April 19, 2019
Defining the limit of transplantScience or an art?Jennifer C. Lai, MD, MBAAssociate Professor in ResidenceUCSF Division of Gastroenterology & HepatologyDirector of Hepatology Clinical Research
Conflicts of Interest
None relevant to this presentation
Consulting affiliations:- Axcella Health, Inc
High-Risk Medical Decision-Making
Photo by Edwin Andrade on Unsplash
Ms. Davis, 54 year woman with HCV cirrhosis
Foggy, memory loss, ascites more diuretics, rifaximin
3 months ago
ascites, MELD 16, listed for liver transplant
1 year ago 3 days ago
Legs/belly more swelling mechanical fall, does
not present for care
Son notices she is sleeping much more, eyes turning
yellow, more swelling
NOW
Coma presents to ED
Ms. Davis, Admitted to ICU Bed #4
• Intubated, no sedation• No focal deficits• Non-responsive to stimuli• Hyperreflexia, myoclonus• Jaundiced, anasarca• No appreciable muscle
wasting of the temples, biceps, muscle bulk preserved
• Platelets 25• TB 40, Cr 2.9, INR 3.4, Na 135
• UA+ Pan-sensitive E. Coli
MELDNa40
Head CT
Head CT report:
8 mm hyperdensity in the left frontal lobe
- May represent foci of active extravasation
- Given lack of blooming on post-contrast sequences, small vascular malformation is not excluded
Neurology consulted
GoLytely flush for hepatic encephalopathy1
Treat her UTI If not evolving on repeat head CT, this is likely venous
angioma and not a contraindication to transplant
• ?Small intracerebral hemorrhage but favor venous angioma (low flow, low pressure)
• Unlikely to be contributing to her altered mental status• Typically not susceptible to further bleeding not likely
to bleed during liver transplant
1 Rahimi et al. JAMA Intern Med 2014.
The next day
• Repeat head CT stable
• BP stable, still intubated
• 4L of stool (after GoLytely)
• Grimaces to painful stimuli, minimal spontaneous movement
• Infection appeared controlled
MELDNa40+
Proceed with transplant?
Is this the limit of transplant?
Patient A Patient B Patient CPre-transplant Vulnerability:
Post-transplant Vulnerability:
Favorable Intermediate Marginal
Transplant:
Outcome:
Patient-dependentAcceptableHighTransplant Benefit:
MELD 40MELD 40
MELD 40
Transplant Responsive(e.g., liver dysfunction, ascites, encephalopathy)
Transplant Non-responsive(e.g., older age, multi-morbidity, advanced undernutrition/sarcopenia)
Legend
Framework to Guide Transplant Decision-Making
Lai JC. Liver Transplantation 2017. Adapted from Lai JC; Clin Liver Dis 2016 and Flint KM, et al; Circ Heart Failure 2012.
• May die before she gets a better offer
Accept
• Will clear her hepatic encephalopathy recover cognitive function
39 yo DCD30% large droplet fat Tennessee
A (expanded criteria) liver offer
Decline
• Neurology said unlikely to bleed
Spectrum of Post-Transplant Risk with Donor Livers
Feng / Lai. Clinics in Liver Disease 2014.
Disease Transmission
IDEAL• Whole liver (vs. split)• Donor who died from
brain death• <40 years old• Cause of death: trauma
LOWEST RISK
STANDARD• Not ideal• Not expanded
AVERAGE RISK
EXPANDED CRITERIA• Older donors• Fatty livers• Donation after cardiac death
(risk for ischemic injury)• Donors with risk factors for
having HCV/HIV
HIGHEST RISK
Graft Failure
Patient A Patient B Patient CPre-transplant Vulnerability:
Post-transplant Vulnerability:
Favorable Intermediate Marginal
Transplant:
Outcome:
Patient-dependentAcceptableHighTransplant Benefit:
MELD 40MELD 40
MELD 40
Transplant Responsive(e.g., liver dysfunction, ascites, encephalopathy)
Transplant Non-responsive(e.g., older age, multi-morbidity, advanced undernutrition/sarcopenia)
Legend
Framework to Guide Transplant Decision-Making
Lai JC. Liver Transplantation 2017. Adapted from Lai JC; Clin Liver Dis 2016 and Flint KM, et al; Circ Heart Failure 2012.
ECD Liver Ideal liver ECD Liver
Futile
Very Poor
Stan
dard
• May die before she gets a better offer
Accept
• Delayed graft function worsening coagulopathy worsening hemorrhage
• Will clear her hepatic encephalopathy recover cognitive function
39 yo DCD30% large droplet fat Tennessee
A (expanded criteria) liver offer
Decline
• Neurology said unlikely to bleed • May not recover from surgery
• Someone else could benefit more
Proceed with transplant?
Is this the limit of transplant?
• May die before she gets a better offer
Accept
• Delayed graft function worsening coagulopathy worsening hemorrhage
• Will clear her hepatic encephalopathy recover cognitive function
The (ideal) liver offer
• Neurology said unlikely to bleed • May not recover from surgery
• Someone else could benefit more
Proceed with transplant?
Is this the limit of transplant?
19 yo woman died from
head trauma after a car accident
• May not recover from surgery
Decline
Mrs. Smith, ICU Bed #9
• 64 yo woman with cirrhosis 2/2 primary biliary cholangitis• Admitted 3 weeks ago with spontaneous bacterial peritonitis hepatorenal syndrome Type 1
• Now in the ICU on continuous renal replacement therapy
• 5 foot 2 inches waiting for 3 weeks for a size-appropriate liver
• Starting to ooze from hyperfibrinolysis
MELDNa39
IDEAL DONOR19 year old
woman
Offers Per Wait-List Candidate
Transplanted
Accept
Listing Transplant
Wait-list time = 60 days
DIED BEFORE TRANSPLANTWait-list time = 160 days
DeathListing
84% of those who died/were too sick received at least 1 liver offer prior to
their death
Lai JC et al, Gastroentol 2012.
Women awaiting liver transplant are vulnerable
• Women are more likely to die/be delisted on the liver transplant waitlist than men
• This is due in large part to women’s shorter stature
Moylan C, et al; JAMA 2008. Lai JC et al, AJT 2010.
Cumulative incidence of death/delisting by gender
Nephew L, CGH 2017.
Women awaiting liver transplant are “short” relative to donors
% women and men on the waitlist by height
Most women are “short” (5’5”)
Lai JC et al, AJT 2010.
• Most (60%) donors are male
• Median height : 5’10”
Lai JC et al, AJT 2011.
• May die before she gets a better offer
Accept
• Delayed graft function worsening coagulopathy worsening hemorrhage
• Will clear her hepatic encephalopathy recover cognitive function
The (ideal) liver offer for Ms. Davis
Decline
• Neurology said unlikely to bleed • May not recover from surgery
• Someone else could benefit more
Proceed with transplant?
Is this the limit of transplant?
19 yo woman died from
head trauma after a car accident
• May not recover from surgery
Bioengineered Livers: No Donor Scarcity
• May die before she gets a better offer
Accept
• Delayed graft function worsening coagulopathy worsening hemorrhage
• Will clear her hepatic encephalopathy recover cognitive function
When donor supply is infinite
Decline
• Neurology said unlikely to bleed • May not recover from surgery
• Someone else could benefit more
Proceed with transplant?
Is this the limit of transplant?
• May not recover from surgery
Jerome, we have a liver offer for your sister. It is
from an ideal donor, and it is her best chance to live.
Jerome, Ms. Davis’ brother
Ms. D, at the bedside
Jerome, Ms. Davis’ brother
Ms. D, at the bedside
Doctor, our father passed away last year, after a long battle with dementia. At the end of his life,
he was fully dependent on us and wasn’t his same self. My sister
made it very clear to me that she would never want to live that way,
nor would she want aggressive treatments if she wasn’t able to
have a good quality of life. Is she going to be able to achieve
that with transplant?
Proceed with transplant?
Is this the limit of transplant?
Candidate need
Candidate suitability for transplant
surgery
Donor quality
Donor availability
Defining the limit of transplant
Patient values Transplant
To live longer?
Patient Values in High-Risk Medical/Surgical Conversations
• Sampling of 43 recorded conversations between patients and surgeons prior to high risk surgical procedures
Nabozny / Schwarze. Ann Surg 2017.
• Patients/family assumed a common understanding about how to care for the patient in the event of a serious post-operative complication
“[My doc] knows that we cross-country ski, we bike, so I think
that whatever complication there would be, he would try to lessen it so that QOL could remain close
to the same.”
“We didn’t [discuss it]…but he knows …I don’t want to be a
vegetable, common sense tells him that.”
Patients express a broad range of treatment limitations
Nabozny / Schwarze. Ann Surg 2017.
Assertion Representative QuotesAll-in, unconditional, unlimited
“Blind faith”
“No holds barred. You know, if he’s got to do something else, cut something else out on this side…might as well do it.”
“I have complete confidence in that he would do everything that could possibly be done.”
Denial or suppression of risk
“Unaware”
“I realize that there’s problems that could happen in anything, but normally they don’t.”
“I think anytime you go undergo anesthesia that there’s always going to be risk…”
Desires reconsideration
“Fatalistic”“I’m not afraid of death. It’s all the other bulls**t you go through to getting there.”
“Surgical Buy-in”
• A “contractual” relationship between surgeons and patients that influences decisions re: life-supporting therapy
ML Schwarze, et al. Crit Care Med 2010. ML Schawarze, et al. Crit Care Med 2013.
Transplant
transplant clinicians
• Process by which the surgical team “negotiates” with patients a commitment to post-operative care prior to undertaking high-risk surgical procedures
• “This is a package deal, this is what the operation entails.”
• Leads to unwillingness to provide surgery if patients express desire to limit post-operative therapy
• 60% of surgeons said they would “sometimes” or “always” refuse to operate on a patient if they expressed preferences to limit life support
Clinicianclinicians
But if things don’t go as planned, do you know what is important to your patient?
Defining the limit of transplant
Patient values
To live longer?
Jerome, Ms. Davis’ brother
Ms. D, at the bedside
Doctor, our father passed away last year, after a long battle with dementia. At the end of his life,
he was fully dependent on us and wasn’t his same self. My sister
made it very clear to me that she would never want to live that way,
nor would she want aggressive treatments if she wasn’t able to
have a good quality of life. Is she going to be able to achieve
that with transplant?
Ms. Davis, 54 yo woman in ICU Bed #4
• 2 years of cirrhosis, low MELDNa 16• Complicated by ascites controlled with diuretics
• Hepatic encephalopathy developed 3 months ago• Initially controlled
• 3 days of severe hepatic encephalopathy and a fall
MELDNa40
• Intubated, no spontaneous movement• No appreciable muscle wasting
Is she going to achieve her
goal of a high quality of life?
Patient A Patient B Patient CPre-transplant Vulnerability:
Post-transplant Vulnerability:
Favorable Intermediate Marginal
Transplant:
Outcome:
Patient-dependentAcceptableHighTransplant Benefit:
MELD 40MELD 40
MELD 40
Transplant Responsive(e.g., liver dysfunction, ascites, encephalopathy)
Transplant Non-responsive(e.g., older age, multi-morbidity, advanced undernutrition/sarcopenia)
Legend
Framework to Guide Transplant Decision-Making
Lai JC. Liver Transplantation 2017. Adapted from Lai JC; Clin Liver Dis 2016 and Flint KM, et al; Circ Heart Failure 2012.
Futile
Very Poor
Functional Assessment In Liver Transplantation
R03 AG045072, K23 AG048337, R01AG059183
Study coordinatorsAdrienne LebsackYara MohamadRandi WongTab SrisengaBlanca LizaolaHilary HayssenRachel Mustain
FrAILT Post-DocsConnie WangLaila Fozouni
Mariya SamoylovaChristine Haugen
MentorsSandy Feng
Kenneth CovinskyNorah Terrault
Dorry Segev
BiostatisticiansJennifer DodgeCharles McCulloch
The Liver Frailty Index
Calculator available at: www.liverfrailtyindex.ucsf.edu. Lai JC, Hepatology 2017.
90 s
+ +
10 sec each
Using Frailty / Sarcopenia in Transplant Decision-Making
Categorize, establish cut-points
Lai JC, Hepatology 2017.Liver Frailty Index
Net Reclassification of 3-Month MortalityBy MELDNa + Frailty Index vs. MELDNa alone
Deaths/delistings16%
p=0.005
Non-deaths/delistings3%
p=0.17
Net reclassification index19%
p<0.001
Frailty before and after liver transplant
• The only predictor of post-transplant frailty was pre-transplant frailty
Only 2 out of 5 met criteria for “robust”
Pre-transplant Post-transplant
Lai / Feng. AJT 2018.
Using Frailty / Sarcopenia in Transplant Decision-Making
• 3 months ago, in clinicLiver Frailty Index = 3.2
During this hospitalization, Skeletal muscle index = 42 cm/m2
(<39 cm/m2 = sarcopenia)Carey/Lai, Liver Transpl 2017.
Patient A Patient B Patient CPre-transplant Vulnerability:
Post-transplant Vulnerability:
Favorable Intermediate Marginal
Transplant:
Outcome:
Patient-dependentAcceptableHighTransplant Benefit:
MELD 40MELD 40
MELD 40
Transplant Responsive(e.g., liver dysfunction, ascites, encephalopathy)
Transplant Non-responsive(e.g., older age, multi-morbidity, advanced undernutrition/sarcopenia)
Legend
Framework to Guide Transplant Decision-Making
Lai JC. Liver Transplantation 2017. Adapted from Lai JC; Clin Liver Dis 2016 and Flint KM, et al; Circ Heart Failure 2012.
Futile
Very Poor
Proceed with transplant?
Is this the limit of transplant?
Mrs. Davis, post-transplant course
• Underwent liver transplant with a standard donor• Discharged on POD14• Post-operative renal failure requiring 2 weeks of hemodialysis
recovered renal function• Complicated by anastomotic biliary stricture ERCP x 3
4 months later:• Admitted with septic shock from cholangitis with Klebsiella bacteremia• Complicated by DIC• Stent exchanged, hemodynamics improved
• Vomited sudden loss of mental status STAT head CT
The limit of transplant
Your Thoughts?
Frailty before and after liver transplant
3.7 3.9 3.73.4
4.3 4.4
4.03.8
3.23.5
3.23
2
2.5
3
3.5
4
4.5
5
PreLT 3 mo postLT 6 mo postLT 12 mo postLT x
Live
r Fra
ilty
Inde
x
3 moPost-LT
6 moPost-LT
12 moPost-LT
p=0.07p=0.02
p<0.001
Robust
Frail
Pre-LT
Well-compensated, low MELD, HCC patient
57 yo community-dwelling adult
Lai / Feng. AJT 2018.
Zone of Adverse Outcomes
Acute event
Phys
iolo
gic
rese
rve High reserve
(“non-frail”)
Low reserve (“frail”)
Frailty : A “Geriatric” Construct
“A distinct biologic syndrome of decreasing physiologic reserve and increasing vulnerability to health stressors”
Fried L. J Gerontol A Biol Sci Med Sci 2001.
Women awaiting liver transplant are vulnerable
• Women are more likely to die/be delisted on the liver transplant waitlist than men
This is due largely to women’s shorter stature
Lai JC et al, AJT 2010.
Moylan C, et al; JAMA 2008. Lai JC et al, AJT 2010.
Cumulative incidence of death/delisting by gender
Receipt of a “size-appropriate” liver (pediatric liver offer) eliminates the gender difference in waitlist mortality
Women whose first offer is from an adult donor
Ge J / Lai JC. Hepatology 2018.
Subh
azar
dra
tio o
f dea
th/d
elis
ting
Women whose first offer is from a pediatric donor
MELDNa 14 frail
MELDNa 23 frail
MELDNa 14 robust
MELDNa 23 robust
* Robust / Frailty defined as the 20% / 80%ile Liver Frailty Index values.
LFI predicts mortality better than MELDNa alone
MELDNa 14
Robust
Frail
MELDNa 23
Robust
Frail
Frailty = 9 MELDNapoints of mortality risk
Discussion
Did we do the right thing by transplanting her?
Would you / your center have transplanted her?
Are issues related to quality of life as important as survival? What if this patient had been frail / sarcopenic?
What is our responsibility as transplant clinicians to be good stewards of the scarce donor resource?
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