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Ann Thorac Surg 2003;75:S42-S47
© 2003 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Newark Beth Israel Medical Center, Newark, New Jersey, USA
* Address reprint requests to Dr Goldstein, Department of Cardiothoracic Surgery, Newark Beth Israel Medical Center, 201 Lyons Ave, Suite G5, Newark, NJ 07112, USA.
e-mail: dgoldstein{at}sbhcs.com
Presented at the Heart Failure & Circulatory Support Summit, Cleveland, OH, Aug 22–25, 2002.
Abstract
Bleeding is the most common postoperative complication after implantation of left ventricular assist devices, necessitating reoperation in up to 60% of recipients. The implications of massive blood transfusions are great and include infection, pulmonary insufficiency, increased costs, right heart failure, allosensitization, and viral transmission, some of which can prove fatal or preclude transplantation. Preoperative evaluation and preparation are essential, intraoperative hemostasis is imperative, and "shotgun" product replacement should be avoided. Adherence to protocols emphasizing "hemostatic readiness" could reduce the incidence of bleeding complications that pervade left ventricular assist device therapy and potentially improve current successes in bridging to transplantation.
Bleeding is the most common postoperative complication after left ventricular assist device (LVAD) implantation, necessitating reoperation in up to 60% of cases irrespective of device used or indication for insertion. Postoperative hemorrhage often leads to massive transfusions, which carry significant morbidity. Despite the frequency and morbidity of bleeding complications, a scarcity of literature exists on the topic of bleeding after LVAD insertion. Therefore, the purpose of this manuscript is to provide a blueprint for the longitudinal treatment of the potential LVAD recipient from the preoperative assessment of risk factors for bleeding to the intraoperative techniques to minimize intraoperative hemorrhage and through the postoperative period.
Because of the dearth of literature on the subject, most recommendations outlined below are derived from personal experience and communication with leading investigators in the field. Whereas some recommendations are applicable to any mechanical support device, many of the intraoperative "tricks of the trade" advanced here are germane to the more commonly implanted large intracorporeal pulsatile devices and may not apply to the smaller axial flow pumps or extracorporeal systems.
Significance of bleeding
Bleeding is undoubtedly the most common postoperative complication after LVAD implantation [1–4]. Whether indicated for postcardiotomy support or as a bridge to transplant, the incidence of perioperative bleeding after assist device insertion remains significant, necessitating reoperation in up to 60% of implants regardless of device used [4]. More importantly, the shotgun massive transfusion that usually ensues is associated with markedly increased morbidity and mortality.
First, several studies suggest that blood transfusion induces an immunosuppressive state that can contribute to the development of nosocomial infections [5, 6]. Second, blood transfusion is associated with a risk of pulmonary insufficiency [7] that can progress to overt adult respiratory distress syndrome, a process thought to be induced by passively transfused complement-activating antibodies. Third, in the present era of cost containment, the costs associated with blood bank use and operating room use for reoperation can not be overstated.
Whereas the issues of infections, pulmonary insufficiency, and cost are important, they are not particular to LVAD recipients per se. Three additional complications of massive blood transfusion become more relevant to LVAD recipients, namely, right heart failure, allosensitization, and transplant-precluding viral transmission.
There is a well-established relationship between bleeding, massive blood product resuscitation, and subsequent right heart failure [8]. For yet incompletely understood reasons, LVAD recipients are prone to develop right heart failure in the immediate postoperative setting [9]. Massive blood product resuscitation causes right heart distension and release of proinflammatory cytokines, which can induce pulmonary hypertension and further exacerbate the preexisting conditions that favor the development of right heart failure. The latter can lead to hepatic congestion, coagulopathy, and further bleeding, thus generating a vicious self-perpetuating cycle.
Each unit of blood transfused increases the risk of allosensitization and can result in elevated panel reactive antibodies that can complicate or even prevent successful transplantation. Finally, there also remains the increased risk of serious viral transmission and, though modest, carries detrimental consequences for an LVAD recipient awaiting transplantation. In fact, it can render the patient unacceptable as a candidate for transplantation.
Preoperative evaluation
Because of the unequivocal propensity for bleeding, every prospective LVAD candidate should be evaluated early with an eye on potential risk factors. The goal is to attain a state of "hemostatic readiness." The preoperative history should focus on: (1) a history of spontaneous bleeding; (2) use of medications known to affect platelet function or coagulation factor synthesis; and (3) use of herbal supplements that often interfere with platelet function [10–16] (Table 1).
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From a hemodynamic standpoint, most of the patients will have central monitoring in place at the time of initial consultation. The most important variable as it relates to potential bleeding problems is the central venous pressure (CVP), as this is a fair reflection of the pressures in the hepatic venous system and can suggest the presence of congestive hepatopathy and risk of bleeding. In a way, the CVP could be viewed as the hepatic afterload. The combination of elevated CVP and low pulmonary arterial pressure (often accompanied by severe tricuspid regurgitation on echocardiography) is particularly ominous, as it suggests severe right heart failure, and use of biventricular mechanical support should be strongly considered.
Laboratory analyses will easily disclose coagulopathies, thrombocytopenia, renal or hepatic dysfunction, anemia, and hypoalbuminemia, any or all of which can contribute to perioperative bleeding. Presence of any of these should elicit a search for offending agents (ie, coumadin, H2 blockers, alcohol abuse, etc) and aggressive institution of replacement therapies (ie, transfusion, vitamin K, hyperalimentation, etc). Bleeding time or coagulation factor levels are not routinely ordered unless the patient has a history of spontaneous or profuse bleeding. If so, a hematological consultation should be sought.
Preoperative optimization
Based on the above bleeding risk assessment, we attempt to adhere to an all-encompassing optimization protocol (Table 2) in prospective LVAD candidates. Patients are transfused as necessary to achieve adequate platelet, coagulation factor, and hemoglobin levels. Single donor platelets are used and products are given after leukoreduction. Inotropic agents and diuretics are used as indicated to achieve a CVP less than 16 mm Hg. If unachievable, biventricular support is strongly considered. We follow the Cleveland Clinic Foundation’s recommendation regarding preoperative vitamin K administration [17] and supplement this with vitamin C. Deficiency of the latter has been shown to induce a postoperative bleeding diathesis, which is easily reversible [18]. As suggested previously, efforts are made to discontinue any and all drugs that may interact with platelet number or function and coagulation cascade factor levels. A 3-day drug-free interval is attempted if hemodynamics permit.
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If possible, LVAD implantation should be scheduled as an early morning case and as an only case; other cases should not be planned for the particular operative theater or surgeon. Availability of nitric oxide in the operating room should be ensured. Mechanical right heart support devices, for example, Abiomed BVS 5000 (Abiomed Inc, Danvers, MA) or Thoratec (Thoratec Corp, Berkeley, CA), should also be readily available. Additionally, the surgeon should ensure that BioGlue (CryoLife Inc, Kennesaw, GA), Aprotinin (Bayer Corp., West Haven, CT), and Goretex patches (WL Gore, Flagstaff, AZ) are available. If preoperative laboratories document a hemoglobin of 12 mg/dL or greater, consideration should be given to removing 1 to 2 U of whole blood before administration of heparin. These can then be warmed and returned after protamine administration.
Intraoperative strategies: tricks of the trade
Once candidacy for transplantation has been verified and preoperative evaluation and optimization have been completed, a number of intraoperative strategies can be undertaken to reduce the chances of intraoperative and postoperative bleeding. In general terms, hemostatic mechanisms can be surgical or medical. The former can be subdivided into LVAD-related and LVAD-unrelated aspects.
Surgical hemostasis: Non-LVAD related
The potential non-LVAD surgical bleeding sites are the right atrial and aortic cannulation sites, the sternal edges, the pleural fat pads, and, in reoperative cases, the adhesions between the epicardium and pericardium and exposed lung surface (particularly in the case of previous coronary artery bypass graft with left internal mammary artery and violated left pleurae).
A number of suggestions can be advanced to minimize bleeding from these sites. First, the aortic and right atrial cannulation sites should be reinforced with pledgets. The ascending aorta is subject to very high pressures as a result of the ability of the pulsatile LVAD to generate very high dp/dt. This can weaken a suboptimal closure. Attainment of a hemostatic right atrial cannulation site is also critical. The right atria of end-stage heart failure patients are usually tensely distended and quite friable, and can fall apart quickly and catastrophically. We recommend placing a pledget with every bite of the right atrium purse string so that, when the cannula is removed and the suture snared, a rosette of pledgets is created that is perfectly hemostatic and resistant to elevations in the central venous pressure that are common in the postoperative period.
For reoperative patients, particular attention should be given to the exposed left lung and left pericardium after administration of protamine to ensure hemostasis on these surfaces. On the right side, a space is usually created underneath the distal right hemisternum to allow optimal lie of the outflow graft. This area is rich in small arterial vessels derived from the right internal mammary artery that supply the pericardium and pleura. Troublesome bleeders in this area often retract and then reopen after rewarming in the intensive care unit and can result in significant postoperative blood loss (so-called "midnight cowboys"). Great effort should therefore be taken at the end of the procedure to retract the outflow graft medially and use the electrocautery generously in this area even if no obvious bleeding areas are identified. As in all cardiac surgical cases, meticulous attention to sternal edge and wire-hole bleeding and avoidance of sternal wire injury to the mammary arteries behind closed pleurae are essential.
Surgical hemostasis: LVAD related
Ventricular assist device–related bleeding sites include the preperitoneal pocket and the driveline tunnel, the apical inflow, the outflow graft, and the aortic outflow anastomosis.
The driveline tunnel and preperitoneal pocket (if the decision is made to place the device preperitoneally instead of intraperitoneally) should be created prior to heparinization. Hemostasis in the pocket should be ensured with particular care to control the inferior epigastric vessels if visible. Efforts should be made to avoid separating the rectus muscle from the underlying posterior fascia, as device motion under the exposed rectus muscle can lead to bleeding into the pocket. Unfortunately, the preperitoneal layer is often very thin and it becomes necessary to separate the posterior rectus fascia to allow a more substantial LVAD pocket "floor." Peritoneal violation should be averted, as the ascitic fluid in the peritoneal cavity is rich in tissue plasminogen activator [19, 20] which can promote fibrinolysis.
After securing the inflow apical cannula, we apply BioGlue (CryoLife Inc) circumferentially to the mattress sutures and inflow cuff. Because the glue must be applied on a dry field, the left ventricular vent is turned up to prevent any blood from exiting through the apex while the glue is being applied. For the outflow aortic anastomosis, we recommend using 12 double-pledgetted sutures such that the anastomosis is everted with a pledget on either side. Again, BioGlue should be applied circumferentially once the field is dried. We favor wrapping the outflow graft with a GoreTex patch to protect it during transplant sternal reentry. The recent iterations of the Thoratec HeartMate device incorporate an outflow graft straightener/protector that usually covers most of the outflow graft length once the graft is cut and tailored to reach the aorta. Many investigators place a GoreTex patch on top of the outflow to create an artificial pericardium that will afford additional protection during transplant reentry. Finally, great efforts should be taken to avoid entry into the right pleural space to prevent erosion of the right mammary artery or its branches by the pulsating outflow graft. If the pleura is inadvertently violated during sternal entry, it can be easily reapproximated with absorbable sutures before chest closure.
Nonsurgical hemostasis
Nonsurgical hemostasis relates to the effects of cardiopulmonary bypass (CPB) on hemostatic mechanisms, the adequacy of protamine reversal, the ability to attenuate fibrinolysis, and the control of CVP, or hepatic after load.
High-dose aprotinin is always used for its hemostatic and antiinflammatory properties. In the early 1990s, it was shown that aprotinin use in LVAD recipients is associated with reduced blood loss and blood product use, and reduced incidence of right heart failure [8]. The safety of aprotinin readministration at the time of LVAD removal and transplantation has also been demonstrated [21].
Clearly, one way of reducing the pathologic effect of CPB is to reduce CPB time. This can be accomplished in many instances by performing the outflow anastomosis to the aorta before institution of CPB. Briefly, after creation of the driveline tunnel and pocket, the pump is placed in the pocket. Heparin is administered and the aorta and right atrium are cannulated. A partial occluding clamp is then placed on the ascending aorta. After ensuring hemodynamic stability for a couple of minutes, a longitudinal aortotomy is created and enlarged, and the outflow graft is cut to comfortably reach the pump in the pocket. For the Thoratec HeartMate, this is usually 13 to 14 cm of stretched graft. In our experience, this strategy reduces the CPB time by 15 to 20 minutes. Nitric oxide (iNO) should be available in the operating room as outlined earlier. If right ventricular (RV) function supervenes, iNO is started at 20 ppm. In patients with a high preoperative CVP or elevated pulmonary vascular resistance, iNO is often started prophylactically just before separation from CPB. It is critical that the surgeon not leave the operating room until hemostasis is optimal. Infrequently, coagulopathy is so severe that additional time in the operating room with consequent hypothermia is unadvisable, and the best option is to pack the mediastinum and pursue aggressive targeted blood product resuscitation and warming in the intensive care unit, with plans to return for evacuation of clot and chest closure within 12 to 24 hours. Some investigators suggest taking this approach in all cases, as residual clot prone to superinfection will always remain even in cases where no significant postoperative bleeding occurs (O.H Frazier, personal communication).
Efforts should be directed at optimal heparin reversal with protamine. Several investigators have documented the poor correlation between activated clotting time and circulating heparin levels. Excess protamine weakens clotting and decreases platelet aggregation, and the resulting increase in activated clotting time often leads to additional protamine administration with potential detrimental effects [22]. It has been therefore suggested that measurement of direct circulating heparin levels and use of point-of-care testing [23, 24] may aid in achieving more accurate heparin reversal.
Postoperative strategies
The postoperative management of these patients differs from that of other cardiac surgical patients. The expectation of LVAD-induced coagulopathy allows acceptance of higher chest tube outputs than that seen after conventional surgery. The prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR), platelet count and fibrinogen are checked every 4 hours until normalized. These indices are corrected as necessary to achieve a PT less than 16 seconds, INR less than 1.5, PTT less than 40 seconds, platelet more than 150 x 103/mm3, and fibrinogen more than 100 mg/dL. Several investigators rely on the use of thromboelastography to guide blood product replacement and, most recently, bedside monitoring of hemostasis is being actively pursued in an effort to reduce the delay associated with routine coagulation tests [23].
If renal insufficiency, evidenced by serum creatinine more than 2.0 is present, preoperatively desmopressin (DDAVP) is administered to optimize platelet function. Recently, recombinant activated factor VII has been successfully used to treat bleeding diathesis in an LVAD recipient [25] and in other clinical scenarios after cardiopulmonary bypass [26]. Whereas the authors have no experience with this therapy, this therapy appears particularly attractive because VIIa binds to tissue factor expressed at the site of tissue (surgical) injury, resulting in site-specific thrombin activation. The tissue factor-VIIa complex initiates the coagulation cascade and provides thrombin necessary for platelet activation.
Though advocated by some, we do not reinfuse shed mediastinal blood. The latter has been shown to be depleted of platelets and prone to bacterial superinfection. As mentioned previously, we continue aprotinin for 6 hours into the postoperative period, though the efficacy of this strategy has not been reported. Aspirin, heparin, and coumadin are withheld until coagulation factors and platelet count have normalized.
When transfusion is required, only leukoreduced packed red cells and platelets are used. The leukoreduction process is performed in the blood bank, and we no longer use Pall filters because of the incidence of anaphylactic reactions [27]. Blood product replacement should be targeted and not shotgun. Fresh-frozen plasma should be used for correction of factor deficiency, reversal of warfarin or elevated prothrombin time, or partial thromboplastin times. Cryoprecipitate should be reserved for documented hypofibrinogenemia, whereas platelets should be administered only for thrombocytopenia and platelet dysfunction. Factor concentrates are almost never required, though recombinant FVIIa has been used successfully for intractable life-threatening bleeding as mentioned previously.
Most present mechanical support systems (except for HeartMate) require chronic anticoagulation. When indicated, heparin is started at 500 U/h without a bolus and is slowly titrated upwards to reach therapeutic levels. When introducing coumadin therapy, it is essential to be mindful of potential drug interactions. Amiodarone (Wyeth-Ayerst Pharm, Philadelphia, PA) and Levaquin (Ortho McNeil Pharm, Raritan, NJ) are particularly notorious for drastic and unpredictable augmentation of coumadin effects, and hence, we attempt to avoid these drugs. Because of the platelet-inhibiting activity of histamine blockers, gastric prophylaxis is preferentially accomplished with sulcralafate (Aventis Pharm, Parsippany, NJ) or proton pump inhibitors.
Perhaps the most important concept to underscore is the relationship between bleeding, massive transfusion, and right heart failure. Left ventricular assist device placement is associated with perioperative right heart failure. And whereas the mechanisms underlying this observation are incompletely understood, it has become clear that the induced injury to the right heart is only compounded when massive transfusion is required. Rapid infusion of large volume of blood products not only causes the fragile right heart to distend, but also stimulates the release of cytokines, which results in increased pulmonary vascular resistance. Invariably, this results in increased right heart afterload and further elevations in CVP. This elevation translates into hepatic congestion, coagulopathy, and increased venous oozing from surgical areas. More coagulopathy leads to further bleeding and transfusion, thus perpetuating the vicious cycle. As this cycle progresses, the ability of pharmacologic therapies like dobutamine, phosphodiesterase inhibitors, and even inhaled nitric oxide to reduce right heart afterload are overwhelmed and RVAD support becomes necessary. Unfortunately, institution of RVAD support in this setting is associated with a nearly uniform fatality.
Finally, a growing body of literature is documenting a unique entity: device-induced coagulopathy in recipients of the Thoratec HeartMate LVAD. This device has received much of the attention because of its uncanny thromboresistant surface [28, 29]. Investigators have described the parallel induction of activated coagulation and fibrinolytic cascades, whereby platelets are activated to release their granules (platelet factor 4, ß-thromboglobulin, and thromboxane B2), thrombin is generated (thrombin-antithrombin complexes, prothrombin fragments, and fibrinopeptide elevations), and fibrinolysis is induced (plasmin-antiplasmin complexes and D-dimer elevation) despite normal coagulation values and platelet counts [30, 31]. These events occur independently of cardiopulmonary bypass or heart failure state. The working hypothesis is that this LVAD induces a state where procoagulant and prothrombotic forces delicately balance one another. However, if a stress situation is imposed, such as sepsis, ongoing bleeding, or an operation, the balance can be tipped and result in diffuse bleeding or thromboembolic events.
Comment
Bleeding is the most common postoperative complication after implantation of LVAD. The implications of massive blood transfusions are great and include infection, pulmonary insufficiency, increased costs, right heart failure, allosensitization, and viral transmission, some of which can prove fatal or preclude transplantation. Preoperative evaluation and preparation are essential, intraoperative hemostasis is imperative, and "shotgun" product replacement should be avoided. Adherence to protocols emphasizing "hemostatic readiness" is likely to reduce the incidence of bleeding complications that pervade LVAD therapy and could potentially improve current successes in bridging to transplantation.
Acknowledgments
The authors would like to thank Dr Yoshifumi Naka (Columbia Presbyterian, New York) for sharing his left ventricular device implantation "tricks of the trade" and being a constant source of innovative hemostatic ideas.
References
This article has been cited by other articles:
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  D. A. Hehir, R. A. Niebler, C. C. Brabant, J. S. Tweddell, and N. S. Ghanayem Intensive Care of the Pediatric Ventricular Assist Device Patient World Journal for Pediatric and Congenital Heart Surgery, January 1, 2012; 3(1): 58 - 66. [Abstract] [Full Text] [PDF]
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 J. C. Matthews, F. D. Pagani, J. W. Haft, T. M. Koelling, D. C. Naftel, and K. D. Aaronson Model for End-Stage Liver Disease Score Predicts Left Ventricular Assist Device Operative Transfusion Requirements, Morbidity, and Mortality Circulation, January 19, 2010; 121(2): 214 - 220. [Abstract] [Full Text] [PDF]
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 J. M. Gelow, A. S. Desai, C. P. Hochberg, J. N. Glickman, M. M. Givertz, and J. C. Fang Clinical Predictors of Hepatic Fibrosis in Chronic Advanced Heart Failure Circ Heart Fail, January 1, 2010; 3(1): 59 - 64. [Abstract] [Full Text] [PDF]
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 J. Klovaite, F. Gustafsson, S. A. Mortensen, K. Sander, and L. B. Nielsen Severely Impaired von Willebrand Factor-Dependent Platelet Aggregation in Patients With a Continuous-Flow Left Ventricular Assist Device (HeartMate II) J. Am. Coll. Cardiol., June 9, 2009; 53(23): 2162 - 2167. [Abstract] [Full Text] [PDF]
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