Cranial Vena Caval Thrombosis Associated With Endocardial Pacing Leads in Three Dogs
Three dogs were examined several years following implantation of transvenous, single-lead, endocardial, right-ventricular permanent pacing systems for signs consistent with cranial vena caval syndrome. Angiograms performed in all dogs revealed filling defects within the cranial vena cava and, in some instances, intracardiac filling defects. Medical therapy was instituted in two dogs, with one surviving several weeks. One dog underwent surgery to address intra-cardiac thrombosis but did not survive the immediate postoperative period. Postmortem examinations were performed in two dogs and confirmed cranial vena caval and intracardiac thrombosis. Cranial vena caval thrombosis associated with transvenous pacing leads appears to carry significant morbidity and mortality.
Introduction
Permanent pacemaker implantation is the recommended treatment for third-degree atrioventricular (AV) block, sick sinus syndrome, high-grade second-degree AV block, and persistent atrial standstill in the dog—with resolution of clinical signs in as many as 90% of dogs with the former two rhythm disorders.1 Major complications (including life-threatening loss of pacing or complications requiring replacement of the pacing system) and minor complications (nonlife-threatening) are reported to occur in 13% to 33% and 11% to 31% of veterinary patients, respectively.1–3 Thrombosis associated with pacing leads has been reported in 23% to 50% of human patients.4–6 The thrombosis is often asymptomatic, believed to be due to the gradual onset of obstruction and formation of adequate collateral circulation.7
In a recent study of dogs paced with dual-chamber endocardial pacing systems, two dogs were diagnosed with small thrombi associated with their atrial leads on echocardiography 6 months after implantation. These dogs were asymptomatic and treated with acetylsalicylic acid.8 Symptomatic deep vein thrombosis associated with pacing leads, such as superior vena caval syndrome, is uncommon and reported to occur in 0.6% to 3.5% of human patients.7 Therapies described for these conditions range from medical therapy with anticoagulants and thrombolytics to surgical intervention.6 We present here three cases of symptomatic cranial vena cava (CVC) thrombosis associated with transvenous pacing leads in the dog.
Case No. 1
A 9-year-old, castrated male Alaskan malamute was presented to the hospital with a progressive history of tachypnea, swelling of the right forelimb, exercise intolerance, inappetence, and coughing. Thirty-three months earlier, the dog had a permanent transvenous pacemaker implanted for treatment of idiopathic, third-degree AV block causing exercise intolerance and syncope. An endocardial leada was placed in the right ventricle (RV) via the right jugular vein and was connected to a pulse generatorb placed subcutaneously (SC) in the neck. No complications were encountered during this procedure, and clinical signs resolved afterward. Pacemaker interrogation was last performed 1 year prior to presentation, revealing normal function. The dog was asymptomatic at that time.
Physical examination revealed pitting edema of the right forelimb, mild pyrexia (39.7°C), and tachypnea (60 breaths per minute) with increased lung sounds. Pacemaker interrogation, electrocardiogram, and a Holter monitor recording confirmed normal pacemaker function. Thoracic radiographs revealed mild bronchial changes in the lungs, and echocardiography was unremarkable. Thrombosis was suspected based on the clinical presentation, and further diagnostics were pursued to confirm the diagnosis and identify a cause for hypercoagulability.
A complete blood count (CBC) revealed leukocytosis (28.5 × 109/L, reference range 4.9 to 15.4 × 109/L) characterized by neutrophilia (25.37 × 109/L, reference range 2.9 to 10.6 × 109/L) with a regenerative left shift (1.71 × 109/L, reference range 0.0 to 0.3 × 109/L) and lymphopenia (0.57× 109/L, reference range 0.8 to 5.1 × 109/L). Serum biochemical profile revealed a mild elevation in the steroid-induced isozyme of alkaline phosphatase (134 U/L, reference range 0 to 84 U/L). However, an adrenocorticotropic hormone stimulation test was within normal limits (pre: 182 nmol/L, reference range 30 to 300 nmol/L; 1 hour post: 509 nmol/L, reference range <600 nmol/L). Urinalysis was unremarkable, and urine culture was negative. Antithrombin III levels were also within normal limits (0.94 U/mL, reference range 0.77 to 1.30 U/mL).
Abdominal ultrasonography was unremarkable. Angiograms were performed by hand injection of diatrizoate sodium megluminec in the right (0.6 mL/kg) and left (0.6 mL/kg) cephalic veins [Figures 1A, 1B]. On the right side [Figure 1A], several small, tortuous vessels were seen to anastomose from the cephalic to the vertebral veins, and failure of opacification of the external jugular and CVC was evident. On the left side [Figure 1B], filling was normal to the level of the axilla, where a dilatation of the vein was identified with abrupt interruption of flow beyond it. Filling of a prominent lateral thoracic vein was noted, which appeared to be involved in shunting of venous return. A diagnosis of CVC and jugular thrombosis was made, and treatment was initiated with enoxaparind (1 mg/kg SC q 24 hours) and acetylsalicylic acide (0.6 mg/kg per os [PO] q 24 hours). The dog died at home 2 weeks later, and postmortem examination was declined.
Case No. 2
A 7-year-old, spayed female Brittany spaniel was presented to the hospital with a progressive history of dyspnea, gagging, anorexia, and abnormal sleeping behavior. Forty-five months earlier, the dog underwent permanent transvenous pacemaker implantation for treatment of idiopathic, third-degree AV block causing exercise intolerance and syncope. An endocardial leadf was placed in the RV via the right jugular vein, and it was connected to a pulse generatorg placed SC in the neck.
During this procedure, the temporary lead became dislodged while a pocket was being created SC for the permanent pulse generator. The permanent pulse generator was connected; however, a lack of capture existed with this system as well, so thoracic compressions were initiated. The positions of the temporary and permanent leads were adjusted, with successful capture regained. Interrogation of the permanent system revealed elevated lead impedance, which could not be resolved. The permanent system was removed and replaced without complication. A complete resolution of clinical signs was reported on follow-up examination. On subsequent examinations prior to presentation for CVC syndrome, the dog was clinically normal, and pacemaker function was normal.
On physical examination, the jugular veins were distended, heart sounds were muffled, and lung sounds were decreased in the ventral thorax bilaterally. A CBC revealed a mild monocytosis (1.84 × 109/L, reference range 0.0 to 1.1 × 109/L) and leukocytosis (36.8 × 109/L, reference range 4.9 to 15.4 × 109/L) characterized by neutrophilia (33.86 × 109/L, reference range 2.9 to 10.6 × 109/L). Serum biochemical profile and urinalysis were unremarkable. Thoracic radiographs revealed pleural effusion, and thoracocentesis yielded approximately 1.5 L of a white, turbid fluid. Cytology of the fluid was consistent with a chylous effusion. An echocardiogram revealed large masses associated with the transvenous lead within the right atrium (RA), RV, and CVC. Angiography was performed by hand injection of diatrizoate sodium megluminec (1 mL/kg) intravenously (IV) in the left jugular vein, and it demonstrated filling defects within the CVC, RA, and RV [Figure 2].
A diagnosis of CVC and intracardiac thrombosis was subsequently made. A thoracotomy was performed, and an epicardial pacing leadh was placed and connected to the same pulse generator used previously, which was repositioned SC in the flank. Successful capture was noted. Following total venous inflow occlusion and crystalloid cardioplegia, a right atriotomy was performed. The endocardial lead, along with as much of the associated thrombus as possible, was removed. Upon removal of inflow occlusion and reversal of cardioplegia, normal cardiac function did not return, and internal cardiac massage was initiated. The position of the epicardial pacing lead ultimately had to be adjusted to regain capture and achieve cardiac resuscitation. It was suspected that the myocardium in contact with the epicardial lead at its initial position became nonresponsive to pacing stimulus perhaps because of ischemic injury during cardioplegia. However, problems with impedance or threshold at the initial position cannot be ruled out, as these parameters were not measured.
Postanesthesia, the dog continued to require constant positive-pressure ventilation because of a lack of spontaneous respiration. The following day an electroencephalogram was performed and was indicative of cerebral death. The dog was subsequently euthanized. A postmortem examination revealed marked SC edema in the ventral neck; a firm, yellow, 3 × 7-cm thrombus completely obliterating the CVC and extending into the RA; and a second thrombus attached to the RV free wall, tricuspid valve leaflets, and chordae tendineae. Histopathological analysis of the thrombus removed at surgery described a nonseptic thrombus with peripheral endothelialization and stromal reaction.
Case No. 3
A 6-year-old, spayed female Labrador retriever was presented to the hospital with a 6-day history of anorexia and dyspnea and a 1-month history of neck pain. Twenty-six months earlier, the dog underwent permanent transvenous pacemaker implantation for treatment of idiopathic, third-degree AV block causing exercise intolerance. An endocardial leadi was placed in the RV via the right jugular vein and was connected to a pulse generatorg placed SC in the neck. During the procedure, temporary pacing caused rapid ventricular tachycardia; therefore, temporary pacing was aborted as the inherent escape rate was sufficient to maintain normal blood pressure during implantation of the permanent pacing system. A complete resolution of clinical signs was reported postoperatively. The dog was examined regularly by the referring veterinarian prior to presentation for CVC syndrome and was reported as being asymptomatic.
Thoracic radiographs taken by the referring veterinarian on the day of presentation demonstrated pleural effusion, and a thoracocentesis yielded 2 L of fluid. On physical examination, the dog was dyspneic, pyrexic (40.1°C), had a distended left jugular vein, muffled heart sounds, and SC edema of the ventral neck. A CBC and serum biochemical profile were both unremarkable. Urinalysis revealed proteinuria (sulfosalicylic acid precipitation test 0.5 g/L, normal 0.0 g/L); however, the urine protein:creatinine ratio was normal (0.5, reference range 0.0 to 0.5). Urine and blood cultures were negative. The pleural fluid was characterized as a modified transudate with a large number of plasma cells, but it was inconsistent with chyle given the serum and thoracic fluid triglyceride levels (0.57 mmol/L and 0.4 mmol/L, respectively).
Repeat thoracic radiographs revealed the presence of mild pneumothorax (presumably iatrogenic) and mild residual pleural effusion. Echocardiography demonstrated a mass within the CVC and extending into the RA [Figure 3], with incomplete obstruction of flow noted on color Doppler. An abdominal ultrasound was unremarkable. Ultrasonography of the cervical region demonstrated tapering of the lumen of the right jugular vein and increased echogenicity surrounding the pacing lead. Furthermore, a structure consistent with a thrombus was visualized in the cranial portion of the CVC.
A diagnosis of CVC syndrome was made, and treatment was initiated with enoxaparind (1 mg/kg SC q 12 hours). Thoracic radiographs were repeated 5 days later and demonstrated moderate pleural effusion and air in the ventral thorax. A thoracocentesis was performed, yielding 1.3 L of fluid. Furosemidej (2 mg/kg PO q 12 hours) was added in an attempt to decrease pleural effusion. Two weeks after the diagnosis of CVC syndrome, the dog was reported to be eating and breathing well and had returned to a normal activity level.
An additional 2 weeks later, the dog was presented for a recheck examination and was still doing well. Repeat thoracic radiographs demonstrated significant pleural effusion. A thoracocentesis yielded 1.7 L of fluid. On a repeat echocardiogram, the portion of the thrombus in the RA appeared subjectively smaller. Enoxaparin and furosemide were continued as before.
The dog was presented to the hospital 1 month later because of increasing dyspnea, lethargy, inappetence, and rapidly accumulating pleural effusion that was necessitating weekly thoracocentesis. An echocardiogram demonstrated complete occlusion of the CVC by the thrombus, with extension to the level of the tricuspid valve. Thoracic radiographs demonstrated pleural fluid, pneumothorax, and restrictive pleuritis characterized by prominent and rounded pleural margins. Thoracocentesis yielded 2.8 L of a lymphocyte-rich transudate. An angiogram was performed by power-assisted injection of diatrizoate sodium megluminec (0.7 mL/kg at 3 mL per second) in the left jugular vein. A large filling defect was noted in the CVC with no venous return to the RA via the CVC [Figure 4]. Therapy was initiated with recombinant tissue plasminogen activator.k The dog was given a 0.18 mg/kg bolus IV over 5 minutes via a jugular catheter followed by a constant-rate infusion of 0.6 mg/kg per day IV for 5 days. Hemorrhage around the jugular catheter necessitated the constant-rate infusion to be given via the right cephalic vein. A repeat echocardiogram showed little change in the size of the thrombus. Because of the continued decline in the dog’s condition, euthanasia was elected.
Postmortem examination revealed approximately 2 L of fluid in the thoracic cavity; collapsed lung lobes with rounded borders and fibrinous pleuritis; a thickened pericardium with ecchymotic hemorrhages; and a 5 ×3-cm thrombus in the RA, extending up the CVC to the level of the thoracic inlet and occluding >90% of the lumen [Figure 5]. The thrombus surrounded the pacing lead. Histopathology demonstrated changes consistent with restrictive pleuritis, congestion of the liver, disseminated intravascular coagulation, and a well-organized thrombus. No infectious agents or neoplasia were identified.
Discussion
Cranial vena caval syndrome associated with transvenous leads in dogs appears to be rare and, to our knowledge, has only once been reported in detail previously. In a paper by Van De Wiele et al, two canine cases are described of CVC syndrome secondary to stricture of the vessel several years following transvenous pacemaker implantation. These dogs were successfully treated with balloon angioplasty.9 Interestingly, in the cases presented here, CVC syndrome similarly occurred several years following pacemaker placement; however, these cases were related to CVC thrombosis. Stricture of the CVC was not found on any of the diagnostics performed in the above cases, including postmortem examinations in the latter two. Furthermore, the diagnostic findings (including CVC and intracardiac filling defects seen on angiography), therapeutic implications (such as aggressive thrombolytic therapy or highly invasive surgical intervention), and prognosis (seemingly poor) appear to be quite different following CVC thrombosis as compared to stricture.
Several causes of CVC syndrome have been documented in the dog; they include turbulence and trauma to vascular endothelium by jugular catheters, systemic or local inflammation, neoplasia, and alterations in blood constituents such as antithrombin III.10 In general, a prothrombotic state can develop whenever alteration to vascular endothelium, disruption of laminar blood flow, or hypercoagulability occurs. Hypercoagulability can occur in any disease state that results in decreased levels of antithrombin III, altered quantity or function of proteins C and S, platelet hyperaggregability, and increased levels of plasminogen activator inhibitor. Examples of such disease states include glomerular disease, hyperadrenocorticism, disseminated intravascular coagulation, neoplasia, heart disease, diabetes mellitus, and various systemic inflammatory conditions.11 In the cases presented, concurrent disease predisposing to thrombosis could not be identified at the time of presentation for CVC syndrome. At the time of pacemaker implantation, preexisting structural heart disease was not found, and all dogs were treated with intraoperative and postoperative antibiotics.
Transvenous pacing leads may possibly create conditions suitable for thrombosis in animals already in a hypercoagulable state at the time of pacemaker implantation, or in those who later become hypercoagulable for other reasons. One study examined the gross and histological changes in the heart associated with endocardial leads in dogs. Findings in this study included fibrous sheath formation around the leads, endocardial papillary thickening, cartilaginous metaplasia of the interatrial septum with inflammatory cell infiltrates, and myocardial damage.12 These changes may predispose to thrombosis by creating turbulence or exposing subendocardial tissue. Cranial vena caval thrombosis has also been documented in dogs associated with central venous catheterization.13 One study examined the gross and histological lesions caused by jugular catheterization. Findings included hyperplastic and poorly differentiated endothelium with surface denudation and diffuse, intimal thickening caused by myointimal hyperplasia and deposition of extracellular matrix.14 In humans, mechanical stress associated with transvenous leads resulting in vessel wall inflammation, fibrosis, stenosis, and occlusion has been proposed as a factor in the pathogenesis of pacing lead thrombosis.15
Several studies have been undertaken in an effort to elicit variables associated with pacing lead thrombosis in humans. One study found an increased risk of thrombosis with implantation of multiple pacing leads and a decreased risk of thrombosis with prophylactic use of antiplatelet/anticoagulant therapy.16 However, other similar studies have been performed that have not supported the above associations.4,5,15 Taking into account the cases presented here and those reported by Hildebrandt et al, it is apparent that thrombosis associated with transvenous pacing leads can occur in both single- and dual-lead systems in dogs.8 None of the dogs in the cases presented here were treated with prophylactic anticoagulants or antithrombotics during the years they were managed with permanent transvenous pacemakers. This raises the issue as to whether postoperative thrombosis prophylaxis should be considered in transvenous pacemaker cases.
During the time period from presentation of case no. 1 to the present, the incidence of lead-associated CVC thrombosis at our hospital is 4.9%—slightly higher than the 0.6% to 3.5% incidence seen in humans.7 Whether this incidence warrants pharmacological prophylaxis in the form of antithrombotics or anticoagulants is uncertain, and ultimately more information is needed on the institution-wide incidence of thrombosis before clear conclusions can be drawn. Considering these cases were presented 2 to 4 years following pacemaker placement, this would imply that thrombosis prophylaxis would have to be continued very long term to have been effective, which carries its own intrinsic risks. Furthermore, as mentioned above, no consensus presently exists in the human literature as to whether prophylactic anticoagulation will decrease the incidence of thrombosis with pacemaker placement.15 It appears currently that only humans with preexisting risk factors for thromboembolic disease or stroke (such as concurrent structural heart disease or atrial fibrillation) are treated prophylactically when receiving a pacemaker. The most current human practice guidelines on pacemaker therapy make no recommendations on the routine use of anticoagulants or antithrombotics.17 Prophylactic screening for hypercoagulable states may be considered at the time of pacemaker implantation; however, this may be low yield in cases where hypercoagulability is not suspected. Furthermore, an underlying hypercoagulable condition may not be necessary for thrombosis to develop. For instance, in all three cases presented here, no underlying condition could be found at presentation for CVC syndrome, nor at necropsy in two cases to explain a hypercoagulable state.
Routine diagnostic imaging to screen for lead-associated thrombosis is another consideration in the management of pacemaker patients. Given the low incidence of symptomatic thrombosis, we consider the invasiveness of angiography as a routine screening method in dogs to be unwarranted. Echocardiography would be a less invasive screening method and could potentially be useful if less advanced or earlier thrombosis were detectable, thereby favorably altering outcome. However, given the limited extent of visibility of the CVC on echocardiography, only a more advanced thrombosis may be detectable, rendering echocardiography a low-yield routine monitoring tool. Echocardiography is not currently part of recommended guidelines for routine monitoring of human pacemaker patients.18,19
In humans, several therapies have been described for pacing lead thrombosis, such as anticoagulant and thrombolytic therapy, percutaneous removal of implants, and more invasive surgical removal of implants.15,20,21 The use of low-molecular weight heparins and thrombolytics, such as recombinant tissue plasminogen activator, have been described in humans with superior vena caval syndrome.7,15,22 However, pharmacological therapy is suggested to be minimally effective if treatment is not initiated early in the course of disease.15,23 Thrombolytic therapies have been successfully employed in dogs for thrombosis of varying causes, including one case of catheter-associated thrombosis of the CVC.13,24 Because of the resilient nature of the thrombus as it matures, surgical removal and replacement of implants might have been an effective treatment in the cases presented; however, the invasiveness and difficulty of such a procedure are important limitations.
Conclusion
Although rare, CVC syndrome associated with pacing leads may result in significant morbidity and mortality in dogs, even occurring years after pacemaker placement. Further studies would be required to determine if diagnostic screening for thrombosis or treatment with prophylactic anticoagulation would be of value. Owners should be made aware of clinical signs suggestive of thrombosis and have their animal examined expediently to allow medical intervention early in the course of disease. Ultimately, removal and replacement of all implants may be necessary to achieve a cure.
CaptureFix 5068; Medtronic Inc., Minneapolis, MN 54432-5604
Prelude DR 1226; Cardiac Pacemakers, Inc., St. Paul, MN 55112-5798
Hypaque; Amersham Health, Princeton, NJ 08540-6231
Lovenox; Aventis Pharma Inc., Laval, Quebec, H7L 4A8 Canada
Aspirin; Bayer Inc., Toronto, Ontario, M9W 1G6 Canada
Target Tip 5058; Medtronic Inc., Minneapolis, MN 54432-5604
Topaz 3 SSIR; Vitatron USA, Minneapolis, MN 54432
CapSure Epi 4965; Medtronic Inc., Minneapolis, MN 54432-5604
Fixation Lead IS-1BI; Medtronic Inc., Minneapolis, MN 54432-5604
Novo-semide; Novopharm Ltd., Toronto, Ontario, M1B 2K9 Canada
Activase; Hoffman-La Roche Ltd., Mississauga, Ontario, L5N 6L7 Canada
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460186
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460186
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460186
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460186
Citation: Journal of the American Animal Hospital Association 46, 3; 10.5326/0460186
Angiograms performed via the right and left cephalic veins. In both images, the endocardial lead is marked with a long, white arrow. (A) Lateral view at the level of the shoulder. From the right thoracic limb, several small, tortuous vessels (short, white arrows) are seen to anastomose from the cephalic to the vertebral veins. (B) Dorsoventral view of the left axilla and cranial thorax. Seen from the left thoracic limb are a dilatation of the vein at the level of the axilla (short, white arrow) and a filling of a prominent lateral thoracic vein (black arrow) shunting venous return.
Lateral view. Angiogram performed via the left jugular vein demonstrated filling defects within the cranial vena cava (outlined by black arrows), right atrium (A), and right ventricle (V).
Echocardiographic, right parasternal, long-axis, four-chamber view. A mass (white arrow), later confirmed to be a thrombus, is seen surrounding the pacing lead and extending from the cranial vena cava into the right atrium.
Lateral view. Angiogram performed via the left jugular vein demonstrated a large filling defect seen within the cranial vena cava (outlined by black arrows), with no venous return to the right atrium evident. Retrograde filling of costocervical-vertebral veins is noted. The endocardial lead is marked with a long white arrow.
Postmortem evaluation demonstrating a thrombus in situ completely effacing the right atrium (A) and extending up the cranial vena cava (white arrows). The endocardial lead (L) and right ventricle (V) are labeled for orientation.
