Defining the limit of transplant · • Non-responsive to stimuli • Hyperreflexia, myoclonus • Jaundiced, anasarca • No appreciable muscle wasting of the temples, biceps, muscle

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

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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




Transplant:

Outcome:


MELD 40MELD 40

MELD 40



Legend



ECD Liver Ideal liver ECD Liver

Futile

Very Poor

Stan

dard


Accept

• Delayed graft function worsening coagulopathy worsening hemorrhage


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




Accept



The (ideal) liver offer





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”



Accept



The (ideal) liver offer for Ms. Davis

Decline





19 yo woman died from

head trauma after a car accident


Bioengineered Livers: No Donor Scarcity


Accept



When donor supply is infinite

Decline






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



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?



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?



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?




Transplant:

Outcome:


MELD 40MELD 40

MELD 40



Legend



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

http://www.liverfrailtyindex.ucsf.edu/

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.




Transplant:

Outcome:


MELD 40MELD 40

MELD 40



Legend



Futile

Very Poor



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


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?

Documents

Defining the limit of transplant · • Non-responsive to stimuli • Hyperreflexia, myoclonus • Jaundiced, anasarca • No appreciable muscle wasting of the temples, biceps, muscle