TITLE: Levothyroxine for Solid Organ Donors: A Review of the Clinical-Effectiveness and Guidelines DATE: 20 May 2009 CONTEXT AND POLICY ISSUES: Organ transplantation is a life-saving treatment for patients with end-stage cardiac, pulmonary, renal, hepatic, or endocrine failure. 1 Most organs come from donors who die in the intensive care unit after being declared brain dead. 2 Many patients with end-stage organ failure will not get a transplant because the number of indications for transplant and potential recipients have increased, but the number of available organs has not increased sufficiently. 1,2 In 2001, there were 420 deceased organ donors in Canada, for a rate of 13.5 donors per million population. Seventy-seven per cent of them provided more than one organ or tissue. Currently, more than 4,000 patients are waiting for a transplant. In 2008, 1,803 transplants occurred and 195 persons died while waiting. 3 During the development of brain death, electrocardiographic, hemodynamic, and histopathological changes occur, with subsequent depletion of circulating hormones and deterioration of organ function. 4 These changes occur in up to 85% of donors and may affect the quality of the donor organ and success of transplant. 4 Aggressive donor management strategies are required to preserve donor organ function. The use of hormonal therapy in potential donors, including thyroxine, corticosteroids, vasopressin and insulin, is one strategy that may improve organ viability and function post-transplantation. 4 There are arguments for using aggressive therapy in hemodynamic unstable donors only (approximately 80% of donors are unstable 5 ), or using aggressive therapy in all donors. 5,6 Studies on the use of thyroxine in hemodynamic stable organ donors have produced conflicting results. 2,4 One group reports that hypothyroidism has a protective effect against liver damage in rats, and although this data can not be directly applied to humans, it may be possible that the administration of thyroxine could damage human liver tissue during harvesting. 7 Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
A United Network for Organ Sharing (UNOS) retrospective cohort study using consecutive records of 10,292 brain-dead donors provides evidence that triple hormone therapy has benefit (i.e., improved one-month survival and lower early graft dysfunction) with minimal risk compared to not using triple therapy. 8 The Canadian guidelines on organ donor management 9 endorse the use of combined hormonal therapy which includes, in adults: tetraiodothyronine (levothyroxine; L-thyroxine; T 4 ) 20 µg intravenous bolus followed by 10 µg/ hour by intravenous infusion; vasopressin 1 unit intravenous bolus followed by 2.4 units/ hour by intravenous infusion; and methylprednisolone 15 mg/ kg ( 1 g) intravenously every 24 hours. Yet, the same guidelines identify gaps in research: 1) There is a need to study orally and intravenously administered T 4 and tri-iodothyronine (T 3 ) in humans to determine the kinetics, biological effects, optimum dosing, peripheral conversion times, and effect of corticosteroids; 2) There is a need for studies to determine whether or not combined hormonal therapy improves hemodynamics, organ function, and organ utilization. This report reviews the evidence for the use of levothyroxine in combination with vasopressin and methylprednisolone administered to solid organ donors: whether or not the combined hormonal therapy improves graft survival in the recipient; whether or not similar outcomes are obtained if levothyroxine is not used; and whether or not levothyroxine should be given as a bolus or as an infusion. RESEARCH QUESTIONS: 1. What are the clinical benefits and harms of levothyroxine used in combination with vasopressin and methylprednisolone administered to solid organ donors to increase the number of viable organs? 2. What are the guidelines for dosing and administering levothyroxine when used in combination with vasopressin and methylprednisolone in solid organ donors? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, the Cochrane Library (Issue 2, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between 2004 and April 2009. No filters were applied to limit the retrieval by study type. Internet links were provided, where available. HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials, controlled clinical trials, observational studies, and evidence-based guidelines. SUMMARY OF FINDINGS: There were no health technology assessments, systematic reviews, or meta-analyses identified on the clinical benefits and harm of levothyroxine used in combination with vasopressin and methylprednisolone. Levothyroxine for Solid Organ Donors 2
Randomized controlled trials No randomized controlled trials (RCT) were identified. However, a randomized, double-blind, placebo controlled phase 1/ phase 2 trial is underway at the London Health Sciences Centre in London, Ontario to determine the efficacy and pharmacokinetics of oral thyroid therapy in organ donors. 10 Specifically, this trial compares the pharmacokinetics and the reversibility of hemodynamic instability in organ donors of oral versus intravenous administration of thyroid hormone (T 3 and T 4 ). The primary outcome is the percentage of time patients require inotropic support prior to organ procurement. Secondary outcomes include the pharmacokinetic profiles of oral versus intravenous T 3 and T 4, the number of organs donated, and thyroid function at time of brain death. Observational studies Three retrospective cohort studies were retrieved and study details can be found in Appendix 1. Van Bakel et al. reviewed 119 consecutive donor records. 11 The donors were divided into three groups: a hormonal group receiving thyroxine (T 4 ), methylprednisolone, dextrose and insulin, a steroid group receiving methylprednisolone only, and a control group without hormonal or corticosteroid therapies. There was no statistical difference between the three groups for vasopressin use, for pulmonary capillary wedge pressure, and for the number of organs procured. Both the hormonal group and the steroid groups required less α- and β-adrenergic support (i.e., dopamine, phenylephrine, dobutamine etc.) compared to the control group, but only the hormonal group reached statistical significance (see Appendix 1). Adrenergic agents are required to support blood pressure; however in high doses, they can cause injuries to organs intended for transplantation. The authors concluded that a reduction in adrenergic use confirms the hemodynamic benefits of hormonal therapy. Two studies were conducted by Salim et al. 5,12 using database records. One study evaluated aggressive donor management (ADM) as a strategy to decrease the number of donors lost due to cardiovascular collapse (CVC). 12 The ADM protocol consisted of: 1) early identification of potential donors; 2) ICU admission with management by a dedicated team; and 3) early and aggressive resuscitation with fluids, vasopressors (agents not specified), and hormonal therapy (1 ampoule of 50% dextrose, 2 g methylprednisolone, 20 units of regular insulin, and 20 µg of levothyroxine followed by an intravenous infusion of 10 µg/h) before the declaration of brain death and before consent for donation. Three groups were compared: one centre that began using the ADM protocol in 1999 (LAC-post, n=341); the same centre before it began using the ADM protocol between 1995 and 1998 (LAC-pre, n=694); and eight other centres that served as the control group (Centre A, n=2,915). Results are reported in Appendix 1. The incidence of CVC per potential donor was statistically significantly less in the group after ADM was instituted compared to the group before ADM and compared to the control group. Similarly, more organs were harvested per potential donors with the ADM protocol. The number of organs recovered per actual donor was less with ADM compared to the other two groups, but it was not reported if this was statistically significant. Salim et al. used ANOVA to test for overall differences between the three groups, but the overall p value was not reported. In the methods section of their report, it was unclear what type of post-hoc test was used. It would appear that Student s t-test was used for pairwise comparisons. Using the records of patients who donated organs, the same authors compared patients who received levothyroxine (T 4 ) to those who did not. 5 Of 123 patients, 96 (78%) received T 4. This group required vasopressor therapy (indicating a more hemodynamically unstable population) Levothyroxine for Solid Organ Donors 3
whereas donors that did not get T 4 had no or minimal vasopressor requirement. The T 4 group had significantly more organs procured per donor compared to the group that did not get T 4. A sub-group analysis of donors who died with traumatic head injuries revealed no differences in the number of organs donated per patient when comparing those who received T 4 and those who did not. Conversely, in the group with non-traumatic head injuries, there was a statistical difference in favor of the T 4 group for the number of organs donated compared to the group who did not receive T 4. There was no difference in the type of organ recovered or in brain-death associated complications with or without T 4. The authors concluded that the addition of T 4 in hemodynamically unstable donors yielded significantly more organs donated per patient compared with a group of hemodynamically stable donors. Limitations No high quality evidence from health technology assessments, systematic reviews, metaanalyses, or randomized controlled trials was indentified. The statistical significance reported in one observational study is invalid because of the use of erroneous statistical methods and should not be considered. 12 A student s t-test was used to compare the three groups, which is inappropriate. The other two cohort studies had sample sizes of 119 patients and 123 and were based on retrospective records obtained between 2000 and 2005. Cohort studies may be subject to selection bias. The studies did not account for potential confounders. This review is limited in that it only considered studies published since 2004 and in English. Guidelines on dosage and dosage form Regarding dosage, no studies were found that evaluated the optimal dosing regimen of levothyroxine when used in combination with methylprednisolone and vasopressin. Regarding the route of administration, no studies on the stability of levothyroxine sodium in intravenous solutions were retrieved. In Canada, levothyroxine sodium is indicated for thyroid replacement or supplemental therapy in patients suffering from hypothyroidism. 13 It is available in a tablet form for oral use (Synthroid, Eltroxin ) and in a powder form for intravenous or intramuscular injection (Levothyroxine Sodium for Injection). The powder form contains special buffers that permits reconstitution with 5 ml of normal saline. 13 Once reconstituted, stability tests have shown that levothyroxine is stable for up to 48 hours, if retained in its original vial. 14 Otherwise, levothyroxine is hydrophobic and adsorbs to glass and plastic containers and tubings. The extent of adsorption is not known but is believed to be significant. Furthermore, it is poorly soluble at the ph of many intravenous solutions and undergoes rapid degradation in aqueous solutions. Storage of such solutions is not recommended for more than two hours, after which significant loss of potency occurs. The administration of levothyroxine as an intravenous piggyback is not recommended. 14 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: The studies identified focused on the organ donors. They did not consider clinical outcomes in the transplanted patients such as improved graft survival in the short- and long-term. One retrospective cohort study showed no difference in the number of organs procured between a donor group receiving combination hormonal therapy, a steroid group, and a control group. Another retrospective cohort study showed a statistically significant increase in the number of organs donated with the use of levothyroxine. One on-going RCT will determine the efficacy and pharmacokinetics of thyroid replacement therapy in organ donors. Whether or not levothyroxine is stable in mini-bags and can be administered as an infusion has not been studied. Similarly, Levothyroxine for Solid Organ Donors 4
no information was identified on what constitutes the optimal dosing regimen of levothyroxine combined with methylprednisolone and vasopressin. Considerations for decision-making about use of levothyroxine for solid organ donors include the lack of high-quality evidence from systematic reviews or randomized controlled trials, and the paucity of information on clinical benefit and harms to the donor or recipient. PREPARED BY: Christine Perras, BSc Phm MPH, Research Officer Michelle Clark, BSc, Research Assistant Emmanuel Nkansah, BEng, MLS, MA, Information Specialist Health Technology Inquiry Service Email: htis@cadth.ca Tel: 1-866-898-8439 Levothyroxine for Solid Organ Donors 5
REFERENCES: 1. Salim A, Vassiliu P, Velmahos GC, Sava J, Murray JA, Belzberg H, et al. The role of thyroid hormone administration in potential organ donors. Arch Surg 2001;136(12):1377-80. 2. Mascia L, Mastromauro I, Viberti S, Vincenzi M, Zanello M. Management to optimize organ procurement in brain dead donors. Minerva Anestesiol 2009;75(3):125-33. 3. Organ and tissue donation. In: Transplant.ca [web site]. Ottawa: Canadian Association of Transplantation; 2009. Available: www.transplant.ca/pubinfo_orgtiss.htm (accessed 2009 May 11). 4. Phongsamran PV. Critical care pharmacy in donor management. Prog Transplant 2004;14(2):105-11. Available: http://www.natco1.org/members/progress_articles/june2004cearticle.pdf. 5. Salim A, Martin M, Brown C, Inaba K, Roth B, Hadjizacharia P, et al. Using thyroid hormone in brain-dead donors to maximize the number of organs available for transplantation. Clin Transplant 2007;21(3):405-9. 6. Cooper DKC. Hormonal resuscitation therapy in the management of the brain-dead potential organ donor. International Journal of Surgery 2008;6(1):3-4. 7. Imberti R, Vairetti M. Thyroid hormone therapy in organ donors [letter]. CMAJ 2007;176(12):1737. Available: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1877844&blobtype=pdf (accessed 2009 Apr 27). 8. Rosendale JD, Kauffman HM, McBride MA, Chabalewski FL, Zaroff JG, Garrity ER, et al. Hormonal resuscitation yields more transplanted hearts, with improved early function. Transplantation 2003;75(8):1336-41. 9. Shemie SD, Ross H, Pagliarello J, Baker AJ, Greig PD, Brand T, et al. Organ donor management in Canada: recommendations of the forum on Medical Management to Optimize Donor Organ Potential. CMAJ 2006;174(6):S13-S32. Available: http://www.cmaj.ca/cgi/content/full/174/6/s13. 10. Thyroxine replacement in organ donors. In: DrugLib.com [web site]. Brooklyn (NY): DrugLib.com; 2009. Available: http://www.druglib.com/trial/30/nct00238030.html (accessed 2009 May 11). 11. Van Bakel AB, Pitzer S, Drake P, Kay NA, Stroud M, Sade RM. Early hormonal therapy stabilizes hemodynamics during donor procurement. Transplant Proc 2004;36(9):2573-8. 12. Salim A, Martin M, Brown C, Rhee P, Demetriades D, Belzberg H. The effect of a protocol of aggressive donor management: Implications for the national organ donor shortage. Journal of Trauma - Injury, Infection and Critical Care 2006;61(2):429-32. Levothyroxine for Solid Organ Donors 6
13. Levothyroxine Sodium for injection. In: Compendium of pharmaceuticals and specialties(cps) [database online]. Ottawa: Canadian Pharmaceutical Association; 2009 (accessed 2009 May 11). 14. Levothyroxine. In: DRUGDEX Evaluations [database online]. New York: Micromedex Healthcare Series. Thomson Reuters; 2009 (accessed 2009 May 11). Levothyroxine for Solid Organ Donors 7
Appendix 1: Summary of Retrospective Cohort Studies on the Clinical-Effectiveness of Levothyroxine in Solid Organ Donors Author Study design Interventions Outcomes Results Van Bakel 2004 11 n=119 consecutive donor records July 2000 to October 2001 (15 months) control group n=64 no hormonal therapy or corticosteroids vs. steroid group n=19 methylprednisolone 1 to 2 g IV at start of donor management vs. combination group n=36 T 4 20 µg bolus then 10 µg/ h IV, methylprednisolone 2 g IV, 50% dextrose 25 g IV, and regular insulin 20 units IV at start of donor management vasopressin use pulmonary capillary wedge pressure (PCWP) α- and β-adrenergic support (dopamine, phenylephrine, or combination of various agents) no statistical differences between the 3 groups for vasopressin use (p=0.58) no statistical differences between the 3 groups in PCWP at any time point (p=0.945) greater decrease in the use of adrenergic support in the combination group compared to the control group (p=0.02 for α-adrenergic drugs and p=0.002 for β-adrenergic drugs) number of organs procured no difference in the number of organs procured between the 3 groups (p=0.6) Levothyroxine for Solid Organ Donors 8
Author Study design Interventions Outcomes Results Salim 2006 12 database records from the Southern California regional organ procurement organization of patients admitted to Level 1 trauma teaching centres # referrals for donation incidence of cardiovascular collapse (CVC) conversion rates LAC-pre=341 Centre A=694 LAC-post=2,915 1995 to 2003 aggressive donor management (ADM): early identification of potential donors; ICU admission with management by a dedicated team; early and aggressive resuscitation with fluids, vasopressors, and hormone therapy (1 ampoule of 50% dextrose, 2 g methylprednisolone, 20 units of regular insulin, and 20 µg of levothyroxine then 10 µg/h IV) before consent for donation (n=1 centre using data from 1999 to 2003 and referred to as LAC-post) vs. no ADM (n=9 centres; includes 8 centres referred to as Centre A and 1 centre using data from 1995 to 1998 referred to as LAC-pre) number of organs harvested per potential donor number of organs recovered per actual donor LAC-pre=19.63%, p<0.001 Centre A=8.67%, p<0.0001 LAC-post=1.60% LAC-pre=26.6% Centre A=41.2% LAC-post=41.4% (statistical significance not reported) LAC-pre=2.07, p=0.02 Centre A=2.09, p<0.01 LAC-post=2.41 LAC-pre=3.81 Centre A=3.89 LAC-post=3.55 (statistical significance not reported) CAUTION: please consider absolute numbers only and not statistical significance Levothyroxine for Solid Organ Donors 9
Author Study design Interventions Outcomes Results Salim 2007 5 n=123 all patients received ADM* T 4 use T 4 used in 78% (n=96) of with or without T 4 donors records of patients who successfully donated organs sub-group analysis: trauma (n=97) vs. no trauma patients number of organs donated per donor T 4 group: 3.9±1.7 no T 4 group: 3.2±1.7, p=0.048 trauma: no difference between T 4 group vs. no T 4 group non-trauma: T 4 group: 3.0±1.7 no T 4 group: 1.7±1.3, p=0.052 2001 to 2005 type of organ donated brain-death associated complications no difference in the type of organ recovered except for pancreas: T 4 group: 46% no T 4 group: 5%, p=0.01 no difference between those with or without T 4 in either the trauma and non-trauma groups * ADM included pulmonary artery catheterization; aggressive IV fluid resuscitation; vasopressor infusion for mean arterial pressure <70 mmhg; hormonal therapy was used when the combined vasopressor need exceeded 10 µg/kg/min of epinephrine, dopamine, or their combination; hormonal therapy consisted of one ampoule of 50% dextrose, 2 g methylprednisolone, 20 units of regular insulin, and 20 µg of levothyroxine sodium (T 4 ) followed by 10 µg/ h IV infusion 5 ADM=aggressive donor management; ICU=intensive care unit; IV=intravenous Levothyroxine for Solid Organ Donors 10