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Management of the Potential Organ Donor Kenneth E. Wood, D.O. Professor of Medicine and Anesthesiology Senior Director of Medical Affairs Director of Critical Care Medicine and Respiratory Care The Trauma and Life Support Center University of Wisconsin Hospital and Clinics Disclaimer No Financial Support Slides Available by Request [email protected] Maximal Utilization and Optimal Management of Potential Organ Donors • Surveillance to identify patients with severe neurologic injury likely to progress to brain death • Standardized method for brain death declaration • Uniform request for consent • Optimal medical management of donor Optimal Medical Management of the Potential Organ Donor • Continued intensity of support • Focus shift from cerebral protective strategies to optimizing donor organs for transplantation • Simultaneous critical care to organs of multiple patients • Critical period • Facilitates donor somatic survival • Maintains organs to be procured best condition • Donor management impact recipient function Role of Clinical Care Team in Donation • Donor Medical Management = Critical Care Management • Integrative multi-disciplinary collaborative approach between OPO and Clinical Care Team •Intensivists •Pulmonary Consultants •Cardiac Consultants •Nursing •Respiratory •Hemodynamics •Ventilatory Management •Echocardiography •Diagnostic Procedures • Donor Management Team/Defined Champions • Donor Family Support Cardiac Transplant Continuum Mechanism •Catecholamine Hypothesis NEURO INJURY Approach •Standard •Autonomic Surge •Endocrinopathy •MVO2 supply demand imbalance • Coronary perfusion •Aerobic Anerobic BRAIN DEATH •Pretreatment ? •Sympathetic antagonists •Calcium blockers •Cardiac sympathectomy DONOR •Fluids •Immunomodulators catecholamines •Vasopressin •Thyroid hormone •Steroids •Insulin Improvement of Donor Myocardial Function After Treatment of Autonomic Surge During Brain Death •Defined by Systolic BP > 200 mmkg •AS less with head injury and tachycardia > 140 beats/min. •Treated with esmolol, urapidil •Observed in 63% or nicardipine •Duration 1.2 hours (30 min-6hr) •Followed by BP which never occurred when AS absent •Treatment independently associated with EF > 50% Audibert Transplantation 2006;82:1031-1036 Complications of Brain Death and Impact on Organ Retrieval “…hypothesized that brain death related complications would have no effect on the number of organs donated if an aggressive donor management protocol was in place.” •Vasopressor requirement 97.1% •Cardiac ischemia 30.4% •Coagulopathy 55.1% •Lactic acidosis 24.6% •Thrombocytopenia 53.6% •Renal failure 20.3% •Diabetes Insipidus 46.4% •ARDS 13% Salim Am Surgeon 2006;72:377-381 Aggressive Donor Management and Organ Donor Shortage Salim 2006;61:429-435 Transforming Unacceptable Donors Potential Multi-organ Donors (150) Acceptable 65% (98) Unacceptable 35% (52) • • • • • • • • • • 40% (21) MAP < 55 (mean 47 mmHg) despite inotropic support 19% (10) CVP > 15 (mean 18 mmHg) 4% (2) inotropes > 20 (mean 25 ug/Kg/min) 25% (13) PCWP > 15 (mean 20 mmHg) 12% (6) LVSWI < 15 (mean 12.8 gm) Outcomes Optimum Management • • • • • Invasive monitoring Bolus steroids (15mg/Kg/MP) Insulin/glucose Argine vasopressin 1U bolus and 1.5 U/hr Tri-iodothyronine 4 ug bolus and 3 ug/hr MAP > 60 mmHg CVP < 12 mmHg PCWP < 12 mmHg LVSWI > 15 gm Inotropes < 5 ug/Kg/mm • • • 44/52 “unacceptable” donors yielded transplantable organs 84% alive (13-48 months) 92% of initially unacceptable organs were capable of functional resuscitation Wheeldon J Heart Lung Txp 1995; 14:734-742 Donor Management Trial Hormonal Therapy Randomization T3 0.8 ug/Kg Bolus Followed by 0.113 μg/Kg/hr T3 And Methylprednisolone Methylprednisolone 1000 mg Bolus Placebo Venkateswaran Eur Heart J 2009 Hemodynamic Effects ofMarginal Adjunctive Hormonal•MAP Therapy < 70 mmHg Functional •CVP < 12 mmHg •PCWP < 14 mm Hg Brain Stem Death (80) with • Trauma•CVP 24%or PCWP > 14 mmHg •CI > 2.5 L/min • Vascular event/tumor 64% and •Minimal vasoactive • Hypoxia/Infection 13% support •CI < 2.4 L/min Management •No gross LVH or palpable Brain Death OR Consent Management HRT Retrieval Coning CAD on inspection •Dopamine > 5 μg/Kg/min or 10.7 hrs 2 hrs 1 hr 5.9 hrs •Norepi > 0.06 μg/Kg/min 12.7 hrs or 19.6 hrs 6.9 hrs •Epi > 0.03 Venkateswaran μg/Kg/minEur Heart J 2009 Hemodynamic Parameters for Entire Trial Cohort Venkateswaran Eur Heart J 2009 Cardiac Index and Treatment Venkateswaran Eur Heart J 2009 Donor Heart Function and Thyroid Function • • • • 58% Low free T3 or T4 18% co-existent low TSH Initial CI no different with low T3 or T4 CI ↑ regardless of initial T3 or T4 or T3 Tx Venkateswaran Eur Heart J 2009 Cardiac Index and Pre-Tx Thyroid Venkateswaran Eur Heart J 2009 Donor Heart Function and Norepinephrine • Association between NE withdrawal and cardiac functional improvement • 60% (48/80) initially receiving NE • Significantly lower LVSWI (43.5 vs 36.6) • Vasopressin introduced 60/80 → NE withdrawn in 26/48 or reduced to 0.06 μg/Kg/min CI SVR Norepi Vasopressin 3.18 1190 3.72 964 Venkateswaran Eur Heart J 2009 Hemodynamic Effects of Adjunctive Hormone Therapy Trial Donors (80) 50% Non-Marginal at Initial Assess (40) 35% Unsuitable at End Assessment (14) •CAD (5) •RV Dysfunction (5) •LV Dysfunction (4) 50% Marginal at Initial Assess (40) 65% Suitable at End Assessment (26) 35% Suitable at End Assessment (14) 58% Retrieved for TXP (15) 71% Retrieved for TXP (10) 65% Unsuitable at End Assessment (26) •CAD (15) •RV Dysfunction (6) •LV Dysfunction (5) Total Suitable at End Assessment (40) 63% Hearts Txp (25) Venkateswaran Eur Heart J 2009 37% Non-Txp (15) •No Recipient (10) •Age > 60 (3) •Poor Donor Txp (2) Donor Management “Active donor management improves circulatory function and has the capacity to increase the yield of suitable hearts from the existing pool of potential donors. Neither T3 nor MP, alone or in combination, appears fundamental to this improvement.” Venkateswaran Eur Heart J 2009 Donor Management “Our study demonstrates that not only may donor circulatory status be improved by active management but also there is the potential to increase the yield of transplantable hearts if decisions on organ acceptance are deferred until a period of resuscitation and assessment is complete. Active donor management with PAFC monitoring is the cornerstone of this objective but this has implications for planning donor retrieval services. The simple introduction of hormone therapy is not a substitute for the detailed haemodynamic assessment and management of the potential heart donor.” Venkateswaran Eur Heart J 2009 Role of Brain Death in Donor Lung Injury Neurogenic Pulmonary Edema • “Blast Injury Theory” → Hemodynamic mechanism • Sympathetic surge Left ↑ SVR ↓CO ↑LAP Right ↑ Pvc ↑ VR ↑PAP ↑Pul Volume • Transient massive ↑ hydrostatic pressure with structural damage to capillary endothelium • Sympathetic alteration of capillary permeability Inflammatory Response • Cytokines → TNF IL-1 activate endothelial cells to express adhesion molecules and mediate production of IL-8 → neutrophil activator → bind to endothelial cells → migrate to interstitium/alveolar spaces → release ROS and proteolytic enzymes Alvonitis Trasnaplantation 2003; 75:1928-1933 Potential Lung Donor Ideal Lungs • • • • • • PaO2/FiO2 > 300 PEEP = 5cmH2O Clear chest x-ray Age < 55 Tobacco < 20 pk/yr Absence of trauma, surgery, aspiration, secretions, malignancy purulent secretions “Marginal” Lungs Unacceptable Lungs Baseline Status Acquired reversible Atelactasis Alveolar Flooding Aspiration Impact of Donor Management Protocol on Lung Donation and Recipient Outcomes Education • Transplant Pulmonologists and OPO staff training sessions on Donor selection and management • Emphasis upon every donor as a lung donor • Request and consent should be attempted for every donor • Education regarding donor management strategies Angel AJRCCM 2006;174:710-716 Impact of Donor Management Protocol on Lung Donation and Recipient Outcomes Active Management • Recruitment Maneuvers • Pressure control ventilation 25 cm H2O and PEEP 15 cm H2O for 2 hours • Switch to conventional volume control mode with TV 10 ml/kg and PEEP 5 cm H2O • Fluid balance • Minimized use of crystalloids • Diuretics to maintain neutral or negative balance • Aspiration risk • Elevated head of bed to 300 • Inflate ET balloon to 25 cm H2O • Bronchosopy with BAL to eval CXR area of infiltrate Angel AJRCCM 2006;174:710-716 Impact of Donor Management Protocol on Lung Donation and Recipient Outcomes Absolute • PaO2/FIO2 > 300 • No infiltrates • No copious purulent secretions • No bronchoscopically demonstrated aspiration •Ideal •All absolute criteria •No extended criteria •Extended •All absolute criteria •One or more extended criteria •Poor •Did not satisfy ALL absolute criteria Extended • Age > 55 years • Pack years > 20 • History of pulmonary disease • Severe chest trauma • Mechanical ventilation > 4 days • Positive gram stain of tracheal or BAL fluids Poor Poor Ideal Extended Angel AJRCCM 2006;174:710-716 Impact of Donor Management Protocol on Lung Donation and Recipient Outcomes Angel AJRCCM 2006;174:710-716 Impact of Donor Management Protocol on Lung Donation and Recipient Outcomes Angel AJRCCM 2006;174:710-716 Early Donor Management Increases Retrieval Rate of Lung for TXP TRIAL Timing NON - TRIAL Within 2 hrs Consent Continued for 6.9 hrs OR Active management using protocols by on site team Standard ICU approach Pul Art. Cath 2 hours post consent OR Fem – A Line 2 hours post consent OR EVLWI Measured None PVPI Calculated None Early OR 1 hour into management OR Protocol optimization for vent/hemodynamics Bronchoscopy Trial Meds Venkateswaran Ann Thorac Surg 2008; 85: 278-86 Early Donor Management Increases Retrieval Rate of Lungs for TXP Management Points • Commenced Management • 2 hours post consent • 12.5 hours post brain death and continued for 6.9 hours • Respiratory Management • Bronchoscopy early • TV 10 ml/Kg PEEP 5 cm H2O • Frequent Suctioning • Volume recruitment by turning every 2 hours • Active hemodynamic management • Specific algorithms for • CI > 2.5 L/min m2 • CVP and PCWP < 12 mm Hg • MAP 65-85 • SVR 800-1200 dynes/cm/sec-5 → vasopressin • Fluid Resuscitation • Small amount blood (Hgb > 10 g/dl), gelatin or colloid • 376 ml of colloid /27 ml crystaloid Venkateswaran Ann Thorac Surg 2008; 85: 278-86 Early Donor Management Increases Retrieval Rates of Lungs for TXP Management Outcomes • Respiratory function – deteriorated • ↓ PaO2/FIO2 • ↑ EVLWI and PVPI • PaO2/FIO2 rose after final inspection • Bronchoscopy • Abnormalities in 20 donors • BAL positive cultures in 31 donors • Methylprednisolone • No effect on any absolute indicator • Associated with reduced accumulation of EVLWI and lower preretrieval PCWP • Did not improve EVLWI in marginal • Norepinephrine → PaO2 / FIO2 ratio deteriorated and EVLWI increased significantly NOT prevented by withdrawal of NE Venkateswaran Ann Thorac Surg 2008; 85: 278-86 Early Donor Management Increases Retrieval Rate for Lungs for TXP Potential Lung Donors (182) Non Trial Lungs (244) Trial Lungs (120) T3 (34) Placebo (28) Non-MP Lungs (62) 35.5% Lungs Retrieval (22/62) 27% Lungs Transplanted (66/244) MP(30) T3 + MP(28) MP Donors (58) 44.8% Lungs Retrieval (26/58) 40% Lungs Transplanted (48/120) Venkateswaran Ann Thorac Surg 2008; 85: 278-86 Early Donor Management “Although nontrial donor care was based on a similar management protocol, albeit without bronchoscopy or invasive monitoring, management was overseen by donor procurement coordinators, who are simultaneously engaged in a logistic process that includes acquisition of consent, donor family support, offering of organs to recipient centers, arranging the multiorgan retrieval procedure, and transportation of organs and tissue. In contrast, the donor research fellow was wholly dedicated to donor management, and we would suggest that this dedicated donor management role is fundamental to maximize yield.” Venkateswaran Ann Thorac Surg 2008; 85: 278-86 3.75 OPD Subtle Changes or Paradigm Shift? Joseph Kambe, M.D. Improving What We Do. There are short term goals and long term goals. 3.75 Organs per Donor is a short term goal. Multiple hospitals have shown this is attainable. In reality, by paying attention to detail. Why it happened is not so clear. Improved because we were looking? Is it sustainable across multiple institutions? Donor Management Goals If all are met, great results. If only some are met, variable results. As an example: CVP and C.O. (BP). If you met the CVP goal and not use pressors. Does this mean you did something useful? Or does it mean that the cardio/pulmonary axis was intrinsically good anyway? Or both? How Useful is a CVP? What affects the CVP? Volume? Cardiac Status? Pulmonary Status? Fluids being infused? Patient position? Who does the measurement? Vasomotor tone? The Computer: CVP = 17 Would you diurese this patient? CVP should estimate dLVP CVP will be falsely high. Positive pressure ventilation. PEEP. Pulmonary disease. The Clinical Picture PEEP = 12 cm H2O. BP = 105/50 mmHg. CI = 2.3 l/min/m2. Vasoactive Drugs - Goals Blood Pressure or Cardiac Output or Both. One organ perfuses by pressure alone. HEART: diastolic root pressure - ventricular wall tension. Increase myocardial O2 Consumption All other organs are cardiac output dependent. There is a point where pressure comes at the expense of perfusion. Vasoactive Drugs Dopamine: Highest incidence of arrhythmias, organ dysfunction, death. Causes norepinephrine release from the storage granules in the synapse. Does not increase renal blood flow. Acts as the antagonist to Renin-Angiotension. Recent articles in CCM argue that it should not be used. Norepinephine Activity depends on the number of alpha and beta receptors in the target organ. Under stimulation receptors are used up. Only vasoactive drug we do not dose by weight. Why I know not. Neosynephrine Pure alpha agonist. Causes peripheral vasoconstriction. In neurogenic shock: there is peripheral vasoconstriction and cardiac depression. After-load increase = increased wall tension. Hormone Replacement N = 701 Historical Control Non-Hormone Replacement Hormone Replacement Age < 40 3.8 opd 4.2 opd Age > 40 2.5 opd 3.1 opd So, Why Is this Controversial? Repeating this has been difficult/impossible. Used T3, most of us use T4. These patients were all fed. The Company says T4 is not stable in D5W. The Company says T4 is not stable as an infusion. As of now there is no data about these issues from the Company. Conversion of T4 T4 is not the active hormone. T4 must be converted to T3 in the periphery. This conversion is decreased in illness. May take up to 8 hours. Has an immediate action on vasomotor tone. Actions of T3 Intracellular T3 Activity T3 Action in the Nucleus Increases RNA transcription/protein synthesis. Increases Glucose and protein metabolism. Where does the fuel for this come from? Remember in the original article, all were fed. We have lost the ability to convert fat into glucose. Burning intrinsic protein to make energy. In illness, studies show giving T4. Increases organ dysfunction and mortality. Furthermore How critical is the 6 – 8 hour delay in T3 function in terms of repair (protein synthesis)? Should we all be using T3? In terms of protein metabolism. Robbing Peter to pay Paul. Protein breakdown to generate energy. Given the Company’s guidelines. Are we even giving adequate amounts? So. What to Make of This? If we are going to use parameters. Education. Everyone needs to do it the same way. Does it matter? How are we going to find out? What to do about hormone replacement? Do we need to upgrade our technology? There are noninvasive ways to measure C.O. Other ways to estimate LV filling pressure. Plea for a National Database. Old medical axiom: WNL = we never looked. If you don’t measure it, you can’t improve it. Critical Care has spend a lifetime looking. DMG’s are a beginning to this end. We need to refine these. The larger the numbers the better the accuracy. DONOR MANAGEMENT GOALS: Moving Toward a National Strategy NIL Get Connected Webinar October 13, 2009 Darren Malinoski, MD Assistant Professor of Surgery Director, Surgical Intensive Care Unit Chair, Organ Donor Council University of California, Irvine BACKGROUND • Donor Management Forum – August 2009 – Intensivists, Transplant Surgeons, OPO representatives, National Organizations • Four predominant REQUESTS: 1.Increase Intensivist involvement 2.Increase the science of donor management 3.Tie donor management data to SRTR outcomes 4.Funding for research PLAN FOR THIS SESSION • • • • • Background on Donor Management Goals (DMGs) Region 10 Region 5 DMG initiative Survey Monkey results National DMG initiative OTPD and DMGs 3.6 3.4 3.2 OTPD when DMGs met OTPD when DMGs NOT met OTPD Total 3 2.8 2.6 2.4 2.2 2 Nov-07 Dec-07 Jan-08 Feb-08 CONSENSUS 1 -- 4 • • • • Sodium < 155 MAP > 60 pH 7.25 – 7.5 CVP < 10 (or serum osmolality 285 – 295) CONSENSUS 5 & 6 • Pressors 1 or none (one pressor plus Vasopressin to treat DI is OK) • pO2 > 300 if on 100% O2 ( or a P/F ratio > 3) RESULTS FULL YEAR 2008 • 774 TOTAL CASES • 264 Met Criteria = 34% • 510 Did not meet criteria = 66% INCREASE IN ORGANS TRANSPLANTED PER DONOR WHEN DONOR MANAGEMENT GOALS ARE MET SORTED BY DONOR TYPE UNOS REGION 10 ORGANS PER DONOR 5 4.5 1.36 4 3.5 3 2.5 1.77 0.59 0.15 2 1.5 1 SCD ECD DCD TOT DONOR MANAGEMENT GOALS: The Region 5 DMG Project Part 1: Retrospective Part 2: Prospective PROPOSED DMG’S for REGION 1. 2. 3. 4. MAP 60-100 CVP 4-10 EF > 50% </= 1 pressor used AND: a. Dopamine </= 10 mcg/kg/min b. Neosynephrine </= 100 mcg/kg/min c. Norepinephrine </= 10 mcg/kg/min d. Vasopressin </= 2.4 units/hour (0.04 units/min) 5. ABG pH 7.3-7.45 6. Pao2:Fio2 ratio >300 on PEEP = 5 7. Serum Sodium 135-160 8. Urine output 1-3 cc/kg/hour 9. Glucose < 150 10. Hemoglobin > 10 Track hormone replacement usage PART 1 - RETROSPECTIVE Universal template 40 SCD’s from each OPO Retrospective collection of data regarding proposed DMG’s (prior to procurement) and organ disposition information Statistical analyses: – – – – 80% DMG’s = goal met >/= 4 OTPD = primary outcome measure DMG-specific results Other notable findings DMG’S AND OTPD Mean # DMG’s with >/= 4 OTPD = 7.2 Mean # DMG’s with < 4 OTPD = 6.1 – T-test: p<0.001 When “goals met” – Mean OTPD = 4.4 – 70% >/= 4 OTPD When “goals not met” – Mean OTPD = 3.3 (t-test, p<0.001) – 39% >/=4 OTPD (Pearson’s Chi-square, p<0.001) Multivariate analysis - >/= 4 OTPD Variable age CVP 4-10 EF > 50% </1 pressor P:F > 300 Na 135-160 Thyroid hormone Serum creatinine OR 0.95 1.7 4.5 1.006 4.8 2.7 1.7 0.612 95% CI 0.93-0.97 0.96-3.1 2.5-8.3 0.51-1.98 2.6-8.6 0.99-7.4 0.97-3 0.4-0.93 p value <0.001 0.071 <0.001 0.986 <0.001 0.053 0.067 0.022 Moving Forward – Current Project The Region agreed on 9 DMG’s to prospectively implement and track for 6 months. DMG’s will be measured at consent, 12-18 hours later, and prior to going to OR OTPD and graft outcome data will be analyzed MAP > 60 CVP 4-10 EF > 50% </= 1 pressor and low dose (vasoP eliminated) pH 7.3-7.45 P:F > 300 Sodium 135-155* Glucose < 150 UOP 1-3 cc/kg/hr over preceding 4 hours General Data Part 1 320 donors 100% SCD DMG’s prior to OR Purely retrospective data DMG’s met = 8/10 Part 2 – July-Dec 2008 492 donors 380 (77%) SCD DMG’s at 3 time points Prospective implementation DMG’s met = 7/9 Graft Function Data Can we make a difference or is fate sealed before we start? DMG data (SCD’s only – n=255) <4 OTPD (n=132) >/=4 OTPD (n=123) p value DMG’s at consent (1) 4.5 5 0.001 DMG’s at 12-18 hrs (2) 5.1 6.1 <0.001 DMG’s prior to OR (3) 5.5 6.3 <0.001 Delta DMG 1-2 0.71 1.1 0.050 Delta DMG 2-3 0.3 0.19 0.522 Delta DMG 1-3 1 1.3 0.210 Multivariate analysis – Part 2 >/= 4 OTPD (n=376, 4 missing) Variable Age Terminal creatinine DMG 1 met DMG 2 met DMG 3 met OR 0.95 0.74 1.9 1.6 2.2 95% CI 0.93-0.96 0.6-0.9 1.02-3.7 0.92-2.6 1.3-3.6 p value <0.001 0.004 0.044 0.097 0.002 Ejection fraction 3 Pao2:Fio2 3 3.3 3.2 1.8-6 1.6-6 <0.001 0.001 PART 2 CONCLUSIONS DMG’s are still associated with OTPD Changes in DMG’s over time are associated with OTPD Pre-donor management is associated with outcomes SURVEY MONKEY RESULTS 41 OPO’s responding… Does your OPO use DMGs? Does your region have a uniform DMG initiative? • 38 responses – YES: 25 (66%) – NO: 13 (34%) • More than one response from 9 regions – One response from region1 – No response from region 6 If your region does not have uniform DMGs, would you be willing to do so? Would your OPO be interested in participating in a National DMG Project? How important is a National DMG initiative for advancing the science of donor care? CONCLUSIONS • REGION 10: – Retrospective: Meeting all six DMG’s prior to the OR more OTPD • REGION 5: – Retrospective and Prospective data suggest that meeting DMG’s throughout case more OTPD • National Survey suggests strong support for DMG’s and a donor database Future Directions Refine DMG’s Develop Web-based data entry system Create national DMG’s and donor database Continue to engage intensivist community Create a network for large-scale research