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Gastrointestinal bleeding from arteriovenous malformations in patients supported by the Jarvik 2000 axial-flow left ventricular assist device
Gastrointestinal Bleeding From Arteriovenous Malformations in Patients Supported by the Jarvik 2000 Axial-Flow Left Ventricular Assist Device George V. Letsou, MD,a Nyma Shah, BS,b Igor D. Gregoric, MD,b Timothy J. Myers, BS,b Reynolds Delgado, MD,c and O. H. Frazier, MDb,d The long-term effects of axial-flow mechanical circulatory support in humans are unclear. We report 3 cases of chronic gastrointestinal bleeding after implantation of a Jarvik 2000 axial-flow left ventricular assist device. The bleeding was refractory to aggressive management and in 2 cases resolved only after orthotopic cardiac transplantation. J Heart Lung Transplant 2005;24:105–9. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
In 1958, Heyde reported an association between gastrointestinal (GI) bleeding and aortic stenosis.1 Afterward, others made similar clinical observations,2,3 but establishing a direct link between the 2 entities in controlled studies has been difficult. In our initial clinical experience with the non-pulsatile axial-flow Jarvik 2000 left ventricular assist device (LVAD) in patients with heart failure, we observed a similar association with GI bleeding from unusual sources. Because both aortic stenosis and non-pulsatile left ventricular assistance involve the common physiologic pathway of narrowed arterial pulse pressure, this led us to examine our experience more closely. We report 3 cases of GI bleeding due to arteriovenous malformations (AVM) in patients supported with the Jarvik 2000 LVAD. JARVIK 2000 LEFT VENTRICULAR ASSIST DEVICE The Jarvik 2000 is an electrically powered, axial-flow LVAD. The pump is small, about the size of a D-cell battery, and is placed within the left ventricle. Its outflow graft extends from the left ventricular apex to the descending thoracic aorta. A power cable containing electric wires leads from the pump through the chest wall to the right upper quadrant of the abdomen, From the aDepartment of Cardiothoracic and Vascular Surgery, The University of Texas–Houston Medical School; and bCullen Cardiovascular Research Laboratories, cHeart Failure Clinic and dCardiopulmonary Transplantation Service, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas. Submitted June 24, 2003; revised October 6, 2003; accepted October 8, 2003. Reprint requests: George V. Letsou, MD, Department of Cardiothoracic and Vascular Surgery, The University of Texas–Houston Medical School, 6410 Fannin, Suite #450, Houston, TX 77030. Telephone: 713-500-5323. Fax: 713-500-0650. E-mail: george.v.letsou@uth. tmc.edu Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2003.10.018
where the cable is externalized and connected to an analog controller. The pump is powered by lithium ion or lead acid batteries. Electromagnetic force is used to rotate the pump’s impeller at speeds ranging from 8,000 to 12,000 rpm, yielding a maximal blood flow of 7 liters/min. The pump speed is controlled by a pulsewidth-modulated, speed-controlled circuit that is adjusted manually. CASE REPORTS Case 1 Presentation, History, and Treatment. A 60-year-old man with a history of coronary artery disease, coronary artery bypass surgery in 1985, and implantation of an automatic internal cardiac defibrillator in 1998 presented with chest pain. On admission, he was found to have renal insufficiency and pulmonary edema. He had no history of GI bleeding. Catheterization revealed ischemic cardiomyopathy, and he was placed on the cardiac transplantation waiting list. Despite treatment with continuous intravenous inotropes and diuretics, the patient’s condition deteriorated until he ultimately required mechanical circulatory support. After the patient met all inclusion criteria and gave informed consent, a Jarvik 2000 LVAD was implanted via a left thoracotomy with partial cardiopulmonary bypass. Blood loss was minimal. After weaning from cardiopulmonary bypass, LVAD support was initiated at a flow rate of 4.8 liters/min. In the immediate postoperative period, re-exploration was necessary to evacuate a residual hemothorax. Extubation was performed expeditiously, and the immediate postoperative recovery was otherwise uneventful. However, during the subsequent course of LVAD support, multiple episodes of GI bleeding developed. Bleeding was first diagnosed on postoperative day (POD) 6 on the basis of heme-positive stools and a drop in hemoglobin concentration. Later, another drop 105
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in hemoglobin concentration (from 8.3 g/dl on POD 17 to 6.7 g/dl on POD 18) was seen. After extensive evaluation with endoscopy, mesenteric angiography, and exploratory laparotomy, it was determined that bleeding was occurring in the small intestine. The definitive diagnosis of GI bleeding from AVMs was determined by endoscopy on POD 44. Numerous blood transfusions were necessary as well as selective intraarterial vasopressin infusion. Multiple recurrences of bleeding necessitated colonoscopic cauterization on POD 44, 58, and 62, which provided only temporary cessation of GI bleeding. Low hemoglobin concentrations, ranging from 6.6 g/dl to 12.9 g/dl, necessitated multiple blood transfusions. On POD 90, the patient underwent a colectomy with ligation of AVMs in the small intestine. Bleeding AVMs were directly visualized at surgery via enterotomies. Pathologic examination of surgical specimens revealed subtle changes in the venous anatomy that could be consistent with angiodysplasia or the edge of an AVM. No GI bleeding occurred during the remaining period of LVAD support. After 215 days of support, successful orthotopic cardiac transplantation was performed. There has been no recurrence of GI bleeding after cardiac transplantation. Management of Anticoagulation. Intravenous heparin and then oral warfarin were administered with the aim of achieving an international normalized ratio (INR) of 2.0 to 3.0. Attempts to provide anticoagulation therapy during support resulted in GI bleeding. Warfarin therapy was discontinued on POD 6 because of GI bleeding. Antiplatelet therapy (aspirin) was initiated on POD 15, but again had to be discontinued 4 days later because of GI bleeding. All anticoagulation and antiplatelet therapies were withheld from POD 19 until transplantation. During support, the average INR was 1.06, and the average hemoglobin concentration was 9.34 g/dl. Case 2 Presentation, History, and Treatment. A 51-year-old man with a history of ischemic cardiomyopathy after massive myocardial infarction and coronary artery bypass surgery in 1993 presented with shortness of breath and fatigue. There was no history of intestinal hemorrhage. Cardiac catheterization confirmed the presence of an ischemic cardiomyopathy not amenable to repeat revascularization. The patient was placed on the cardiac transplantation waiting list but decompensated before an appropriate organ became available. Treatment with continuous intravenous inotropes and diuretics was not sufficient to maintain adequate cardiac function. After the patient met all inclusion criteria and gave his informed consent, a Jarvik 2000 LVAD was implanted
The Journal of Heart and Lung Transplantation January 2005
Figure 1. Endoscopic image revealing an arteriovenous malformation and bleeding (white arrow) in the ileum of a patient supported with a Jarvik 2000 axial-flow left ventricular assist device.
via a left thoracotomy with partial cardiopulmonary bypass. Intraoperatively, 1 liter of packed red blood cells (RBCs) and 1.8 liters of fresh frozen plasma (FFP) were administered. After weaning from partial cardiopulmonary bypass, LVAD support was initiated at a flow rate of 3.3 liters/min. Chronic GI bleeding developed after 5 weeks. Melena was noted on POD 46; the hemoglobin concentration decreased to 9.7 g/dl on POD 33. Mesenteric angiography and endoscopy documented that GI bleeding was due to AVMs in the small intestine (Figure 1). Numerous blood transfusions and selective infusion of vasopressin did not resolve the bleeding. On POD 34, abdominal exploration of the ischemic bowel was performed to locate the source of bleeding; during the procedure, adhesions were lysed, a cholecystectomy was performed, and exploration for ischemic bowel was carried out. However, chronic GI bleeding continued. The hemoglobin concentration dropped to 9.8 g/dl on POD 38 and to 8.5 g/dl on POD 69 despite continued blood transfusions. On POD 70, the patient underwent smallbowel enteroscopy to help control the bleeding. A total of 15 AVMs were definitively identified and cauterized with a bipolar cautery probe. Still, GI bleeding continued. A subsequent infusion of vasopressin selectively into the superior mesenteric artery and an intravenous infusion of antistatin also failed to stop the GI bleeding. The patient’s condition worsened. Multiorgan failure ensued, and the patient died after 121 days of support.
The Journal of Heart and Lung Transplantation Volume 24, Number 1
Management of Anticoagulation. Warfarin was administered beginning on POD 4. Due to the development of GI bleeding, warfarin was discontinued on POD 34. Anticoagulation therapy was reinstituted intermittently, but could not be routinely established because of continued intermittent intestinal hemorrhage. During the 121 days of support, heparin was administered on 63 days, anti-platelet therapy with aspirin on 6 days, and warfarin on 3 days. During support, the average INR was 1.16, and the average hemoglobin concentration was 11.72 g/dl. Case 3 Presentation, History, and Treatment. A 66-year-old woman with a history of ischemic cardiomyopathy after myocardial infarction in 1999 presented with recurrent syncope and shortness of breath. She had no history of GI hemorrhage. Echocardiography revealed an ejection fraction of less than 20%. The patient was placed on the waiting list for cardiac transplantation. Despite treatment with continuous intravenous inotropes, refractory cardiac failure developed before an appropriate organ for transplantation became available. After the patient met all inclusion criteria and gave her informed consent, a Jarvik 2000 LVAD was implanted via a left thoracotomy with partial cardiopulmonary bypass. Intraoperatively, 1 liter of packed RBCs, 1.8 liter of platelets, and 1.32 liter of FFP were administered. On weaning from partial cardiopulmonary bypass, LVAD support was initiated at a flow rate of 3.2 liters/min. The initial postoperative recovery was uneventful. On POD 70, melena developed, and the hemoglobin concentration fell to 8.0 g/dl. As a result, transfusion of packed RBCs was required. Nuclear RBC imaging revealed GI bleeding due to the formation of AVMs in the small intestine. Numerous transfusions of packed RBCs were administered as well as intravenous vasopressin. On POD 86, colonoscopy showed no AVMs and no clear cause of the GI bleeding. Chronic, slow GI bleeding continued despite all treatment efforts until the patient underwent heart transplantation after 169 days of support. Gastrointestinal bleeding resolved after orthotopic cardiac transplantation and has not recurred. Management of Anticoagulation. Initially, heparin and warfarin were administered with the aim of achieving an INR of ⬎ 2.0. This therapy was discontinued intermittently because of melena and GI bleeding. The anti-platelet agent dipyridamole was started on POD 118. During the 169 days of support, heparin was given on 31 days, warfarin on 61 days, and dipyridamole on 40 days. During support, the average INR was 1.97, and the average hemoglobin concentration was 10.3 g/dl.
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DISCUSSION Mechanical circulatory support with an implantable ventricular assist device is applied routinely in patients needing temporary circulatory assistance while awaiting cardiac transplantation.4 – 6 Less frequently, a ventricular assist device is used to support patients with acute heart failure until myocardial function improves7 or to provide permanent support to patients who have end-stage heart failure, are not candidates for heart transplantation, and have no hope for improvement in myocardial function.8 Axial flow pumps are being developed to address the needs of patients who are too small to be fitted with current pulsatile devices and to reduce some of the complications associated with the pulsatile technology.9 Initial clinical studies with axial flow pumps are in progress.10,11 Twenty-one patients have been supported by the Jarvik 2000 axial-flow LVAD as a bridge to heart transplantation at the Texas Heart Institute, and 3 of them had chronic GI bleeding secondary to AVMs during the period of circulatory support. This led us to examine a possible association between gastrointestinal AVMs and the partially pulsatile blood flow provided by the axial flow pumps. Gastrointestinal bleeding is not uncommon in critically ill patients requiring intensive support and LVAD therapy. However, the incidence of life-threatening bleeding from all GI sources requiring operation is low when pulsatile ventricular assist systems such as the Novacor (World Heart Inc., Oakland, CA) and HeartMate (Thoratec Corporation, Pleasanton, CA) are used. Gastrointestinal bleeding was not identified as a clinically significant problem in 2 recent reviews of the clinical experience with the HeartMate pulsatile LVAD.12,13 Thus, the incidence of GI bleeding in 3 of our first 21 patients supported with the Jarvik 2000 (14%) is distinctly unusual. An association between GI bleeding and aortic stenosis was first called to attention by Heyde in a letter to the New England Journal of Medicine in 1958, resulting in the appellation Heyde’s syndrome.1 Schwartz reported a similar observation in a letter to the New England Journal of Medicine later that same year.14 Afterward, reports of a similar association in larger series of patients appeared.3 In 1979, Boley and colleagues15 reported an approximately 15% incidence of aortic stenosis in patients with vascular ectasias of the colon. Despite the correlation between aortic stenosis and GI bleeding in these reports, some groups still questioned it. In 1988, Imperiale and Ransohoff16 performed a quantitative and methodologic analysis of the literature. They cited problems in the above-mentioned studies and others, including non-blinded data collec-
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tion, non-comparable diagnostic examination, and noncomparable demographic groups. They emphasized that most of the studies referred to an association between aortic stenosis and chronic GI bleeding, not angiodysplasia. They concluded that the association between GI bleeding and AVMs was not supportable by a careful literature review and suggested that controlled studies were necessary. The most frequently recommended treatment for AVMs associated with aortic stenosis has been aggressive localization of the bleeding source by endoscopic and radiologic means. If the site of bleeding can be identified and medical management fails, surgical resection should be performed. In cases of occult intestinal bleeding, 2 approaches have been recommended. The first approach is a blind right hemicolectomy. The second approach, recommended more recently, is replacement of the aortic valve with a bioprosthetic valve, an approach that has successfully stopped bleeding.17 Several explanations for the association between AVMs and aortic stenosis have been proposed. Boley suggested that increased intraluminal pressure along with muscular contraction may result in dilated mucosal veins that favor the development of an arteriovenous communication that may bleed when exposed to trauma or stress.18 Alternatively, Cappell and Lebwohl17 proposed a neurovascular etiology with increased sympathetic tone resulting in smooth muscle relaxation and a subsequent propensity for angiodysplasia. Another proposed explanation is the hypoperfusion of the intestines that results from the lowered pulse pressure characteristic of aortic stenosis. According to this theory, hypoxia leads to vascular dilation and angiodysplasia. Left ventricular cardiac assistance with a minimally pulsatile LVAD produces physiologic changes similar to aortic stenosis, i.e., narrowed arterial pulse pressure. In our 3 cases, patients with no previous history of intestinal bleeding exhibited bleeding after institution of non-pulsatile mechanical support with an LVAD. The bleeding was extremely difficult to control during the period of non-pulsatile left ventricular assistance. However, in the 2 patients who survived to cardiac transplantation, the bleeding ceased after cardiac transplantation and the restoration of normal circulatory physiology without other interventions. Unlike other currently available implantable cardiac assist devices, the Jarvik 2000 uses axial flow technology in which an impeller provides forward flow from the left ventricle into the descending aorta. Other ventricular assist devices provide pulsatile flow. The practical difference between the 2 types of devices is that flow during support with the Jarvik 2000 exhibits diminished pulsatility. The diminished
The Journal of Heart and Lung Transplantation January 2005
pulsatility is due to native ventricular contraction and its contribution to cardiac output. The pulse pressure varies with the speed (and thus the output) of the device. This may result in the same altered intestinal physiology seen in aortic stenosis, i.e., diminished pulse pressure. Some may infer from the present case reports that candidates for Jarvik 2000 pump implantation would benefit from a more profound gastrointestinal evaluation preoperatively. However, AVMs are notoriously difficult to detect when not actively bleeding, and the AVMs in all 3 cases reported here occurred in patients who had no previous history of gastrointestinal bleeding. Therefore, efforts to detect such lesions preoperatively are not recommended. Two important observations have arisen from our experience with implantation of the non-pulsatile Jarvik 2000 pump, and both have therapeutic implications. First is the observation of GI bleeding from AVMs in a minority of patients. Second is the resolution of GI bleeding after orthotopic cardiac transplantation and restoration of normal physiology in 2 of those patients, both of whom continue to do well with no subsequent GI bleeding. Thus, it appears that GI hemorrhage from intestinal AVMs in patients supported by an axial-flow LVAD may be successfully treated by minimizing axial flow (and thereby increasing pulse pressure) or by cardiac transplantation. REFERENCES 1. Heyde EC. Gastrointestinal bleeding in aortic stenosis [letter]. N Engl J Med 1958;259:196. 2. Weaver GA, Alpern HD, Davis JS, et al. Gastrointestinal angiodysplasia association with aortic valve disease. Gastroenterology 1979;77:1–11. 3. Williams RC. Aortic stenosis and unexplained gastrointestinal bleeding. Arch Intern Med 1961;108:859 –63. 4. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device. Ann Thorac Surg 1992;53:1080 –90. 5. Farrar DJ, Hill JD. Univentricular and biventricular Thoratec VAD support as a bridge to transplantation. Ann Thorac Surg 1993;55:276 –82. 6. McCarthy PM, Portner PM, Tobler HG, Starnes VA, Ramasamy N, Oyer PE. Clinical experience with the Novacor ventricular assist system: bridge to transplantation and the transition to permanent application. J Thorac Cardiovasc Surg 1991;102:578 –86. 7. Frazier OH, Myers TJ. Left ventricular assist system as a bridge to myocardial recovery. Ann Thorac Surg 1999;68: 734. 8. Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg 1999;67:723– 30.
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9. Myers TJ, Gregoric I, Tamez D, et al. Development of the Jarvik 2000 Heart ventricular assist system. J Heart Failure Circ Support 2000;1:133–40. 10. Westaby S, Katsumata T, Evans R, Pigott D, Taggart DP, Jarvik RK. The Jarvik 2000 Oxford system: increasing the scope of mechanical circulatory support. J Thorac Cardiovasc Surg 1997;114:467–74. 11. Frazier OH, Gregoric ID, Delgado RM, et al. Initial experience with the Jarvik 2000 left ventricular assist system as a bridge to transplantation: report of 4 cases. J Heart Lung Transplant 2001;20:201. 12. McCarthy PM, Smedira NO, Vargo RL, et al. One hundred patients with the HeartMate left ventricular assist device: evolving concepts and technology. J Thorac Cardiovasc Surg 1998;115:904 –12. 13. McBride LR, Naunheim KS, Fiore AC, Moroney DA,
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14. 15. 16.
17.
18.
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Swartz MT. Clinical experience with 111 Thoratec ventricular assist devices. Ann Thorac Surg 1999;67:1233–8. Schwartz BM. Additional note on bleeding in aortic stenosis [letter]. N Engl J Med 1958;259:456. Boley SJ, Sammarteno R, Brandt LJ, Sprayregan S. Vascular ectasias of the colon. Surg Gynecol Obstet 1979;149:353–9. Imperiale TF, Ransohoff DF. Aortic stenosis, idiopathic gastrointestinal bleeding, and angiodysplasia: is there an association? A methodologic critique of the literature. Gastroenterology 1988;95:1670 –6. Cappell MS, Lebwohl O. Cessation of recurrent bleeding from gastrointestinal angiodysplasias after aortic valve replacement. Ann Intern Med 1986;105:55–7. Boley SJ, Sammartano R, Adams A, et al. On the nature and etiology of vascular ectasias of the colon. Gastroenterology 1977;72:650 –60.
In 1958, Heyde reported an association between gastrointestinal (GI) bleeding and aortic stenosis.1 Afterward, others made similar clinical observations,2,3 but establishing a direct link between the 2 entities in controlled studies has been difficult. In our initial clinical experience with the non-pulsatile axial-flow Jarvik 2000 left ventricular assist device (LVAD) in patients with heart failure, we observed a similar association with GI bleeding from unusual sources. Because both aortic stenosis and non-pulsatile left ventricular assistance involve the common physiologic pathway of narrowed arterial pulse pressure, this led us to examine our experience more closely. We report 3 cases of GI bleeding due to arteriovenous malformations (AVM) in patients supported with the Jarvik 2000 LVAD. JARVIK 2000 LEFT VENTRICULAR ASSIST DEVICE The Jarvik 2000 is an electrically powered, axial-flow LVAD. The pump is small, about the size of a D-cell battery, and is placed within the left ventricle. Its outflow graft extends from the left ventricular apex to the descending thoracic aorta. A power cable containing electric wires leads from the pump through the chest wall to the right upper quadrant of the abdomen, From the aDepartment of Cardiothoracic and Vascular Surgery, The University of Texas–Houston Medical School; and bCullen Cardiovascular Research Laboratories, cHeart Failure Clinic and dCardiopulmonary Transplantation Service, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas. Submitted June 24, 2003; revised October 6, 2003; accepted October 8, 2003. Reprint requests: George V. Letsou, MD, Department of Cardiothoracic and Vascular Surgery, The University of Texas–Houston Medical School, 6410 Fannin, Suite #450, Houston, TX 77030. Telephone: 713-500-5323. Fax: 713-500-0650. E-mail: george.v.letsou@uth. tmc.edu Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2003.10.018
where the cable is externalized and connected to an analog controller. The pump is powered by lithium ion or lead acid batteries. Electromagnetic force is used to rotate the pump’s impeller at speeds ranging from 8,000 to 12,000 rpm, yielding a maximal blood flow of 7 liters/min. The pump speed is controlled by a pulsewidth-modulated, speed-controlled circuit that is adjusted manually. CASE REPORTS Case 1 Presentation, History, and Treatment. A 60-year-old man with a history of coronary artery disease, coronary artery bypass surgery in 1985, and implantation of an automatic internal cardiac defibrillator in 1998 presented with chest pain. On admission, he was found to have renal insufficiency and pulmonary edema. He had no history of GI bleeding. Catheterization revealed ischemic cardiomyopathy, and he was placed on the cardiac transplantation waiting list. Despite treatment with continuous intravenous inotropes and diuretics, the patient’s condition deteriorated until he ultimately required mechanical circulatory support. After the patient met all inclusion criteria and gave informed consent, a Jarvik 2000 LVAD was implanted via a left thoracotomy with partial cardiopulmonary bypass. Blood loss was minimal. After weaning from cardiopulmonary bypass, LVAD support was initiated at a flow rate of 4.8 liters/min. In the immediate postoperative period, re-exploration was necessary to evacuate a residual hemothorax. Extubation was performed expeditiously, and the immediate postoperative recovery was otherwise uneventful. However, during the subsequent course of LVAD support, multiple episodes of GI bleeding developed. Bleeding was first diagnosed on postoperative day (POD) 6 on the basis of heme-positive stools and a drop in hemoglobin concentration. Later, another drop 105
106
Letsou et al.
in hemoglobin concentration (from 8.3 g/dl on POD 17 to 6.7 g/dl on POD 18) was seen. After extensive evaluation with endoscopy, mesenteric angiography, and exploratory laparotomy, it was determined that bleeding was occurring in the small intestine. The definitive diagnosis of GI bleeding from AVMs was determined by endoscopy on POD 44. Numerous blood transfusions were necessary as well as selective intraarterial vasopressin infusion. Multiple recurrences of bleeding necessitated colonoscopic cauterization on POD 44, 58, and 62, which provided only temporary cessation of GI bleeding. Low hemoglobin concentrations, ranging from 6.6 g/dl to 12.9 g/dl, necessitated multiple blood transfusions. On POD 90, the patient underwent a colectomy with ligation of AVMs in the small intestine. Bleeding AVMs were directly visualized at surgery via enterotomies. Pathologic examination of surgical specimens revealed subtle changes in the venous anatomy that could be consistent with angiodysplasia or the edge of an AVM. No GI bleeding occurred during the remaining period of LVAD support. After 215 days of support, successful orthotopic cardiac transplantation was performed. There has been no recurrence of GI bleeding after cardiac transplantation. Management of Anticoagulation. Intravenous heparin and then oral warfarin were administered with the aim of achieving an international normalized ratio (INR) of 2.0 to 3.0. Attempts to provide anticoagulation therapy during support resulted in GI bleeding. Warfarin therapy was discontinued on POD 6 because of GI bleeding. Antiplatelet therapy (aspirin) was initiated on POD 15, but again had to be discontinued 4 days later because of GI bleeding. All anticoagulation and antiplatelet therapies were withheld from POD 19 until transplantation. During support, the average INR was 1.06, and the average hemoglobin concentration was 9.34 g/dl. Case 2 Presentation, History, and Treatment. A 51-year-old man with a history of ischemic cardiomyopathy after massive myocardial infarction and coronary artery bypass surgery in 1993 presented with shortness of breath and fatigue. There was no history of intestinal hemorrhage. Cardiac catheterization confirmed the presence of an ischemic cardiomyopathy not amenable to repeat revascularization. The patient was placed on the cardiac transplantation waiting list but decompensated before an appropriate organ became available. Treatment with continuous intravenous inotropes and diuretics was not sufficient to maintain adequate cardiac function. After the patient met all inclusion criteria and gave his informed consent, a Jarvik 2000 LVAD was implanted
The Journal of Heart and Lung Transplantation January 2005
Figure 1. Endoscopic image revealing an arteriovenous malformation and bleeding (white arrow) in the ileum of a patient supported with a Jarvik 2000 axial-flow left ventricular assist device.
via a left thoracotomy with partial cardiopulmonary bypass. Intraoperatively, 1 liter of packed red blood cells (RBCs) and 1.8 liters of fresh frozen plasma (FFP) were administered. After weaning from partial cardiopulmonary bypass, LVAD support was initiated at a flow rate of 3.3 liters/min. Chronic GI bleeding developed after 5 weeks. Melena was noted on POD 46; the hemoglobin concentration decreased to 9.7 g/dl on POD 33. Mesenteric angiography and endoscopy documented that GI bleeding was due to AVMs in the small intestine (Figure 1). Numerous blood transfusions and selective infusion of vasopressin did not resolve the bleeding. On POD 34, abdominal exploration of the ischemic bowel was performed to locate the source of bleeding; during the procedure, adhesions were lysed, a cholecystectomy was performed, and exploration for ischemic bowel was carried out. However, chronic GI bleeding continued. The hemoglobin concentration dropped to 9.8 g/dl on POD 38 and to 8.5 g/dl on POD 69 despite continued blood transfusions. On POD 70, the patient underwent smallbowel enteroscopy to help control the bleeding. A total of 15 AVMs were definitively identified and cauterized with a bipolar cautery probe. Still, GI bleeding continued. A subsequent infusion of vasopressin selectively into the superior mesenteric artery and an intravenous infusion of antistatin also failed to stop the GI bleeding. The patient’s condition worsened. Multiorgan failure ensued, and the patient died after 121 days of support.
The Journal of Heart and Lung Transplantation Volume 24, Number 1
Management of Anticoagulation. Warfarin was administered beginning on POD 4. Due to the development of GI bleeding, warfarin was discontinued on POD 34. Anticoagulation therapy was reinstituted intermittently, but could not be routinely established because of continued intermittent intestinal hemorrhage. During the 121 days of support, heparin was administered on 63 days, anti-platelet therapy with aspirin on 6 days, and warfarin on 3 days. During support, the average INR was 1.16, and the average hemoglobin concentration was 11.72 g/dl. Case 3 Presentation, History, and Treatment. A 66-year-old woman with a history of ischemic cardiomyopathy after myocardial infarction in 1999 presented with recurrent syncope and shortness of breath. She had no history of GI hemorrhage. Echocardiography revealed an ejection fraction of less than 20%. The patient was placed on the waiting list for cardiac transplantation. Despite treatment with continuous intravenous inotropes, refractory cardiac failure developed before an appropriate organ for transplantation became available. After the patient met all inclusion criteria and gave her informed consent, a Jarvik 2000 LVAD was implanted via a left thoracotomy with partial cardiopulmonary bypass. Intraoperatively, 1 liter of packed RBCs, 1.8 liter of platelets, and 1.32 liter of FFP were administered. On weaning from partial cardiopulmonary bypass, LVAD support was initiated at a flow rate of 3.2 liters/min. The initial postoperative recovery was uneventful. On POD 70, melena developed, and the hemoglobin concentration fell to 8.0 g/dl. As a result, transfusion of packed RBCs was required. Nuclear RBC imaging revealed GI bleeding due to the formation of AVMs in the small intestine. Numerous transfusions of packed RBCs were administered as well as intravenous vasopressin. On POD 86, colonoscopy showed no AVMs and no clear cause of the GI bleeding. Chronic, slow GI bleeding continued despite all treatment efforts until the patient underwent heart transplantation after 169 days of support. Gastrointestinal bleeding resolved after orthotopic cardiac transplantation and has not recurred. Management of Anticoagulation. Initially, heparin and warfarin were administered with the aim of achieving an INR of ⬎ 2.0. This therapy was discontinued intermittently because of melena and GI bleeding. The anti-platelet agent dipyridamole was started on POD 118. During the 169 days of support, heparin was given on 31 days, warfarin on 61 days, and dipyridamole on 40 days. During support, the average INR was 1.97, and the average hemoglobin concentration was 10.3 g/dl.
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DISCUSSION Mechanical circulatory support with an implantable ventricular assist device is applied routinely in patients needing temporary circulatory assistance while awaiting cardiac transplantation.4 – 6 Less frequently, a ventricular assist device is used to support patients with acute heart failure until myocardial function improves7 or to provide permanent support to patients who have end-stage heart failure, are not candidates for heart transplantation, and have no hope for improvement in myocardial function.8 Axial flow pumps are being developed to address the needs of patients who are too small to be fitted with current pulsatile devices and to reduce some of the complications associated with the pulsatile technology.9 Initial clinical studies with axial flow pumps are in progress.10,11 Twenty-one patients have been supported by the Jarvik 2000 axial-flow LVAD as a bridge to heart transplantation at the Texas Heart Institute, and 3 of them had chronic GI bleeding secondary to AVMs during the period of circulatory support. This led us to examine a possible association between gastrointestinal AVMs and the partially pulsatile blood flow provided by the axial flow pumps. Gastrointestinal bleeding is not uncommon in critically ill patients requiring intensive support and LVAD therapy. However, the incidence of life-threatening bleeding from all GI sources requiring operation is low when pulsatile ventricular assist systems such as the Novacor (World Heart Inc., Oakland, CA) and HeartMate (Thoratec Corporation, Pleasanton, CA) are used. Gastrointestinal bleeding was not identified as a clinically significant problem in 2 recent reviews of the clinical experience with the HeartMate pulsatile LVAD.12,13 Thus, the incidence of GI bleeding in 3 of our first 21 patients supported with the Jarvik 2000 (14%) is distinctly unusual. An association between GI bleeding and aortic stenosis was first called to attention by Heyde in a letter to the New England Journal of Medicine in 1958, resulting in the appellation Heyde’s syndrome.1 Schwartz reported a similar observation in a letter to the New England Journal of Medicine later that same year.14 Afterward, reports of a similar association in larger series of patients appeared.3 In 1979, Boley and colleagues15 reported an approximately 15% incidence of aortic stenosis in patients with vascular ectasias of the colon. Despite the correlation between aortic stenosis and GI bleeding in these reports, some groups still questioned it. In 1988, Imperiale and Ransohoff16 performed a quantitative and methodologic analysis of the literature. They cited problems in the above-mentioned studies and others, including non-blinded data collec-
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tion, non-comparable diagnostic examination, and noncomparable demographic groups. They emphasized that most of the studies referred to an association between aortic stenosis and chronic GI bleeding, not angiodysplasia. They concluded that the association between GI bleeding and AVMs was not supportable by a careful literature review and suggested that controlled studies were necessary. The most frequently recommended treatment for AVMs associated with aortic stenosis has been aggressive localization of the bleeding source by endoscopic and radiologic means. If the site of bleeding can be identified and medical management fails, surgical resection should be performed. In cases of occult intestinal bleeding, 2 approaches have been recommended. The first approach is a blind right hemicolectomy. The second approach, recommended more recently, is replacement of the aortic valve with a bioprosthetic valve, an approach that has successfully stopped bleeding.17 Several explanations for the association between AVMs and aortic stenosis have been proposed. Boley suggested that increased intraluminal pressure along with muscular contraction may result in dilated mucosal veins that favor the development of an arteriovenous communication that may bleed when exposed to trauma or stress.18 Alternatively, Cappell and Lebwohl17 proposed a neurovascular etiology with increased sympathetic tone resulting in smooth muscle relaxation and a subsequent propensity for angiodysplasia. Another proposed explanation is the hypoperfusion of the intestines that results from the lowered pulse pressure characteristic of aortic stenosis. According to this theory, hypoxia leads to vascular dilation and angiodysplasia. Left ventricular cardiac assistance with a minimally pulsatile LVAD produces physiologic changes similar to aortic stenosis, i.e., narrowed arterial pulse pressure. In our 3 cases, patients with no previous history of intestinal bleeding exhibited bleeding after institution of non-pulsatile mechanical support with an LVAD. The bleeding was extremely difficult to control during the period of non-pulsatile left ventricular assistance. However, in the 2 patients who survived to cardiac transplantation, the bleeding ceased after cardiac transplantation and the restoration of normal circulatory physiology without other interventions. Unlike other currently available implantable cardiac assist devices, the Jarvik 2000 uses axial flow technology in which an impeller provides forward flow from the left ventricle into the descending aorta. Other ventricular assist devices provide pulsatile flow. The practical difference between the 2 types of devices is that flow during support with the Jarvik 2000 exhibits diminished pulsatility. The diminished
The Journal of Heart and Lung Transplantation January 2005
pulsatility is due to native ventricular contraction and its contribution to cardiac output. The pulse pressure varies with the speed (and thus the output) of the device. This may result in the same altered intestinal physiology seen in aortic stenosis, i.e., diminished pulse pressure. Some may infer from the present case reports that candidates for Jarvik 2000 pump implantation would benefit from a more profound gastrointestinal evaluation preoperatively. However, AVMs are notoriously difficult to detect when not actively bleeding, and the AVMs in all 3 cases reported here occurred in patients who had no previous history of gastrointestinal bleeding. Therefore, efforts to detect such lesions preoperatively are not recommended. Two important observations have arisen from our experience with implantation of the non-pulsatile Jarvik 2000 pump, and both have therapeutic implications. First is the observation of GI bleeding from AVMs in a minority of patients. Second is the resolution of GI bleeding after orthotopic cardiac transplantation and restoration of normal physiology in 2 of those patients, both of whom continue to do well with no subsequent GI bleeding. Thus, it appears that GI hemorrhage from intestinal AVMs in patients supported by an axial-flow LVAD may be successfully treated by minimizing axial flow (and thereby increasing pulse pressure) or by cardiac transplantation. REFERENCES 1. Heyde EC. Gastrointestinal bleeding in aortic stenosis [letter]. N Engl J Med 1958;259:196. 2. Weaver GA, Alpern HD, Davis JS, et al. Gastrointestinal angiodysplasia association with aortic valve disease. Gastroenterology 1979;77:1–11. 3. Williams RC. Aortic stenosis and unexplained gastrointestinal bleeding. Arch Intern Med 1961;108:859 –63. 4. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device. Ann Thorac Surg 1992;53:1080 –90. 5. Farrar DJ, Hill JD. Univentricular and biventricular Thoratec VAD support as a bridge to transplantation. Ann Thorac Surg 1993;55:276 –82. 6. McCarthy PM, Portner PM, Tobler HG, Starnes VA, Ramasamy N, Oyer PE. Clinical experience with the Novacor ventricular assist system: bridge to transplantation and the transition to permanent application. J Thorac Cardiovasc Surg 1991;102:578 –86. 7. Frazier OH, Myers TJ. Left ventricular assist system as a bridge to myocardial recovery. Ann Thorac Surg 1999;68: 734. 8. Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg 1999;67:723– 30.
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9. Myers TJ, Gregoric I, Tamez D, et al. Development of the Jarvik 2000 Heart ventricular assist system. J Heart Failure Circ Support 2000;1:133–40. 10. Westaby S, Katsumata T, Evans R, Pigott D, Taggart DP, Jarvik RK. The Jarvik 2000 Oxford system: increasing the scope of mechanical circulatory support. J Thorac Cardiovasc Surg 1997;114:467–74. 11. Frazier OH, Gregoric ID, Delgado RM, et al. Initial experience with the Jarvik 2000 left ventricular assist system as a bridge to transplantation: report of 4 cases. J Heart Lung Transplant 2001;20:201. 12. McCarthy PM, Smedira NO, Vargo RL, et al. One hundred patients with the HeartMate left ventricular assist device: evolving concepts and technology. J Thorac Cardiovasc Surg 1998;115:904 –12. 13. McBride LR, Naunheim KS, Fiore AC, Moroney DA,
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Swartz MT. Clinical experience with 111 Thoratec ventricular assist devices. Ann Thorac Surg 1999;67:1233–8. Schwartz BM. Additional note on bleeding in aortic stenosis [letter]. N Engl J Med 1958;259:456. Boley SJ, Sammarteno R, Brandt LJ, Sprayregan S. Vascular ectasias of the colon. Surg Gynecol Obstet 1979;149:353–9. Imperiale TF, Ransohoff DF. Aortic stenosis, idiopathic gastrointestinal bleeding, and angiodysplasia: is there an association? A methodologic critique of the literature. Gastroenterology 1988;95:1670 –6. Cappell MS, Lebwohl O. Cessation of recurrent bleeding from gastrointestinal angiodysplasias after aortic valve replacement. Ann Intern Med 1986;105:55–7. Boley SJ, Sammartano R, Adams A, et al. On the nature and etiology of vascular ectasias of the colon. Gastroenterology 1977;72:650 –60.