Proceedings of the 4 to Congreso ECVECCS Emergencia y Cuidados Críticos Veterinarios

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1 Close this window to return to IVIS Proceedings of the 4 to Congreso ECVECCS Emergencia y Cuidados Críticos Veterinarios Nov , 2014 Salinas, Ecuador Reprinted in IVIS with the permission of ECVECCS

2 Feline Arterial Thromboembolism John D. Bonagura, DVM, DACVIM Veterinary Clinical Sciences, the Ohio State University Arterial thromboembolism (ATE) is a sudden interruption of blood flow caused by a thrombus that forms proximal to the affected site and is carried by the bloodstream to the location of vascular obstruction. In most cases, the site of thrombus formation is an enlarged left auricle associated with a form of cardiomyopathy. Thromboembolism has also been associated with infective endocarditis of the aortic and mitral valves as well as left-sided, congenital heart defects such as mitral dysplasia with valve stenosis. In terms of noncardiogenic causes of ATE, the formation of a thrombus within the lung is another possibility. This is usually due to pulmonary neoplasia (carcinoma), and in these cases, the embolus might contain neoplastic cells. Presumably, a thrombus with a pulmonary venous origin simply transits through the left side of the heart to reach the systemic arterial circulation. Obstruction to blood flow leads to ischemia (lack of flow to tissues) and related organ dysfunction and tissue injury. In the absence of enough collateral blood flow, cell death or infarction occurs in the territory supplied by the obstructed vascular bed. While localized arterial thrombosis can occur (and is observed in dogs, horses, humans and other species), most cases of arterial thrombosis in cats appear to originate from the left auricle and the consequence is termed a cardiogenic thromboembolism. RISK FACTORS The main diseases associated with feline ATE are cardiomyopathy (primary and secondary); myocarditis; infective endocarditis (comparably rare in cats); congenital heart disease (especially mitral stenosis); and pulmonary neoplasia. More than 95% can be explained as a cardiac originated event. Thrombi (pathological blood clots) develop when the complicated balance between procoagulant and anticoagulant factors is altered. Three pathophysiologic features of Virchow s triad help to explain thrombus formation; these are 1) blood stasis; 2) hypercoagulability; and 3) endothelial (endocardial) injury. Blood stasis is predisposed by left atrial dilatation and loss of atrial and auricular contractility. In vitro studies of blood in feline cardiomyopathy have suggested a possible hypercoagulable state. While speculative, the dilatation and high pressure found within a diseased atrium and auricle could conceivably alter the endocardial (intimal) function or even expose subendocardial collagen, a potent attractor of platelets. Thrombi are platelet-rich but also involve progressive incorporation of fibrin. Both antiplatelet drugs and drugs that inhibit fibrin formation can demonstrate efficacy in the prevention of intracardiac thrombus in humans. Only antiplatelet drugs have been studied to a limited degree in cats as discussed below. From a practical perspective, the echocardiographic assessment of the left atrium (LA) and its appendage (the left auricle) represent key factors in assessing risk of ATE in cats known to have cardiomyopathy (usually HCM). When measured from the long axis 2D image (with no aorta in the plane), a LA of >16 mm in a mature cat is considered abnormal. Once the LA diameter at end-systole exceeds 19 mm, the risk of ATE is considerable, and cats should be treated with antiplatelet drugs. Similarly, if left auricular emptying velocities are Dr. Bonagura Feline Arterial thromboembolism Page 1

3 observed to fall below ~20 cm/sec in a cat with LA dilation, the risk of echogenic contrast ( smoke ) is greater. Smoke represents a prothrombotic event and these cats should be aggressively treated to prevent thrombosis. Obviously, a previously formed thrombus on the atrial wall or a history of prior ATE in a cat indicates a high risk for recurrence. When imaging thrombi in the left atrium, the solid, round thrombus, even if large, is a lesser concern than the soft thrombus with a floating or waving tail. Soft thrombi pose the greatest risk for breaking for and causing an embolization. CLINICAL DIAGNOSIS According to Hogan (see Current Veterinary Therapy XV), the frequency of cardiogenic embolism in cats with heart disease has been reported to be between 6% and 17%. Males are overrepresented, and breeds that appear to have an increased risk are Ragdoll, Birman, Tonkinese, and Abyssinian. The typical history is of a sudden loss of limb function associated with acute onset of severe pain, especially if the thrombus goes to the typical location of the aortic trifurcation (at the origin of the iliac arteries). At necropsy, these saddle thrombi are relatively large and fill the distal aorta, external iliac arteries, and origin of the internal iliac arteries affecting blood flow to the rear limbs and the tail. Old studies of experimental ligation of both femoral arteries in cats (Imhoff) did NOT create the same clinical syndrome. Angiographic studies performed in the 1960 s and 1970 s (Schwab) indicated that a lack of collateral circulation appeared to be important to development of the clinical signs. Presumably, this is due to vasoconstricting chemicals elaborated by the thrombus. Rarely three or even four-limb paresis is observed. When the thrombus is massive and extends cranially to involve the mesenteric blood supply, the cat usually exhibits excruciating pain. Clients usually recognize loud vocalization. Due to metabolic consequences of ischemia and the fact, that many cases are not discovered for hours, some cats are moribund with shock and metabolic acidosis at presentation. Some cats experience a smaller thrombotic event and do not obstruct their terminal aorta. These thrombi these can extend to the brain leading to ischemic seizures or stroke-like signs. Smaller single or bilateral arterial thrombi sometimes lodge in one or both rear limbs but distal to the femoral triangle. Obstructed blood flow in the axillary or brachial artery can lead to sudden forelimb paralysis. While spontaneous lysis of clots is the normal outcome in cats that do not die or undergo euthanasia, a forelimb thrombus is especially likely to recannulate quickly; therefore, clinical signs of paresis can be transient. Recurrent renal thrombosis can alter renal structure and function but are usually silent clinically. Coronary emboli have been observed and lead to myocardial infarction. This is one mechanism for HCM cats to develop into a RCM phenotype. Loss of a peripheral arterial pulse in a cat is supportive of arterial thromboembolism. Terminal aortic embolism is generally more severe, and signs may persist for hours to weeks, although most cats recover partial to complete limb function if given sufficient time and care (see later). The physical diagnosis of terminal aortic embolism is straightforward and characterized by vascular, musculoskeletal, and neurological deficits, and associated laboratory abnormalities. The affected limbs are cool, pulseless, and pale. Occasionally the thrombus is either partial located distal to the femoral triangle and pulses and Doppler flow will be detected proximally. The muscles become firm to rigid due to ischemia. This is the likely source of pain. Limb edema is not an early sign of ATE; although it may be observed days after the event because of severe muscle injury (and predicts a poorer chance for full Dr. Bonagura Feline Arterial thromboembolism Page 2

4 recovery). It is probably related to inflammatory changes following rhabdomyolysis and reperfusion injury. Lower motor neuron paresis/paralysis develops with loss of proprioception, motor function, and eventually sensation. The sensory level moves back down from hip to toes as reperfusion develops. The serum creatine kinase, AST, and ALT (of apparent skeletal muscle origin) are often elevated dramatically in ATE. The AST will be significantly higher than ALT when the elevations are related to striated muscle damage. These enzymes also may be helpful in recognizing ATE in a cat with severe but rapidly improving paresis of a forelimb. NT-proBNP and cardiac troponin I are often increased due to cardiac disease. Marked increases in ctni should prompt consideration of myocardial ischemia/infarction. When the diagnosis is uncertain placing a Doppler crystal over the femoral and brachial arteries should demonstrate the loss of blood flow to the affected limbs. One can measure and compare blood lactate or glucose in affected/unaffected limbs, but this is rarely necessary. If a large aortic thrombus is suspected, the abdominal aorta can be imaged with ultrasound. This is most useful if the diagnosis is in doubt or if a massive aortic embolus is suspected. Angiography is only of historical interest. Body temperature should be obtained as a very low temperature was associate dwith a poor outcome in one retrospective study. The distal rectal temperature can be low due to poor perfusion. Blood pressure should be measured in a forelimb; shock is a poor prognostic finding. Venous blood should be drawn for chemistries, ph/lactate, and baseline clotting times if the cat will be treated. Similarly documentation of CHF is also a poor prognostic sign. In one retrospective study the median survival was nearly three times longer in cats without CHF. MANAGEMENT OF FELINE ARTERIAL THROMBOEMBOLISM The medical management of an acute thromboembolic event demands high quality critical and nursing care. The client should be advised about the 1) need for intensive therapy (typically 2 to 3 days in the hospital); 2) the risk of ATE recurrence (high); 3) the need for future daily home medical care; 4) the likely presence of underlying cardiomyopathy; 5) the attendant costs of managing the condition; and 6) the potential for sudden death during hospitalization (or thereafter). Understandably, these issues prompt euthanasia in many cats, although it is stressed that at least half of cats can be released from the hospital assuming the clients allow aggressive treatment and such therapy is delivered. If the client decides to proceed, the first and most important treatment is analgesia with a strong mu agonist for the first hours following an event. While there are no comparative studies of pain control in this condition, fentanyl is most commonly used in our practice and provides good to excellent analgesia. Transdermal fentanyl therapy is too slow in onset for management of this severe pain and IV administration is needed. Although fentanyl has been administered intravenously to healthy cats at a slow bolus dose of around 5 micrograms/kg, it is suggested to initiate therapy with a lower dose of 3 microgram/kg (very slow IV bolus) and follow that with an intravenous maintenance infusion of 1 to 3 micrograms per kg per hour (not per minute). Morphine (0.1 to 0.2 mg/kg IM or SQ q6h) or buprenorphine (0.01 mg/kg, IM or SQ, q6h) represent other options. Buprenorphine can also provide some analgesia when administered at 0.01 to 0.02 mg/kg (10 to 20 micrograms/kg) on the buccal (oral) mucosa, and it may be useful to dispense one or two doses to client for immediate administration should an ATE occur at home. In the absence of hypothermia or hypotension, acepromazine (0.025 mg/kg subcutaneously) will sedate the cat further and might alleviate vocalization. Pain in most cats is markedly diminished by 36 to Dr. Bonagura Feline Arterial thromboembolism Page 3

5 48 hours, allowing for less aggressive analgesia. The current thrombotic issues can be management either actively with tissue plasminogen activator (tpa) in an attempt to lyse the thrombus, or more conservatively by preventing further thrombosis This is done with unfractionated heparin. Both treatments also can be administered. No prospective studies have assessed the acute management of ATE in cats although a multi-center trial is beginning this year. Administration of tpa is by short-term intravenous infusion with a 1 mg/kg tpa dosage (up to 6 mg maximal dose): 10% of the dose is given as a slow IV bolus and the rest is infused over ~one hour. In general, tpa therapy is only offered if the cat presents within 6h of the (witnessed) event. Tissue plasminogen activator is supplied in a 2 mg vial from Genentech (Activase ) in the US and as a 2 or 10 mg vial from Boehringer Ingelheim (Actilyse ) in Europe. This is expensive therapy (~$1,000), unproven (although observational data indicate it will work in some cats), and carries the risk of bleeding and reperfusion hyperkalemia (that can be fatal). Heparin therapy is recommended, even if tpa is administered to prevent further thrombosis. Standard (unfractionated) heparin consists of heterogeneous molecules with a mean molecular weight near 15,000 Daltons. Heparin molecules bind to anti-thrombin leading to inhibition of clotting factors (including IIa, Xa, IXa, and XIIa) and possibly exerting a mild antiplatelet effect. Heparin therapy should be monitored with a baseline aptt and prothrombin time. Unfractionated heparin is administered at approximately 250 to 300 units/kg IV. Thereafter either a constant rate IV infusion or subcutaneous dosing at approximately U/kg subcutaneously q6 to 8h for hours. Some clinicians will begin clopidogrel as well (18.5 mg PO daily), but the combination of tpa, heparin, and clopidogrel is not advised due to bleeding risk. When only heparin is given, clopidogrel can be started. Alternatively, low-molecular-weight heparin (LMWH) can be administered. These have a smaller molecular weight than unfractionated heparin. These drugs are more expensive. Both human preparations of dalteparin (FragminI 100 IU/kg bodyweight subcutaneously q12h) and enoxaparin (Lovenox 1 to 1.5 mg/kg subcutaneously q12h) have been used.. In addition to analgesia, supportive care is important. Passive warming is undertaken, but the limbs should not be burned. As indicated above, some cats are profoundly hypothermic, and these cats have a poorer prognosis. This finding may indicate shock accompanied by severe metabolic acidosis. Hypotension in the absence of CHF should be treated with fluid therapy initially; when associated with CHF dobutamine at low infusion rates (2.5 micrograms/kg/minute) is preferred. Cats on opiates may pant in a heated, humid environment, creating a situation that can be confused with CHF. This sign will abate once the external environmental temperature is lowered. If true fever occurs following an ATE, IV cefazolin or oral amoxicillin-clavalenic acid are usually effective (this can be a delayed event). The patient should be monitored for potentially fatal hyperkalemia from potassium leaked from necrotic muscles during the first 48 to 72 hours of treatment. Most cats that do improve are better within 72 hours of admission and can be released for home care. There is often asymmetry noted between the limbs. With revascularization, tail function returns and limb function is reinstated from proximal to distal. Reassessment every two to three days is recommended following release until the status of ischemic tissues is determined. Home care includes: 1) protecting the limbs; 2) daily inspection for subcutaneous or muscle edema (a poor prognostic sign); 3) cleaning urine-soaked hair and bedding; 4) providing a soft bed; 5) encouragement to eat; and 6) a low stress area for convalescence. Dr. Bonagura Feline Arterial thromboembolism Page 4

6 Physical therapy of the limbs characterized by passive flexion of the limbs is encouraged. Additional consideration should be given to a soft bandage of a contracted limb (another adverse outcome) to place it in a functional position. If constipation becomes a problem, a small amount of soluble fiber (1/4 teaspoon of guar gum) or some canned pumpkin may be added to food to soften the stool. PREVENTION OF THROMBOEMBOLISM A number of approaches have been advocated for prevention of ATE in cats. These include: 1) aspirin monotherapy (dosed between 5 mg to 81 mg q72h); 2) warfarin (Coumadin 0.5 mg PO daily); 3) low molecular weight heparins including enoxaparin (Lovenox, 1 mg/kg) and dalteparin (Fragmin, 100 IU/kg) injected subcutaneously once or twice daily; or 4) clopidogrel (Plavix, 75 mg tablets, ¼ tablet or mg PO once daily). Retrospective reports have indicated apparently safe or well-tolerated dosages of these drugs and effects on in vitro coagulation tests. The ongoing clinical trial evaluating clopidogrel versus aspirin (FATCAT) has finally released preliminary data and indicates superiority of clopidogrel over aspirin for prevention of recurrent thrombosis in cats with HCM. There was no group receiving both treatments (these drugs work by different mechanisms and might be complementary). Compared to aspirin clopidogrel demonstrated a decreased rate of reoccurrence and an increased time interval between the first and second thrombotic event (lead author: Hogan, D). In this study, median survival time increased to approximately 14.8 months in the clopidogrel group compared to approximately 6.4 months in the aspirin group (p = 0.019; see ACVIM proceedings). In terms of specific recommendations for cats that have never experienced a thrombotic event, the author does not routinely prescribe antithrombotic therapy in asymptomatic cats with a normal or minimally dilated left atrium and auricular emptying velocities >25 cm/s. Clopidogrel (¼ of a 75 mg tablet) is prescribed for the cat with a moderate ( 20 mm) to severely dilated left atrium, or when auricular emptying velocities are <20 to 25 cm/s. Adultregimen 81 mg aspirin dosed at one tablet PO q72h is an alternative to clopidogrel, but is often ineffective and was less effective in FATCAT. For cats at the highest risk for ATE (LA dilation 25 mm, echogenic smoke in LA, auricular emptying velocities <20 cm/s, or a history of prior ATE) the author suggests more aggressive therapy with both clopidogrel (¼ of a 75 mg tablet once daily) and a very low dose daily aspirin (compounded or crumbled to a dose of between 5 to 10 mg per cat daily, mixed in a gel cap; alternative: 40 to 81 mg per cat every three days). The risk of gastric ulceration must be appreciated with these treatments and managed if anorexia, vomiting, or anemia becomes evident; however, this has not been a major problem. Another alternative for cats at high risk of ATE is once or twice-daily administration of a low molecular weight heparin preparation, generally enoxaparin with clopidogrel. There is some controversy about the efficacy of this treatment with LMWH, as well as the best manner of monitoring LMWH therapy in cats. Clinical trials in cats with spontaneous disease are needed to settle the issues. Practically, since these heparins are prohibitively expensive for most clients and require one or two daily injections, the treatment holds a low acceptability to clients. Some clinicians use low molecular weight heparin as a bridge therapy for a few weeks following recovery of aortic ATE. Warfarin therapy is difficult to control in cats and rarely prescribed. PROGNOSIS As indicated previously, experience and published retrospective reports suggest at least 50% chance for functional limb recovery if treatment is administered. Even when euthanasia Dr. Bonagura Feline Arterial thromboembolism Page 5

7 is permitted with the first 48h, the survival rate is 39%. In a one retrospective study (Smith), the median survival time was 223 days for cats not presenting in CHF (median survival for those cats was 77 days). It is emphasized that there are no prospective trials of therapy. Retrospective data probably represent less than optimal outcomes since care is not standardized in these observational studies and many cats are euthanatized at admission. Recurrence rates of 17% to 75% over the first year have been published, but these did not control for preventative therapy and clopidogrel was unavailable (Laste and Harpster and Smith and colleagues).. Further Reading Smith S, Tobias A, Jacob K, et al. (2003) Arterial thromboembolism in cats: acute crisis in 127 cases ( ) and long-term management with low-dose aspirin in 24 cases. Journal of Veterinary Internal Medicine 17, Dr. Bonagura Feline Arterial thromboembolism Page 6