2. Optimizing Organ Donation
Donor Alliance Organ Donation Summit
December 8, 2015
Mary Laird Warner, MD, FCCP
Chairman, Quality Medical Executive Committee
Swedish Medical Center
Associate Professor, Critical Care and Pulmonary Medicine,
National Jewish Health

3. Disclosures - I have no financial conflicts of interest to disclose
Disclosures - I have no financial conflicts of interest to disclose. Level of evidence - Levels 1, 2, 3

4. Outline Discuss the scope of organ donation needs
Review physiologic changes of brain death
Discuss ICU care of the brain dead organ donor
Discuss bundling of Donor Management Goals (DMG)
Review results from DMG protocol at Swedish Medical Center

5. The Need
Every 10 minutes, someone is added to the national organ transplant waiting list.
On average, 22 people die each day waiting for an organ transplant.
The gap between supply and demand of transplanted organs continues to widen.
Updated

6. Gap between patients waiting for transplant and available organs

7. The Numbers: Patient Waiting List for Donated Organs
Site
Kidney
Liver
Pancreas
K/P
Heart
Lung
H/L
Bowel
United States
109,083
15,541
1,046
2,039
4,264
1,576 49
268
133,866
Total
Colorado
1,962
695 11 44 48 19
2,779 Total
18 people die each day waiting for an organ transplant; which translates to close to 7000 pts per year.
Over 127K patients in US are currently listed.
Over 2100 patients in CO and WY are currently listed
Updated

8. How can we bridge the donor gap?
Maximize the number of organs transplanted per donor (OTPD) Goal per HHS/ HRSA = 3.75

9. Organs available by Donor Type
Donation after Brain Death (BD) = 8
Heart, Lungs (2), Kidneys (2), Liver, Pancreas,
Small Intestine
Donation after Cardiac Death (DCD) = 5
Lungs (2), Kidneys (2), Liver

10. Physiologic Changes with Brain Death
Neurologic
Cardiovascular
Pulmonary
Endocrine
Metabolic

11. Hemodynamic Changes with BD
Brainstem herniation causes ischemia that progresses in rostral – caudal direction
Midbrain - parasympathetic activation 
Bradycardia
Medulla - sympathetic activation 
Vasoconstriction, hypertension
Spinal cord – sympathetic deactivation 
Vasodilation, circulatory shock

12. Hemodynamic changes with BD
10-20% donors are lost to cardiovascular collapse as patient evolves to brain death
50% of potential BD donors are volume responsive
Pro-inflammatory state, increased cytokine IL-6
Resultant shock causes
Progressive organ failure
Fewer OTPD
Lower survival of transplanted organs
Muragan, CCM, 2009

13. Volume Depletion in BD Causes multifactorial
Underlying medical condition – blood loss, etc
Prior management – osmotic therapy for ICP
Neuro-hormonal cascade
Capillary Leak
Diabetes Insipidus

14. Pulmonary Changes in BD
Pulmonary edema
Neurogenic
Cardiogenic
Non-cardiogenic – capillary endothelial leak
Delayed alveolar fluid clearance
BAL studies from donor lungs show proinflammatory changes occur in BD not DCD lungs
Neurogenic – catecholamine surge, acute VC, increased SVR, depressed CO, increased hydrostatic pressure in pulmonary vascular bed
SIRS response – capillary endothelial leak, neutrophil infiltration, cytokine infiltration - IL-8
Delayed alveolar fluid clearance due to decreased B-agonist activity, loss of thyroid function

15. Hormonal changes with BD
Catecholamine storm
Ischemia to pituitary and hypothalamus depletes AVP, cortisol, thyroid hormones
Diabetes insipidus – up to 90% BD patients
Hypocortisolism
Hyothyroidism
DI occurs when AVP deficiency causes inappropriate diuresis, resulting in hypovolemia, hyperosmolarity, and hypernatremia
Corticosteroid insufficiency – multiple small studies have yielded conflicting results
Nearly all show low but detectable random serum cortisol and preserved ACTH in BD pts
But most showed blunted response to infused ACTH with Cortrosyn stimulation test suggesting relative adrenal insufficiency
Hypothyroidism
Animal studies show reduced T3 (tri-iodothyronine) and free T4 (thyroxine) with BD
Human studies have revealed more conflicting results
Variably Low TSH, low T4, but normal or high RT3 more c/w sick euthyroid syndrome

16. Metabolic changes with BD
Hypernatremia
Caused by volume depletion, Diabetes insipidus
Na > 170 associated primary non-function (PNF)
of graft liver
Hyperglycemia
Caused by insulin resistance and gluconeogenesis
Glu > 200 associated with PNF of graft pancreas
Glu > 160 associated with PNF of graft kidney
Concern for hypernatremia now subject to debate
Initial goal Na , 155 based on retrospective studies showing increased PNF of transplanted liver
Recent lg prospective study of 1013 BD donors showed no association btw peak and terminal Na levels and survival of liver graft at 1 yr

17. ICU Management of the Brain Dead Potential Donor
Stabilize profound physiologic and homeostatic derangements provoked by BD
Balance competing management priorities between different organs
Avert somatic death and loss of all organs
Revised Uniform Anatomical Gift Act requires hospitals and OPOs to have in place policies and procedures to preserve option for donation for every potential donor and their family.
This includes avoidance of deceleration of care of pts with catastrophic brain injury until the option of organ donation is discussed with family.

18. Multidisciplinary, multi-institutional
Management of the potential organ donor in the ICU: SCCM, ACCP, AOPO Consensus Statement Critical Care Medicine 2015
First US expert report
Multidisciplinary, multi-institutional
Review of available evidence from observational studies and case series
Form of consensus statement
Practical guideline for care of organ donor
Prior Canadian publication from 2004, UK publication – Crystal City from 1997
Crit Care Med 2015; 43:

19. Circulatory support Physiologic goals – Target euvolemia
MAP > 60 mm Hg
UOP > 1 mL/kg/hr
EF > 45%
Low pressor dose – Dopamine 1-10 mcg/kg/hr
Volume Resuscitation
Crystalloid – NS or LR - for volume replacement
Colloids – for acute volume expansion
Avoid Hydroxyethyl starch (HES)
Goal of circulatory support to maximize organ perfusion for organ preservation
Physiologic goals are derived from case series, empiric protocols and consensus statement
Colloids – albumin or PRBCs to target Hgb > 7
Avoid HES – assosicated with AKI, coagullopathy, delayed graft function and graft failure

20. Vasoactive Medications - Pressors
Dopamine
Traditional 1st line pressor
1-10 mcg/kg/min
Inotrope and vasopressor
Pro – suppresses inflammation; mitigates ischemia-reperfusion injury
Con – suppresses anterior pituitary hormone function
Vasopressin
Alternative 1st line pressor
IU/min
Vasoconstrictor
Pro – catecholamine sparing effect; concurrent rx of DI
Con - Decreases splanchnic perfusion
DA at low doses acts via dopaminergic receptors in arterial and venous smooth muscle and on myocardium – pressor and inotorope
VP acts via V1 alpha receptor, NO pathways, K channels to stimulate vasoconstriction
NE and Phenylephrine are riskier due to increased alpha receptor stimulation – pulmonary capillary leak, shunt, coronary and mesenteric vasoconstriction
Ne associated with decreased 1-yr survival in heart transplant recipients
VP recommended by ACCP as pressor of choice in potential organ donor

21. Vasoactive Medications - Inotropes
If EF < 45% despite volume
repletion and pressors,
add inotrope
Dobutamine, Epinephrine
If EF remains depressed despite inotrope, consider starting hormonal replacement therapy (HRT)

22. Hemodynamic Monitoring
Static measurement – Central venous, PA catheter
ScVO2
Lactate
Base deficit
Serial CVP, PAOP, CO, CI
Dynamic measurements – Pulse contour analysis
Echo
Transthoracic (TTE) vs Transesophagael (TEE) EF
No well designed studies of hemodynamic monitoring in BD population
Recommendations extrapolated from care of pts with other shock states
Echo to assess LVSF, check for stress cardiomyopathy
Assess baseline structural heart disease – valvular heart disease, intracardiac shunts
Echo to assess suitability for heart transplant should be delayed until pt weaned off pressors
May need to be repeated in hrs after aggressive donor management

23. Vasoactive support: Treating AVP deficiency
Hypotension despite volume repletion
AVP - Vasopressin IU/min
Diabetes insipidus (DI)
UOP > 3 mL/kg/hr
U Osm < 200 mOsm/kg H2O or S Osm > 305
Serum Na > 145 mmol/L
Desmopressin – 1-4 mcg IVP, then 2 mcg IV Q 6 hrs
AVP treatment associated with
Decreased pressor and inotrope need
increased rate of organ recovery
Vasopressin and desmopressin can be used concurrently
VP studies
Several small retrospectvie studies and 1 prospective study show decreased need for vasoactive meds
Review of OPTN data base showed increased rate of organ recovery

24. Corticosteroids for vasoactive support
CORTISOME study: Prospective, randomized study of low dose hydrocortisone effect on resuscitation of BD donors
Subjects: 259 BD organ donors
Intervention: Hydrocortisone (HC) vs none
Results: Patients receiving HC had
Lower dose and shorter duration pressor needs
No difference in transplantation or graft survival
Prior studies had yielded conflicting results on effect of corticosteroid therapy on pressor needs
Recent well designed, prospective randomized study with relatively larger subject pool
Pinsard, 2014

25. Corticosteroid Therapy for Immunomodulation
Corticosteroid repletion reduces inflammation in donor livers
Lower levels pro-inflammatory cytokines – serum, tissue
Fewer adhesion molecules in tissue
Less ischemia-reperfusion injury
Lower acute rejection rates
Conflicting results in cardiac, lung, renal grafts
Recommended dose: Methylprednisolone
1000 mg IV, 250 mg IV, or 15 mg/kg IV bolus
100 mg/hr IV infusion
Kotsch, 2008
Kotsch study -
Prospective RCT of 100 BD donors – 50 randomized to steroid therapy with 250 mg iv medrol followed by gtt 100 mg/hr
Conflicting results in other organs when promising results of HC therapy in retrospective studies were not born out in prospective studies

26. Thyroid hormone replacement for vasoactive support
Conflicting evidence over years: 16 retrospective studies / case series suggested T3/T4 infusion improved cardiac index Meta- analysis of 4 RCTs of 209 donors No effect on cardiac index Recommendation: Consider thyroid replacement for hemodynamically unstable BD donors or for EF < 45% Dose: T4: 20 mcg IV bolus, 10 mcg/hr IV gtt T3: 4 mcg IV bolus, 3 mcg/hr IV gtt
MacDonald, 2012

27. 3 hormone replacement for vasoactive support of BD Donor
Multicenter, retrospective study by UNOS of 10,292 BD donors using 3-drug HRT cocktail (AVP, methylprednisolone, T3/T4)
22.5% higher OTPD compared to controls
Increased probability organ donation
Kidney, heart, liver, lung and pancreas
Increased probability of organ survival at 1 year
More recent smaller, prospective studies in cardiac transplant recipients have not confirmed these findings
Mason, 1993

28. Insulin therapy in BD
Glucose > 160 associated with reduced post-transplant renal graft function
Glucose > 200 associated with reduced post-transplant pancreas graft function
Potential to deplete graft B-islet cells
No large studies to guide recommendations
Recommend: Serum glucose < 180 mg/dL

29. Pulmonary support Physiologic goals Arterial pH 7.3 – 7.45
PaO2/FiO2 > 300
Avoid excessive fluid resuscitation
Target CVP 4 – 6 mm Hg
Avoid Vasopressors
Ventilator strategy
Conventional – high VT mL/kg IBW + low PEEP
Lung Protective – low VT 6 mL/kg IBW + mod PEEP

30. Lung Protective Ventilation in BD organ donors
RCT of 118 BD patients randomized to 6 hrs of randomized vs conventional ventilation
Lung protective ventilation: (VT 6-8 mL/kg IBW + PEEP 8-10 cm H2O) + recruitment maneuvers + apnea test on CPAP
Conventional ventilation: (VT mL/kg + PEEP 5 cm H2O) no recruitment maneuvers + apnea test off ventilator
Results: Lung protective ventilation resulted in
Higher percentage transplantable lungs (95 vs 54%, P < 0.001)
Higher number lungs transplanted (54 vs 27%, p = 0.004)
Lower inflammatory biomarkers (IL-6, Soluble TNF receptors)
Mascia, 2010

31. Salvage maneuvers to improve lung recovery for transplantation
Donor management protocol improve lung recovery rate 3 fold
Conservative fluid strategy/ diuresis
Lung recruitment maneuvers
Early therapeutic bronchoscopy
Chest physiotherapy Q 4hrs
Salvage ventilator modes improve lung recovery rate 3-4 fold
Bilevel 25/15
Airway pressure release ventilation (APRV)
Lung is most difficult organ to transplant – available from only 15-25% donors
1999 Gabbay Study in Australia showed donor lung management protocol converted 20 of 59 potential donors to PF > 300
2006 Angel Study in San Antonio showed Bilevel vent for recrutiment converted 1/3 of 98 donors to PF > 300
2001 Hanna study showed APRV imrproved lung retrieval
Gabbay, 1999
Angel, 2006
Hanna, 2001

32. Renal Support Physiologic goals - Euvolemia
CVP 4-10 mm Hg
UOP > 1 mL/kg/hr
Resuscitate with crystalloids or colloids
Avoid HES
Delayed graft function
Elevated serum Cr at PTD 10
Single, low-dose pressor use
Dopamine as pressor of choice
AVP may increase renal procurement

33. Effect of donor pretreatment with dopamine on graft function after kidney transplantation
RCT, open-label, parallel study of 264 brain dead donors of 487 kidneys from 60 European centers,
Intervention: low dose DA = 4 mcg/kg/min vs none
Results:
Donors receiving dopamine were less likely to require dialysis (24.7% vs 35.4%, p 0.01)
Multiple dialyses associated with renal graft failure at 3 years. HR 3.61 ( )
Schnuelle, 2009

34. Organ-specific management: Liver
Na > 155 in graft liver risks swelling upon transplantation
Na > 155 in donor associated with
Increased need for re-transplantation at 30d
Increased allograft failure at 90d
Recommend: Serum Na < 155

35. Organ-specific management: Pancreas and Small Intestine
Target Euvolemia
Provide 3x HRT – enhances pancreatic utilization
Target serum glucose < 180 mg/dL
Continue enteral nutrition
Prophylactic antibiotics
Small bowel decontamination regimen
Broad-spectrum iv antibiotic prophylaxis
Avoid use of SB from patients with prolonged shock/ resuscitation or GI bleeding
Benefit EN – trophic feeding to gut mucosa to decrease translocation of gut bacteria into systemic ciruclation
Target euvolemia for pancreas to decrease organ swelling
Target normal to liberal fluid resuscitation for SB to ensure adequate perfusion via mesentary
Abx choices – defer to OPO

36. Competing physiologic needs
Heart: Balanced Fluids, Vasopressin
Lungs: Conservative Fluids, No pressors
Conventional wisdom stated potential kidney donors should receive liberal fluid management while lung donors conservative;
Recent studies show CVP at lower end 4-6 mm Hg – did not decrease renal graft survival or cause delayed renal graft function
Kidney: Liberal Fluids, Dopamine
Liver: Isotonic fluids

37. Protocols to maximize OPTD
Donor Management Goals (DMGs)
Order sets
Intensivist-led organ donor management

38. Donor Management Goals (DMG)
Develop protocols to optimize donor organ function and maximize OTPD
Borrow concept of “bundles” from other disease management models
Represent consensus of physiologic targets based on expert opinion
Modest clinical studies to support use

39. Donor management goals
MAP 60 – 100 mm Hg CVP 4 – 10 mm Hg EF > 50% Pressor < 1; low dose Thyroid hormone
ABG pH 7.30 – 7.45 PaO2: FiO2 > 300 Na mEq/L Glu < 150 mg/dL UOP 0.5 – 3 mL/kg/hr
Developed standardized order sets to target these physiologic parameters
These goals were chosen as important cardiopulmonary, renal, endocrinologic and metabolic goals based on prior retrospective studies. These criteria are also readily measurable and objective.
Low dose pressor = DA <10, Neo < 60, NE < 10 mcg/kg/min
J Trauma Oct;71(4):990-5
Crit Care Med Oct;40(10):
Am Surg 2010 Jun; 76 (6):

40. Retrospective UNOS Region 5 DMG Study
Study of protocolized DMG care of 320 BD donors
Results
Overall OTPD =
Donors with 8+/10 DMG had
More OTPD (4.4 vs 3.3, p<0.001)
More likely 4+ OPTD (70% vs 39%, p < 0.001)
Achieving 4 specific DMGs independently predicted > 4 OTPD
CVP mm Hg (OR 1.9)
EF > 50% (OR = 4.0)
P:F > 300 (OR = 4.6)
Na 135 – 160 mEq/L (OR = 3.4)
One of 1st of studies of DMG goals was retrospective study from region 5, 5 SW states across 8 OPOs in 2007
Independent predictors of > 4 OTPD
Donor-dependent: factors: Age, serum Cr
Care factors: 8+ DMGs met, specific DMGs met, Thyroid hormone rx
J Trauma Oct;71(4):990-5

41. Prospective Region 5 UNOS DMG Study
Study of protocolized care and time dependency of meeting DMG goals in 380 SCD donors
Overall OPTD =
7+/9 DMG met improved over time:
15% at time of consent
33% at hrs
48% at time of recovery
Independent predictors of > 4 OTPD
7+/9 DMG met at consent, recovery
Change in DMG at hr
Donor age
Serum creatinine
Several previous retrospective studies had suggested that optimizing donor physiology by targeting physiologic endpoints could increase the number of organs transplanted per donor.
This was the first study of its kind to ask this question prospectively.
SCD donors
Same UNOS region
Examined time dependency of meeting DMG goals at 3 time ponts – time of consent, hrs later, time of organ recovery .
Crit Care Med Oct;40(10):

42. UNOS Region 11 Prospective DMG Study
Prospective study of 805 SCD donors, total, including ECD, DCD
OPTD
when < 8 DMGs met
when all 8 DMGs met
Lung transplants increased 2.4x when all 8 DMGs met
DMGs associated with highest OTPD
Low VP use
P:F > 200
CVP 4-10
DMGs associated with recovery of specific organs
Heart: Na, low VP use
Lung: CVP, P:F
Pancreas: glucose control
DMG Did not include thyroid hormone
Multivariate analysis showed these 3 DMGs correlated most closely with OTPD
The DMGs of MAP, UOP, and pH were not predictive of OPTD in multivariate analysis
Am Surg 2010 Jun; 76 (6):

43. Intensivist-led management
University of Pittsburgh study
Intensivist-led organ donor support team
Pre-post study design (n= 35 pre/ 45 post)
Results
Increased total organs recovered (66/210 vs 113/258)
Increased lungs recovered (8/70 vs 21/86)
Increased kidneys recovered (31/70 vs 52/86)
Increased OTPD ( 1.9 vs 2.6)
On call faculty insensivist who work collaboratively with organ procurement coordinators to implement DMG, rescue unstable donors, provide bridge between OPC and ICU staff. vs
Similar baseline characteristics of donor
Same DMG order set
Increased lungs from 11 to 24%
Increased kidneys from 44 to 61%
Singbartl, 2011

44. Future Directions
MOniToR Trial – Monitoring Organ donors to improve Transplant Results
Glycemic control – conventional vs intensive glycemic control effects on renal graft function
Alkhafaji, R, 2015
Monitor trial - MRCT of BD donors comparing minimally invasive hemodynamic monitoring of pulse pressure variation (LidCO) with usual care
Subjects: 960 BD pts from 8 OPOs
1° endpoint: OTPD
2° endpoint: # transplantable organs per donor, recipient 6-month HFS, IL-6 levels
Statistics – intention to treat, modified intention to treat
Hypothesis – Protocolised resuscitation using PPV is superior to usual care
Niemmann, in press

45. Organ Viability Research Project at Swedish Medical Center
Focus: Collect data of 9 DMGs from time of BD declaration to DA management
Goal: Develop protocol for donor management to increase OTPD > 3.75
Scope:
Baseline study period
Prospective study, starting June 2013
Gap time 2.5 – 8 hrs:
Original scope was chart review RN chart review showed lack of charting between declaration of BD and initiation of DA management.
Had to retrench/re-educate RNs on charting before study can begin.
Intervention – developed DMG order set; educated nurses on DMG goals/ mgt

46. Swedish Medical Center: Organ and Tissue Donation
2010
2011
2012
2013
2014
October 2015
Organ Donors 18 14 20 22 11
BD/DCD
17/1
11/3
15/5
19/3
12/2
8/3
%DCD 6%
21%
25%
14%
27%
Tissue 53 62 84
115 79
Eye 96 95 80 88 81
HHS goal: DCD > 10% donors

47. Swedish Medical Center: Organ Transplant Rate
2010
2011
2012
2013
2014
October 2015
Organ Donors 18 14 20 22 11
Total Organs 61 44 58 70 45 33
OTPD
3.39
3.14
2.94
3.18
3.21
3.3
Timely Referral
91%
96%
98%
97%
National Goals from HHS
OTPD > 3.75
Timely referral rate > 97%

48. Questions?
Thank You