- Email: [email protected]
Use of Recombinant Factor VIIa to Facilitate Organ Donation in Trauma Patients with Devastating Neurologic Injury
Use of Recombinant Factor VIIa to Facilitate Organ Donation in Trauma Patients with Devastating Neurologic Injury Deborah M Stein, MD, MPH, FACS, Richard P Dutton, MD, MBA, Charlie Alexander, MS, MBA, John Miller, BS, CTBS, Thomas M Scalea, MD, FACS Organ donation serves a public health function but is also an important part of end-of-life care. Nearly 40% of organ donors are the victims of traumatic brain injury (TBI). We report on a series of patients with nonsurvivable TBI and severe coagulopathy or active hemorrhage who went on to successful organ donation with the use of recombinant factor VIIa (rFVIIa). STUDY DESIGN: Organ donors from a 6-year period were identified from the local Organ Procurement Organization (OPO). Medical records were reviewed, and demographics, injury-specific data, coagulation profiles, and medications administered were abstracted. Outcomes data on early graft function after transplantation were obtained. RESULTS: One hundred forty-eight patients had organ recovery after either brain death or withdrawal of care. Twenty-nine patients received rFVIIa and 119 patients did not. rFVIIa was administered before determination of nonsurvivability or brain death in 21 patients. In eight patients, rFVIIa was administered as a specific salvage therapy to allow donation. Mean Injury Severity Score in the rFVIIa group was 43.4 (⫾14.8) versus 34.0 (⫾13.3) in the group that did not receive rFVIIa (p ⫽ 0.001). Organs transplanted per donor were no different in the 2 groups (3.5 versus 3.6; p ⫽ 0.7). There were nearly twice as many successfully recovered lungs from the donors who received rFVIIa (44.1% versus 26.2%; p ⫽ 0.04). There was no difference in early graft function in the two groups when recipient outcomes were compared. CONCLUSIONS: Use of rFVIIa facilitated donation in patients with multisystem injuries who otherwise might have been ineligible for organ donation. Use of rFVIIa did not affect early graft function, although longterm outcomes are unknown. Recombinant factor VIIa is expensive, but its use is justified if the donor organ supply can be increased. (J Am Coll Surg 2009;208:120–125. © 2008 by the American College of Surgeons) BACKGROUND:
donate.2 There have been a number of national and local efforts to improve organ donation rates. In April 2003, the Department of Health and Human Services launched the Organ Donation Breakthrough Collaborative. The goal of the Collaborative is to “dramatically increase access to transplantable organs . . . by spreading known best practices to the nation’s largest hospitals, to achieve organ donation rates of 75% or higher . . . .”2 Many of the efforts of the Collaborative have focused on improvement of referral and conversion rates to improve rates of donation among eligible potential donors. Additionally, there have been efforts to improve organ donation rates with aggressive management of organ donors and reduction in medical failures.3-7 Most of the initiatives that have been instituted have focused on improving processes surrounding referral and consent rates, prompt declaration of brain death, and the aggressive medical care of donors after declaration of brain death. Little attention has been focused on support-
There are nearly 100,000 people waiting for an organ in the US, and an average of 18 people die each day because of the lack of available organs for transplantation.1 Every 12 minutes another name is added to the national organ transplant waiting list, and only about 50% of eligible donors actually Disclosure Information: The following disclosures have been reported by the authors: Drs Stein and Scalea have received research funding from NovoNordisk. Dr Dutton has worked as a paid consultant to NovoNordisk. None of the authors has any financial interest in the company. Abstract presented at 2008 IBIA Seventh World Congress on Brain Injury, Lisbon, Portugal, April 2008. Received July 23, 2008; Revised September 19, 2008; Accepted September 24, 2008. From the R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD (Stein, Dutton, Scalea), and The Living Legacy Foundation, Baltimore, MD (Alexander, Miller). Correspondence address: Deborah M Stein, MD, MPH, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene St, Baltimore, MD 21201. email: [email protected]
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Abbreviations and Acronyms
OPO ⫽ Organ Procurement Organization rFVIIa ⫽ recombinant factor VIIa TBI ⫽ traumatic brain injury
ing neurologically devastated patients long enough to allow for a discussion about donation with the family. Nearly 40% of organ donors are the victims of traumatic injury and devastating neurologic injury.7 Coagulopathy is a frequent finding in patients with severe traumatic brain injury (TBI).8,9 Dilutional coagulopathy from concomitant hemorrhage, preexisting coagulation abnormalities, or preinjury use of anticoagulants can occur in the injured patient. Even in the absence of other factors, coagulopathy can occur as the result of the TBI itself, secondary to release of tissue thromboplastin and abnormalities of fibrinolysis.8,10-12 Many of these injured patients also have substantial concomitant injuries, which can result in cardiac death secondary to hemorrhage and coagulopathy before declaration of brain death is possible. In addition, even in the patient with isolated TBI, marked physiologic derangements and coagulopathy can also lead to cardiac death.13,14 In the patient with devastating neurologic injury who does not progress to brain death but might be a candidate for donation after cardiac death, the same issues can preclude survival until donation. Many clinicians fail to aggressively manage these patients because of the likelihood of death or devastating neurologic outcomes without substantial thought to the potential to save other lives through donation. Concern is raised that perhaps the family will refuse donation or that efforts will be futile at preventing cardiac death and that resources will be wasted with aggressive intervention. Recombinant factor VIIa (rFVIIa; NovoSeven, NovoNordisk) has been used in injured patients on an off-label basis for several years. Approved for use in hemophiliacs with inhibitors and other hematologic disorders,15,16 rFVIIa is commonly used in many hospitals in patients with traumatic hemorrhagic shock and associated coagulopathy and in coagulopathic patients with both traumatic and nontraumatic neurosurgical emergencies.17-30 There have been a number of studies and case series that have reported successful use of rFVIIa in reversing coagulopathy in these patient populations.18,19,22,24,31 At our institution, we use rFVIIa on an off-label basis in coagulopathic patients with severe hemorrhage as an adjunct to surgical hemostasis and in coagulopathic patients with severe TBI. Many of these patients have succumbed to their neurologic injuries and progressed to brain death.
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Other patients in whom rFVIIa has been used have suffered devastating neurologic injury, which has led their families to withdraw care and proceed with donation after cardiac death. There is considerable concern about the potential thrombotic complications of rFVIIa use.32-36 Use in patients whose organs have been transplanted can raise concern about thrombosis in the transplanted organs, leading to graft failure. We sought to evaluate our experience with these patients who had received rFVIIa and went on to successful organ donation.
METHODS After approval by the University of Maryland Institutional Review Board, all deceased organ donors from the R Adams Cowley Shock Trauma Center between January 2002 and December 2007 were identified from the local Organ Procurement Organization (OPO; The Living Legacy Foundation). The medical records of all study subjects were then revieweds and demographics, injury-specific data, laboratory values, administration of rFVIIa, and blood product use were abstracted. Organ donors who received rFVIIa were compared with controls who were treated with conventional therapy alone. Organ-specific recipient outcomes were obtained from the OPO through standardized methods of data collection. Forms with recipient demographics and medical information with both descriptive measures and laboratory values are provided by the recipient’s transplantation coordinator 1 week posttransplantation to the OPO. Student’s and paired t-tests were used to compare differences between continuous variables, and chi-square analysis was used to compare categorical variables. A p value ⬍ 0.05 was considered significant for all statistical tests. At the Shock Trauma Center, rFVIIa is requested by the treating attending surgeon, intensivist, or anesthesiologist. Release by the pharmacy requires approval of an institutional gatekeeper. The gatekeepers monitor usage and recommend dose to be given based on the clinical status of the patient. All patient management before consent for donation was directed by the attending surgeon, intensivist, or anesthesiologist. In patients who did not receive rFVIIa, conventional therapy with reversal of coagulopathy with plasma was used. Substantial hemorrhage was managed in all patients using the principles of “damage control” resuscitation and operation. Management of intracranial hypertension is done according to an institutional protocol for management of severe TBI based on the Brain Trauma Foundation Guidelines.37 Once consent for donation is obtained, management of donors is a collaborative effort of The Living Legacy Foundation and the Shock Trauma Center Critical Care Service.
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Table 1. Baseline Characteristics of All Donors Characteristic
Age (y), mean ⫾ SD ISS, mean ⫾ SD Predicted survival (TRISS), mean ⫾ SD Admission GCS, mean ⫾ SD Admission PT(s), mean ⫾ SD Admission INR, mean ⫾ SD Male, n (%) Blunt injury, n (%)
rFVIIa (n ⴝ 29)
No rFVIIa (n ⴝ 119)
p Value
30.8 ⫾ 15.6 43.4 ⫾ 14.8 0.408 ⫾ 0.31 5.0 ⫾ 3.2 17.9 ⫾ 8.3 1.8 ⫾ 1.13 25 (86.2) 22 (75.9)
34.5 ⫾ 15.7 34.0 ⫾ 13.4 0.422 ⫾ 0.251 4.3 ⫾ 2.7 14.4 ⫾ 3.1 1.2 ⫾ 0.38 92 (77.3) 84 (70.6)
0.257 0.001 0.807 0.238 0.002 ⬍ 0.001 0.293 0.571
GCS, Glasgow Coma Score; INR, International Normalized Ratio; ISS, Injury Severity Score; PT, prothrombin time; rFVIIa, recombinant factor VIIa; TRISS, Trauma and Injury Severity Score.
RESULTS During a 6-year period, there were 148 patients admitted to the R Adams Cowley Shock Trauma Center who went on to become deceased organ donors. All patients had suffered devastating neurologic injury. There were 97 patients who were standard criteria donors, 4 extended criteria donors, and 47 patients who donated organs after cardiac death, for a total of 531 organs transplanted. Of these patients, 29 (19.6%) received rFVIIa and 119 (80.4%) were treated with conventional therapy alone. Baseline characteristics of these groups of patients differed considerably with respect to Injury Severity Score and admission coagulation profiles (Table 1). Use of blood products during hospitalization was considerably higher in the rFVIIa group, as would be expected based on the greater injury severity and extent of coagulopathy in this group (Fig. 1). Of the 29 patients who received rFVIIa, 21 were dosed before determination of nonsurvivability or plans for withdrawal of care. Eight patients were administered rFVIIa as a specific salvage therapy to allow for donation. Mean dose of rFVIIa administered was 44.3 g/kg, with a range of 11.7 to 162.7 g/kg. All 21 patients were coagulopathic at the time of rFVIIa administration, with a mean prothrombin time of 22.6 ⫾ 8.0 seconds (range 15.2 to 49.6) and an International Normalized Ratio of 2.4 ⫾ 1.4 (range 1.5 to 6.8). Indications for rFVIIa administration were active hemorrhage in 13 patients, to allow for neurosurgical intervention in 15, and for reversal of severe coagulopathy in 1 patient. Sources of hemorrhage included the brain and skull in four patients, massive facial bleeding in three, and uncontrolled torso hemorrhage in six patients. Mean prothrombin time was 22.6 ⫾ 8.0 seconds before rFVIIa administration and 13.8 ⫾ 3.4 seconds after (p ⬍ 0.0001). Mean International Normalized Ratio was 2.4 ⫾ 1.4 before rFVIIa administration and 1.1 ⫾ 0.3 after (p ⬍ 0.0001). In the no-rFVIIa group, there were 80 (67.2%) standard criteria donors, 36 (30.2%) donations after cardiac death, and 3 (2.5%) extended criteria donors versus 17 (58.6%),
11 (37.9%), and 1 (3.4%) in the rFVIIa group, respectively. Total number of organs donated by each group was 430 from the 119 conventionally treated patients and 101 from the 29 rFVIIa-treated patients. The number of organs donated per donor was 3.6 in the no-rFVIIa group versus 3.5 in the rFVIIa group (p ⫽ 0.7). The number and percentages of successfully transplanted eligible organs from each group are shown in Table 2. Despite the rFVIIa group having a higher percentage of substantial thoracic injuries (59.3% versus 39.0%; Thorax Abbreviated Injury Scale ⬎ 2; p ⫽ 0.06), there was nearly twice the rate of recovery of donated lungs in the rFVIIa group as compared with the conventionally treated group (p ⫽ 0.04), with no difference in heart donation rates. The rFVIIa group had a significantly higher incidence of abdominal injuries (29.6% versus 4.7%; Abdomen Abbreviated Injury Scale ⬎ 2; p ⫽ 0.0002) and a lower rate of successful liver donation (p ⫽ 0.04), with equivalent kidney, pancreas, and intestine donation rates (Fig. 2). Early recipient organ-specific outcomes data were available for 66% of the organs transplanted. Early recipient outcomes were not different between the 2 groups, with approximately 80% of recipients experiencing good or fair outcomes (Fig. 3).
Figure 1. Mean number of units of blood products administered to donors given recombinant factor VIIa (rFVIIa) compared with those treated with conventional therapy alone. White bar, no rFVIIa; black bar, rFVIIa. All differences p ⬍ 0.05.
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Table 2. Percentage of Eligible Organs Transplanted Heart Group
rFVIIa No rFVIIa
n
SCD
DCD
ECD
n
%
n
Lung %
n
Liver %
Pancreas n %
Intestine n %
29 119
17 80
11 36
1 3
9 45
56 56
15 42
47 26
19 99
65 83
11 52
1 1
39 43
6 1
Kidney n %
43 192
74 81
DCD, donation after cardiac death; ECD, extended criteria donors; rFVIIa, recombinant factor VIIa; SCD, standard criteria donors.
DISCUSSION The national shortage of organ donors and organs available for transplantation is a major public health problem. Hundreds of patients per year in the US die from organ failure while waiting for an organ. Organ donation also is an important part of end-of-life care for many patients and families. Many victims of fatal traumatic injuries are not candidates for organ donation, because of unplanned cardiac death before donation. Allowing patients with fatal or nonrecoverable injuries to survive to donation has received little focus in the literature. In the series of patients reported here, successful donation of 101 organs was achieved with adjunctive use of rFVIIa in patients with severe multisystem trauma who otherwise might not have survived to donation. Patients treated with rFVIIa had substantially greater injury severity and physiologic compromise but were able to donate organs at rates comparable to conventionally treated donors. Despite a higher incidence of severe thoracic trauma in the rFVIIa-treated donors, lung donation rates were nearly double what they were in conventionally treated patients. Not surprisingly, liver donation rates were lower in the rFVIIa group, because of a much higher incidence of abdominal injuries. Coagulopathy is common in the patient with severe injury and TBI. In addition, these fatally injured patients often have concomitant injuries, causing severe hemorrhage. Coagulation abnormalities can occur as a direct result of the brain injury itself and dilution of factors.8,10-12 Coagulopathy in these patients is most commonly reversed with the use of plasma. Correction of coagulopathy and the
attenuation of hemorrhage with plasma alone might not be successful for a variety of reasons. Recombinant factor VIIa has been used off-label as an adjunctive therapy in the bleeding trauma patient for several years.18-22 Numerous reports in the literature describe successful use of rFVIIa for both traumatic and nontraumatic neurosurgical emergencies.25-27,38-40 In our series reported here, rFVIIa used as an adjunctive therapy was uniformly successful in correcting coagulopathy as measured by coagulation profiles. There is a single case report in the literature that describes the use of rFVIIa in three patients with nonsurvivable brain injury secondary to gunshot wounds to the head.41 Two of the patients in that report went on to organ donation. A substantial concern about use of rFVIIa is the issue of cost. Recombinant factor VIIa is expensive, with a single large weight-based dose costing nearly US $10,000. Per policy, the OPO pays for all hospital expenses from the time of consent/brain death declaration through the organ recovery procedure. If rFVIIa is used during this time frame, the OPO would bear the cost. If rFVIIa is used during the initial resuscitation as part of usual clinical practice before consent, the patient or the patient’s insurance company would be the payor. For the eight patients pre-
Figure 2. Percentage of eligible organs transplanted from donors given recombinant factor VIIa (rFVIIa) compared with those not given recombinant factor VIIa. White bar, no rFVIIa; black bar, rFVIIa. Star, p ⬍ 0.05; all other differences not significant.
Figure 3. Early organ function results for organs transplanted from donors given recombinant factor VIIa (rFVIIa) compared with those treated with conventional therapy alone. White bar, no rFVIIa; black bar, rFVIIa. All differences not significant.
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sented here who received rFVIIa as a specific therapy to allow for survival to donation, the timing of administration determined who paid. If rFVIIa allows for an increase in organ donor supply, the public health benefit might outweigh the individual cost. Additional discussion of who should bear the cost in patients in whom rFVIIa is used as a pure salvage therapy before declaration of brain death or consent for donation is obtained is clearly warranted. Thromboembolic events have been reported in patients who have received rFVIIa.33,39,42 These concerns could be extrapolated to a risk of thrombosis in organs from donors who have received rFVIIa. Several recent studies have described the use of rFVIIa in patients undergoing transplantation without an increased risk of thrombotic complications.43-48 Additionally, animal studies have demonstrated no evidence of microvascular thrombosis in the lung tissue of treated animals.49 In this current study, recipient outcomes were equivalent in organs recovered from donors who received rFVIIa and those who did not. This indicates that rFVIIa does not increase risk of vascular thrombosis in donated organs. There are obviously limitations to this study. First, the retrospective design only allows for identification of associations and not determination of cause and effect. The study design also limited the amount of clinical information that could be compared between the two groups, because of the use of medical records, consistency of documented information, and availability of recipient outcomes data. Despite its limitations, this study demonstrates that in patients with severe injury, use of rFVIIa facilitated donation in patients with multisystem injuries who otherwise might have been ineligible for organ donation. Use of rFVIIa did not affect early graft function in recipients, although longterm outcomes are unknown. Recombinant factor VIIa is expensive, but its use is justified if the organ donor supply can be increased. Author Contributions Study conception and design: Stein, Dutton, Alexander, Scalea Acquisition of data: Stein, Alexander, Miller Analysis and interpretation of data: Stein, Dutton, Alexander, Miller, Scalea Drafting of manuscript: Stein, Dutton Critical revision: Stein, Dutton, Alexander, Miller, Scalea
REFERENCES 1. Understanding donation: Statistics. Available at: http://www. donatelife.net/UnderstandingDonation/Statistics.php. Accessed June 11, 2008.
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2. Shafer TJ, Wagner D, Chessare J, et al. Donation Breakthrough Collaborative: increasing organ donation through system redesign. Crit Care Nurse 2006;26:35–49. 3. Jenkins DH, Reilly PM, Schwab CW. Improving the approach to organ donation: a review. World J Surg 1999;23:644–649. 4. Salim A, Martin M, Brown C, et al. Complications of brain death: frequency and impact on organ retrieval. Am Surg 2006; 72:377–381. 5. Salim A, Martin M, Brown C, et al. The effect of a protocol of aggressive donor management: implications for the national organ donor shortage. J Trauma 2006;61:429–435. 6. Gore SM, Ross Taylor RM, Wallwork J. Availability of transplantable organs from brain stem donors in intensive care units. BMJ 1991;302:149–153. 7. Deceased donors recovered in the US by cause of death. Available at: http://www.optn.org/latestData/rptData.asp. Accessed June 22, 2008. 8. Cortiana M, Zagara G, Fava S, Seveso M. Coagulation abnormalities in patients with head injury. J Neurosurg 1986;30:133– 138. 9. Valdivia M, Chamorro C, Romera MA, et al. Effect of posttraumatic donor’s disseminated intravascular coagulation in intrathoracic organ donation and transplantation. Transplant Proc 2007;39:2427–2428. 10. Zygun DA, Kortbeek JB, Fick GH, et al. Non-neurologic organ dysfunction in severe traumatic brain injury. Crit Care Med 2005;33:654–660. 11. Hulka F, Mullins R, Frank E. Blunt brain injury activates the coagulation process. Arch Surg 1996;131:923–928. 12. Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care 2004;1:479–488. 13. Power BM, Van Heerden PV. The physiological changes associated with brain death-Current concepts and implications for treatment of the brain dead organ donor. Anaesth Intensive Care 1995;23:26–36. 14. Croezen DH, Van Natta TL. Presentation and outcomes for organ donation in patients with cerebral gunshot wounds. Clin Transplant 2001;15:11–15. 15. Powner DJ, Hartwell EA, Hoots WK. Counteracting the effects of anticoagulants and antiplatelet agents during neurosurgical emergencies. Neurosurgery 2005;57:823–831. 16. Hedner U. Mechanism of action of factor VIIa in the treatment of coagulopathies. Semin Thromb Hemost 2006;32[Suppl]: S77⫺S85. 17. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999; 354:1879. 18. Dutton RP, McCunn M, Hyder M, et al. Factor VIIa for correction of traumatic coagulopathy. J Trauma 2004;57:709–719. 19. Harrison TD, Laskosky J, Jazaeri O, et al. “Low-dose” recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage. J Trauma 2005;59:150–154. 20. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005;59:8–15. 21. Rizoli SB, Nascimento B, Osman F, et al. Recombinant activated coagulation factor VII and bleeding trauma patients. J Trauma 2006;61:1419–1425. 22. Perkins JG, Schreiber MA, Wade CE, Holcomb JB. Early versus late recombinant factor VIIa in combat trauma patients requiring massive transfusion. J Trauma 2007;62:1095–1101.
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23. Sørensen B, Johansen P, Nielsen GL, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coag Fibrin 2003;14:469–477. 24. Roitberg B, Emechebe-Kennedy O, Amin-Hanjani S, et al. Human recombinant factor VII for emergency reversal of coagulopathy in neurosurgical patients: a retrospective comparative study. Neurosurgery 2005;57:832–836. 25. Park P, Fewel ME, Garton HJ, et al. Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients. Neurosurgery 2003;53:34–39. 26. Karadimov D, Binev K, Nachkov Y, Platikanov V. Use of activated recombinant factor VII (Novoseven) during neurosurgery. J Neurosurg Anesthesiol 2003;15:330–332. 27. Yusim Y, Perel A, Berkenstadt H, et al. The use of recombinant factor VIIa (NovoSeven) for treatment of active or impending bleeding in brain injury: broadening the indications. J Clin Anesth 2006;18:545–551. 28. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004;79:1495–5000. 29. Lin J, Hanigan WC, Tarantino M, et al. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg 2003;98:737–740. 30. Brody DL, Aiyagari V, Shackleford AM, Diringer MN. Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocrit Care 2005;2:263–267. 31. Stein DM, Dutton RP, Kramer ME, et al. Recombinant factor VIIa: decreasing time to intervention in coagulopathic patients with severe traumatic brain injury. J Trauma 2008; 64:620–628. 32. Levy JH, Fingerhut A, Brott T, et al. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 2006;46:919–933. 33. Tawil I, Stein DM, Mirvis SE, Scalea TM. Post traumatic cerebral infarction: incidence, outcome, and risk factors. J Trauma 2008;64:849–853. 34. Thomas GO, Dutton RP, Hemlock B, et al. Thromboembolic complications associated with factor VIIa administration. J Trauma 2007;62:564–569. 35. Siegel LJ, Gerigk L, Tuettenberg J, et al. Cerebral sinus thrombosis in a trauma patient after recombinant activated factor VII infusion. Anesthesiology 2004;100:441–443.
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36. O’Connell NM, Perry DJ, Hodgson AJ, et al. Recombinant FVIIa in the management of uncontrolled hemorrhage. Transfusion 2003;43:1711–1716. 37. Brain Trauma Foundation and AANS/CNS Joint Section on Neurotrauma and Critical Care. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2007;24[Suppl]:S1– S106. 38. White CE, Schrank AE, Baskin TW, Holcomb JB. Effects of recombinant activated factor VII in traumatic nonsurgical intracranial hemorrhage. Curr Surg 2006;63:310–317. 39. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777–785. 40. May AK, Young JS, Butler K, et al. Coagulopathy in severe closed head injury: is empiric therapy warranted? Am Surg 1997;63:233–237. 41. Aiyagari V, Menendez JA, Diringer MN. Treatment of severe coagulopathy after gunshot injury to the head using recombinant activated factor VII. J Crit Care 2005;20:176–179. 42. Pavese P, Bonadona A, Beaubien J, et al. FVIIa corrects the coagulopathy of fulminant hepatic failure but may be associated with thrombosis: a report of four cases. Can J Anaesth 2005;52: 26–29. 43. Meijer K, Hendriks HG, De Wolf JT, et al. Recombinant factor VIIa in orthotopic liver transplantation: influence on parameters of coagulation and fibrinolysis. Blood Coagul Fibrinolysis 2003;14:169–174. 44. Dunkley SM, Mackie F. Recombinant factor VIIa used to control massive haemorrhage during renal transplantation surgery; vascular graft remained patent. Hematology 2003;8:263–264. 45. Pugliese F, Ruberto F, Summonti D, et al. Activated recombinant factor VII in orthotopic liver transplantation. Transplant Proc 2007;39:1883–1885. 46. Hendriks HG, Meijer K, de Wolf JT, et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation a pilot study. Transplantation 2001;71:402– 405. 47. De Gasperi, Baudo F, De Carlis L. Recombinant FVII in orthotopic liver transplantation (OLT), a preliminary single-centre experience. Intensive Care Med 2005;31:315–316. 48. Lisman T, Leebeek FW, Meijer K. Recombinant factor VIIa improves clot formation but not fibrolytic potential in patients with cirrhosis and during liver transplantation. Hepatology 2002;35:616–621. 49. Schreiber MA, Holcomb JB, Hedner U, et al. The effect of recombinant factor VIIa on noncoagulopathic pigs with grade V liver injuries. J Am Coll Surg 2003;196:691–697.
donate.2 There have been a number of national and local efforts to improve organ donation rates. In April 2003, the Department of Health and Human Services launched the Organ Donation Breakthrough Collaborative. The goal of the Collaborative is to “dramatically increase access to transplantable organs . . . by spreading known best practices to the nation’s largest hospitals, to achieve organ donation rates of 75% or higher . . . .”2 Many of the efforts of the Collaborative have focused on improvement of referral and conversion rates to improve rates of donation among eligible potential donors. Additionally, there have been efforts to improve organ donation rates with aggressive management of organ donors and reduction in medical failures.3-7 Most of the initiatives that have been instituted have focused on improving processes surrounding referral and consent rates, prompt declaration of brain death, and the aggressive medical care of donors after declaration of brain death. Little attention has been focused on support-
There are nearly 100,000 people waiting for an organ in the US, and an average of 18 people die each day because of the lack of available organs for transplantation.1 Every 12 minutes another name is added to the national organ transplant waiting list, and only about 50% of eligible donors actually Disclosure Information: The following disclosures have been reported by the authors: Drs Stein and Scalea have received research funding from NovoNordisk. Dr Dutton has worked as a paid consultant to NovoNordisk. None of the authors has any financial interest in the company. Abstract presented at 2008 IBIA Seventh World Congress on Brain Injury, Lisbon, Portugal, April 2008. Received July 23, 2008; Revised September 19, 2008; Accepted September 24, 2008. From the R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD (Stein, Dutton, Scalea), and The Living Legacy Foundation, Baltimore, MD (Alexander, Miller). Correspondence address: Deborah M Stein, MD, MPH, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene St, Baltimore, MD 21201. email: [email protected]
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Abbreviations and Acronyms
OPO ⫽ Organ Procurement Organization rFVIIa ⫽ recombinant factor VIIa TBI ⫽ traumatic brain injury
ing neurologically devastated patients long enough to allow for a discussion about donation with the family. Nearly 40% of organ donors are the victims of traumatic injury and devastating neurologic injury.7 Coagulopathy is a frequent finding in patients with severe traumatic brain injury (TBI).8,9 Dilutional coagulopathy from concomitant hemorrhage, preexisting coagulation abnormalities, or preinjury use of anticoagulants can occur in the injured patient. Even in the absence of other factors, coagulopathy can occur as the result of the TBI itself, secondary to release of tissue thromboplastin and abnormalities of fibrinolysis.8,10-12 Many of these injured patients also have substantial concomitant injuries, which can result in cardiac death secondary to hemorrhage and coagulopathy before declaration of brain death is possible. In addition, even in the patient with isolated TBI, marked physiologic derangements and coagulopathy can also lead to cardiac death.13,14 In the patient with devastating neurologic injury who does not progress to brain death but might be a candidate for donation after cardiac death, the same issues can preclude survival until donation. Many clinicians fail to aggressively manage these patients because of the likelihood of death or devastating neurologic outcomes without substantial thought to the potential to save other lives through donation. Concern is raised that perhaps the family will refuse donation or that efforts will be futile at preventing cardiac death and that resources will be wasted with aggressive intervention. Recombinant factor VIIa (rFVIIa; NovoSeven, NovoNordisk) has been used in injured patients on an off-label basis for several years. Approved for use in hemophiliacs with inhibitors and other hematologic disorders,15,16 rFVIIa is commonly used in many hospitals in patients with traumatic hemorrhagic shock and associated coagulopathy and in coagulopathic patients with both traumatic and nontraumatic neurosurgical emergencies.17-30 There have been a number of studies and case series that have reported successful use of rFVIIa in reversing coagulopathy in these patient populations.18,19,22,24,31 At our institution, we use rFVIIa on an off-label basis in coagulopathic patients with severe hemorrhage as an adjunct to surgical hemostasis and in coagulopathic patients with severe TBI. Many of these patients have succumbed to their neurologic injuries and progressed to brain death.
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Other patients in whom rFVIIa has been used have suffered devastating neurologic injury, which has led their families to withdraw care and proceed with donation after cardiac death. There is considerable concern about the potential thrombotic complications of rFVIIa use.32-36 Use in patients whose organs have been transplanted can raise concern about thrombosis in the transplanted organs, leading to graft failure. We sought to evaluate our experience with these patients who had received rFVIIa and went on to successful organ donation.
METHODS After approval by the University of Maryland Institutional Review Board, all deceased organ donors from the R Adams Cowley Shock Trauma Center between January 2002 and December 2007 were identified from the local Organ Procurement Organization (OPO; The Living Legacy Foundation). The medical records of all study subjects were then revieweds and demographics, injury-specific data, laboratory values, administration of rFVIIa, and blood product use were abstracted. Organ donors who received rFVIIa were compared with controls who were treated with conventional therapy alone. Organ-specific recipient outcomes were obtained from the OPO through standardized methods of data collection. Forms with recipient demographics and medical information with both descriptive measures and laboratory values are provided by the recipient’s transplantation coordinator 1 week posttransplantation to the OPO. Student’s and paired t-tests were used to compare differences between continuous variables, and chi-square analysis was used to compare categorical variables. A p value ⬍ 0.05 was considered significant for all statistical tests. At the Shock Trauma Center, rFVIIa is requested by the treating attending surgeon, intensivist, or anesthesiologist. Release by the pharmacy requires approval of an institutional gatekeeper. The gatekeepers monitor usage and recommend dose to be given based on the clinical status of the patient. All patient management before consent for donation was directed by the attending surgeon, intensivist, or anesthesiologist. In patients who did not receive rFVIIa, conventional therapy with reversal of coagulopathy with plasma was used. Substantial hemorrhage was managed in all patients using the principles of “damage control” resuscitation and operation. Management of intracranial hypertension is done according to an institutional protocol for management of severe TBI based on the Brain Trauma Foundation Guidelines.37 Once consent for donation is obtained, management of donors is a collaborative effort of The Living Legacy Foundation and the Shock Trauma Center Critical Care Service.
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Table 1. Baseline Characteristics of All Donors Characteristic
Age (y), mean ⫾ SD ISS, mean ⫾ SD Predicted survival (TRISS), mean ⫾ SD Admission GCS, mean ⫾ SD Admission PT(s), mean ⫾ SD Admission INR, mean ⫾ SD Male, n (%) Blunt injury, n (%)
rFVIIa (n ⴝ 29)
No rFVIIa (n ⴝ 119)
p Value
30.8 ⫾ 15.6 43.4 ⫾ 14.8 0.408 ⫾ 0.31 5.0 ⫾ 3.2 17.9 ⫾ 8.3 1.8 ⫾ 1.13 25 (86.2) 22 (75.9)
34.5 ⫾ 15.7 34.0 ⫾ 13.4 0.422 ⫾ 0.251 4.3 ⫾ 2.7 14.4 ⫾ 3.1 1.2 ⫾ 0.38 92 (77.3) 84 (70.6)
0.257 0.001 0.807 0.238 0.002 ⬍ 0.001 0.293 0.571
GCS, Glasgow Coma Score; INR, International Normalized Ratio; ISS, Injury Severity Score; PT, prothrombin time; rFVIIa, recombinant factor VIIa; TRISS, Trauma and Injury Severity Score.
RESULTS During a 6-year period, there were 148 patients admitted to the R Adams Cowley Shock Trauma Center who went on to become deceased organ donors. All patients had suffered devastating neurologic injury. There were 97 patients who were standard criteria donors, 4 extended criteria donors, and 47 patients who donated organs after cardiac death, for a total of 531 organs transplanted. Of these patients, 29 (19.6%) received rFVIIa and 119 (80.4%) were treated with conventional therapy alone. Baseline characteristics of these groups of patients differed considerably with respect to Injury Severity Score and admission coagulation profiles (Table 1). Use of blood products during hospitalization was considerably higher in the rFVIIa group, as would be expected based on the greater injury severity and extent of coagulopathy in this group (Fig. 1). Of the 29 patients who received rFVIIa, 21 were dosed before determination of nonsurvivability or plans for withdrawal of care. Eight patients were administered rFVIIa as a specific salvage therapy to allow for donation. Mean dose of rFVIIa administered was 44.3 g/kg, with a range of 11.7 to 162.7 g/kg. All 21 patients were coagulopathic at the time of rFVIIa administration, with a mean prothrombin time of 22.6 ⫾ 8.0 seconds (range 15.2 to 49.6) and an International Normalized Ratio of 2.4 ⫾ 1.4 (range 1.5 to 6.8). Indications for rFVIIa administration were active hemorrhage in 13 patients, to allow for neurosurgical intervention in 15, and for reversal of severe coagulopathy in 1 patient. Sources of hemorrhage included the brain and skull in four patients, massive facial bleeding in three, and uncontrolled torso hemorrhage in six patients. Mean prothrombin time was 22.6 ⫾ 8.0 seconds before rFVIIa administration and 13.8 ⫾ 3.4 seconds after (p ⬍ 0.0001). Mean International Normalized Ratio was 2.4 ⫾ 1.4 before rFVIIa administration and 1.1 ⫾ 0.3 after (p ⬍ 0.0001). In the no-rFVIIa group, there were 80 (67.2%) standard criteria donors, 36 (30.2%) donations after cardiac death, and 3 (2.5%) extended criteria donors versus 17 (58.6%),
11 (37.9%), and 1 (3.4%) in the rFVIIa group, respectively. Total number of organs donated by each group was 430 from the 119 conventionally treated patients and 101 from the 29 rFVIIa-treated patients. The number of organs donated per donor was 3.6 in the no-rFVIIa group versus 3.5 in the rFVIIa group (p ⫽ 0.7). The number and percentages of successfully transplanted eligible organs from each group are shown in Table 2. Despite the rFVIIa group having a higher percentage of substantial thoracic injuries (59.3% versus 39.0%; Thorax Abbreviated Injury Scale ⬎ 2; p ⫽ 0.06), there was nearly twice the rate of recovery of donated lungs in the rFVIIa group as compared with the conventionally treated group (p ⫽ 0.04), with no difference in heart donation rates. The rFVIIa group had a significantly higher incidence of abdominal injuries (29.6% versus 4.7%; Abdomen Abbreviated Injury Scale ⬎ 2; p ⫽ 0.0002) and a lower rate of successful liver donation (p ⫽ 0.04), with equivalent kidney, pancreas, and intestine donation rates (Fig. 2). Early recipient organ-specific outcomes data were available for 66% of the organs transplanted. Early recipient outcomes were not different between the 2 groups, with approximately 80% of recipients experiencing good or fair outcomes (Fig. 3).
Figure 1. Mean number of units of blood products administered to donors given recombinant factor VIIa (rFVIIa) compared with those treated with conventional therapy alone. White bar, no rFVIIa; black bar, rFVIIa. All differences p ⬍ 0.05.
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Table 2. Percentage of Eligible Organs Transplanted Heart Group
rFVIIa No rFVIIa
n
SCD
DCD
ECD
n
%
n
Lung %
n
Liver %
Pancreas n %
Intestine n %
29 119
17 80
11 36
1 3
9 45
56 56
15 42
47 26
19 99
65 83
11 52
1 1
39 43
6 1
Kidney n %
43 192
74 81
DCD, donation after cardiac death; ECD, extended criteria donors; rFVIIa, recombinant factor VIIa; SCD, standard criteria donors.
DISCUSSION The national shortage of organ donors and organs available for transplantation is a major public health problem. Hundreds of patients per year in the US die from organ failure while waiting for an organ. Organ donation also is an important part of end-of-life care for many patients and families. Many victims of fatal traumatic injuries are not candidates for organ donation, because of unplanned cardiac death before donation. Allowing patients with fatal or nonrecoverable injuries to survive to donation has received little focus in the literature. In the series of patients reported here, successful donation of 101 organs was achieved with adjunctive use of rFVIIa in patients with severe multisystem trauma who otherwise might not have survived to donation. Patients treated with rFVIIa had substantially greater injury severity and physiologic compromise but were able to donate organs at rates comparable to conventionally treated donors. Despite a higher incidence of severe thoracic trauma in the rFVIIa-treated donors, lung donation rates were nearly double what they were in conventionally treated patients. Not surprisingly, liver donation rates were lower in the rFVIIa group, because of a much higher incidence of abdominal injuries. Coagulopathy is common in the patient with severe injury and TBI. In addition, these fatally injured patients often have concomitant injuries, causing severe hemorrhage. Coagulation abnormalities can occur as a direct result of the brain injury itself and dilution of factors.8,10-12 Coagulopathy in these patients is most commonly reversed with the use of plasma. Correction of coagulopathy and the
attenuation of hemorrhage with plasma alone might not be successful for a variety of reasons. Recombinant factor VIIa has been used off-label as an adjunctive therapy in the bleeding trauma patient for several years.18-22 Numerous reports in the literature describe successful use of rFVIIa for both traumatic and nontraumatic neurosurgical emergencies.25-27,38-40 In our series reported here, rFVIIa used as an adjunctive therapy was uniformly successful in correcting coagulopathy as measured by coagulation profiles. There is a single case report in the literature that describes the use of rFVIIa in three patients with nonsurvivable brain injury secondary to gunshot wounds to the head.41 Two of the patients in that report went on to organ donation. A substantial concern about use of rFVIIa is the issue of cost. Recombinant factor VIIa is expensive, with a single large weight-based dose costing nearly US $10,000. Per policy, the OPO pays for all hospital expenses from the time of consent/brain death declaration through the organ recovery procedure. If rFVIIa is used during this time frame, the OPO would bear the cost. If rFVIIa is used during the initial resuscitation as part of usual clinical practice before consent, the patient or the patient’s insurance company would be the payor. For the eight patients pre-
Figure 2. Percentage of eligible organs transplanted from donors given recombinant factor VIIa (rFVIIa) compared with those not given recombinant factor VIIa. White bar, no rFVIIa; black bar, rFVIIa. Star, p ⬍ 0.05; all other differences not significant.
Figure 3. Early organ function results for organs transplanted from donors given recombinant factor VIIa (rFVIIa) compared with those treated with conventional therapy alone. White bar, no rFVIIa; black bar, rFVIIa. All differences not significant.
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sented here who received rFVIIa as a specific therapy to allow for survival to donation, the timing of administration determined who paid. If rFVIIa allows for an increase in organ donor supply, the public health benefit might outweigh the individual cost. Additional discussion of who should bear the cost in patients in whom rFVIIa is used as a pure salvage therapy before declaration of brain death or consent for donation is obtained is clearly warranted. Thromboembolic events have been reported in patients who have received rFVIIa.33,39,42 These concerns could be extrapolated to a risk of thrombosis in organs from donors who have received rFVIIa. Several recent studies have described the use of rFVIIa in patients undergoing transplantation without an increased risk of thrombotic complications.43-48 Additionally, animal studies have demonstrated no evidence of microvascular thrombosis in the lung tissue of treated animals.49 In this current study, recipient outcomes were equivalent in organs recovered from donors who received rFVIIa and those who did not. This indicates that rFVIIa does not increase risk of vascular thrombosis in donated organs. There are obviously limitations to this study. First, the retrospective design only allows for identification of associations and not determination of cause and effect. The study design also limited the amount of clinical information that could be compared between the two groups, because of the use of medical records, consistency of documented information, and availability of recipient outcomes data. Despite its limitations, this study demonstrates that in patients with severe injury, use of rFVIIa facilitated donation in patients with multisystem injuries who otherwise might have been ineligible for organ donation. Use of rFVIIa did not affect early graft function in recipients, although longterm outcomes are unknown. Recombinant factor VIIa is expensive, but its use is justified if the organ donor supply can be increased. Author Contributions Study conception and design: Stein, Dutton, Alexander, Scalea Acquisition of data: Stein, Alexander, Miller Analysis and interpretation of data: Stein, Dutton, Alexander, Miller, Scalea Drafting of manuscript: Stein, Dutton Critical revision: Stein, Dutton, Alexander, Miller, Scalea
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