels, it is therefore postulated that giving corticosteroids at the time of a head injury (surgery) will result in a poorer prognosis. However, when dealing with intracranial surgery, the benefits of careful steroid use outweigh the risks. Antimicrobials: The use of antibiotics in instances of intracranial disease is common practice. However, it is essential to know which antibiotics cross the blood brain barrier and achieve adequate concentrations in the CNS. Trimethoprim sulfa, clindamycin, metronidazole and doxycycline are commonly used antimicrobials for treatment of CNS infections. All attain adequate CNS concentration. Trimethoprim sulfa is effective against toxoplasma and neospora. Clindamycin has a broad spectrum of activity against a wide range of bacteria, as well as, protozoal infections. Doxycycline is primarily used to treat rickettsial infections and metronidazole is effective against treating anaerobic infections of the CNS. Metronidazole should be used with caution since one of the possible side effects of this medication is vestibular disease in dogs. Common dosages used to treat giardia, for example can induce toxic side effects. Seizures and central blindness may occur in cats treated with metronidazole. Treatment of the vestibular signs in dogs is through the withdrawal of the medication and it has been shown that oral valium will speed up the recovery. Generally, antimicrobials are used prophylactically during and following intracranial surgery. 60
The benefits of surgical treatment of brain tumors in dogs and cats centers around decompression, debulking, biopsy and control of secondary effects of the brain tumor on adjacent brain (seizures and edema). Survival times following surgical removal of brain tumors is highly dependent on the type of brain tumor, its location in the brain, the species involved and the time at which the mass was discovered. Typically, the discovery of tumors in animals occurs at an advanced state of growth of the mass, as compared to humans. We rely on the patient to show us clinical signs of disease rather than tell us when they are feeling the effects of a brain tumor. The advanced state of growth at the time of discovery, therefore often leads to a poorer prognosis. The most important consideration in the possible success of surgical intervention is the location and accessibility of the tumor. Ideally, all tumors that are superficial and potentially well encapsulated and not infiltrative should be treated with surgery. The most common brain tumor in dogs and cats is the meningioma. However, the behavior of the tumor is quite different between the species. A tumor can be biologically malignant in that it negatively affects surrounding tissue when enclosed in a confined space (such as the cranial vault) and by cytologically benign at the same time. Meningiomas in dogs tend to be infiltrative and therefore not considered biologically benign. Surgical removal of these tumors is therefore complicated by the poor ability to distinguish tumor tissue from normal brain tissue. Aggressive debulking often leads to the removal of normal brain tissue. Despite this the tumor is rarely removed in its entirety and it would be very misleading for a client to think that a “cure” was possible in the approach to removing a meningioma in a dog. That being said, the author has removed several benign meningiomas in dogs and essentially “cured” the patient of the disease. These successes are more often seen in cats with meningiomas. Feline meningiomas tend to be superficial, well encapsulated, biologically malignant but cytologically benign and are therefore excellent candidates for surgical removal. Post‐operative complications in cats are reduced when compared to dogs and in general cats tend to tolerate surgical decompression very well. The prognosis for a cat with a superficial meningioma tends to be good. Of course the ultimate determination of a tumor type cannot be made without a biopsy. Surgical biopsy of brain tumors is riskier than CT guided or MR guided biopsy, however, it has the potential to provide a much more likely definitive diagnosis and the added benefits of decompression and debulking at the same time. The ability to approach a brain tumor surgically with the dynamic potential to change the operative goal is essential with any intracranial neoplasia. The surgical plan may change dramatically if once the tumor becomes accessible it is found that it is either infiltrative or encapsulated. 61
To that end, the surgeon must reasonably discuss all possibilities that might develop during surgery with the clients. Mean survival times associated with intracranial surgery are difficult to predict in dogs and cats. The brain tumor itself is interacting on many levels with systemic function and possible complications associated either with the primary disease and/or surgery. Still, many clients like to have a general “feeling” of what the success might be before committing to brain surgery. It is well recognized that the mean survival time of a patient with an intracranial mass that has no treatment, whether conservative or surgical is days to weeks. Conservative treatment alone, primarily consisting of the use of steroids and anticonvulsants, may be weeks to months. Although, the author has personally treated an older canine with a suspected meningioma with conservative therapy alone that survived for nearly two years and had a good quality of life. Even if that was a “one in a thousand case”, by offering conservative therapy, that patient was able to be a successful outcome. Surgical treatment will extend survival times when compared to conservative treatment alone. Surgical treatment combined with adjunctive therapy such as radiation or chemotherapy has the greatest potential for long‐term survival. The use of steroids in treating patients with demonstrated intracranial neoplasia can be very beneficial. Often improvement is seen within hours to days after being treated with moderate doses of prednisone or prednisolone (0.5 mg/kg BID). Survival times associated with supratentorial masses are significantly longer than those of infratentorial masses. Adequate exposure to the tumor not only gives the best chance of removing the greatest abnormal tissue but also reduces damage to adjacent brain and provides for better decompression. Brain tumors located in the infratentorial space are naturally more difficult to approach and have a greater risk of damage to surrounding brain structures. Additionally, since more critical components of the brain are located in the brainstem, there is a greater risk of intra‐operative or post‐operative complications associated with tumors located near the brainstem. It is of course impossible to approach brain tumors in the lateral or third ventricles without damaging normal brain. Accessibility to the fourth ventricle is possible through a caudal tentorial approach to the brainstem and cerebellum. Pituitary tumors and ventral brainstem tumors are best treated with alternative modalities due to the high risk of complications associated with surgery at these locations. The success of brain surgery is also significantly influenced by the general health of the patient at the time of surgery. Most dogs and cats have had significant systemic deterioration prior t the diagnosis of the brain tumor due to poor nutrition, stress, pain and the side effects of certain medications that may have been used to treat the patient (such as steroids or NSAIDS). Often following 62
the diagnosis of a brain tumor, a waiting period ensues in order to get the patient to the best systemic health to have a more successful surgical outcome. In a patient that has not been treated with steroids, a few days of steroid therapy at moderate doses, may increase survival due to the decrease in intracranial pressure secondary to the steroids ability to reduce peritumor edema. Surgical diseases of the brain have often been thought to be a “lost” cause. As advances in imaging modalities and surgical techniques have occurred over the years, successful management of certain brain diseases via surgery has become more reasonable. Equally important to surgical technique are nursing and supportive care associated with a post‐operative patient. 63
NOTES 64