Views from the Bench Rob Squires, MD, FAAP Clinical Director, - - PDF document

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Views from the Bench Rob Squires, MD, FAAP Clinical Director, - - PDF document

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4/2/2012 Views from the Bench Rob Squires, MD, FAAP Clinical Director, Childrens Hospital of Pittsburgh Professor of Pediatrics, University of Pittsburgh Dream Job: General Pediatrician in El Paso, Texas Observations Residency Dr. Larry Nicky

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SLIDE 1

4/2/2012 1

Views from the Bench

Rob Squires, MD, FAAP Clinical Director, Children’s Hospital of Pittsburgh Professor of Pediatrics, University of Pittsburgh

Observations

  • If the coach isn’t coaching you, you are not a

priority

  • Success can breed arrogance; all glory is fleeting
  • Standing or sitting next to the coach doesn’t help

F h b i h i lif h i

  • For some, the best year in their life was the senior

year.

  • Talent and hard work are often not aligned, but

when they are, sparks fly

  • If you get an opportunity to play, take it; even if it

is not your position

Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

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4/2/2012 2

Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate Where can I do a pediatric neurology externship? Bill Daeschner, MD Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate Where can I do a pediatric neurology externship?

  • St. Louis Children’s Hospital 1977

Bill Daeschner, MD Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Jim Keating, MD Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Jim Keating, MD Janet Endress 1979 Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Jim Keating, MD Janet Endress 1979, Greg 1980 Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Jim Keating, MD Janet Endress 1979, Greg 1980, Jim 1982

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SLIDE 3

4/2/2012 3

Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Jim Keating, MD Private GI Practice

  • Ft. Worth, Texas 1982

Janet Endress 1979, Greg 1980, Jim 1982 Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Jim Keating, MD Private GI Practice

  • Ft. Worth, Texas 1982

Janet Endress 1979, Greg 1980, Jim 1982 Beth 1983 Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Bill Belknap MD Private GI Practice

  • Ft. Worth, Texas 1982

Janet Endress 1979, Greg 1980, Jim 1982 Beth 1983 Bill Belknap, MD Charles Ginsburg, MD UT Southwestern 1987 Clinical Program Development Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Private GI Practice

  • Ft. Worth, Texas 1982

Janet Endress 1979, Greg 1980, Jim 1982 Beth 1983 Will Lee, MD Pat Robuck, PhD UT Southwestern 1987 PALF Consortium 1999 NIH/NIDDK 2005‐15 Clinical Program Development Dream Job: General Pediatrician in El Paso, Texas UT Galveston Residency Galveston

  • Dr. Larry Nicky

Associate

  • St. Louis Children’s Hospital 1977

Private GI Practice

  • Ft. Worth, Texas 1982

Janet Endress 1979, Greg 1980, Jim 1982 Beth 1983 David Perlmutter, MD Mark Lowe, MD, PhD. UT Southwestern 1987 Children’s Hospital of Pittsburgh 2003 Pediatric Intestinal Failure Consortium NIH/NIDDK 2006‐08 Clinical Program Development Clinical Program Development PALF Consortium 1999 NIH/NIDDK 2005‐15

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SLIDE 4

4/2/2012 4

Pediatric Intestinal Failure Consortium (PIFCon)

  • Single site studies requires decades to achieve

sufficient numbers of patients

  • Medical, surgical, nutritional, and transplant
  • ptions vary depending upon the era
  • ptions vary depending upon the era
  • National, multi‐center collaborative is the only

mechanism to achieve sufficient numbers in a contemporary era.

PIFCon’s Inception June 3,2006 Specific Aims

  • To identify demographic, clinical, and nutritional risk

factors within a contemporary cohort of infants and children with intestinal failure that will predict the need for long‐term TPN (< 60 days), weaning from total parenteral nutrition, development of cholestasis, intestinal transplant and death.

  • To identify practice pattern variability and outcomes
  • To initiate planning and feasibility for a prospective,

multi‐center consortium

Pittsburgh Boston Ann Arbor* Chicago Columbus* Cincinnati Omaha Rob Squires (GI) Chris Duggan (GI) Dan Teitelbaum (Ped Surg) Ric Superina (Transplant) Jane Balint (GI) Sam Kocoshis (GI)

  • D. Sudan/D.Mercer (Transplant)

Nucci (D), Burns (PS), Mazariegos (TX) Kamin (GI), Jaksic (PS), Kim (TX) Brown (GI), Johnson (D) Cohran (GI), Superina (PS), Kazermski (D) Valentine (D), Teich (PS) Reichman (PS, TX), Wessel (D), Jeff Rudolph (CO) Antonson (GI), Raynor (PS), Sunderman (D)

PIFCon Site Principal Invest Other Support Personnel

Vanderbilt* Houston* Denver* UCLA UCSF Seattle Toronto Andres Martinez (GI) Beth Carter (GI) Jason Soden (GI) Rob Venick (GI) Susan Rhee (GI) Simon Horslen (GI) Paul Wales (Ped Surg) (PS), Ballew (D), Brent Polk (CO) Brandt (PS), Phillips (D) (PS), Brown/Fidanza (D) Beckwith (D), Dunn (PS), Farmer (TX) Farmer (PS), Kang (TX), Bower (D) Villanueva (D), Reyes (TX), Healey (PS) Pencharz (GI), Fecetau (TX), Courtney‐Martin (D) * = not an intestinal transplant site

Not everything that is good will succeed

  • 2006.6.3: Breakfast meeting
  • 2007.6.14: Submitted R21 application
  • 2008.6.3: R21 DK 081059 awarded
  • 2008.6.15: Funding for R21 begins; retrospective study with 12 + 2 sites
  • 2009.2.20: Efforts to incorporate a GLP‐2 trial into the UO1 fell through
  • 2009.3.27: First letter to NIH requesting application for U34 proposal

– Aim 1: Longitudinal Study – Aim 2: Microbiome Project – Aim 3: Ethanol Lock Trial

  • 2009.4.10: Application to apply rejected
  • 2009.4.30: Second letter to the NIH submitted

– Aim 1: Longitudinal Study – Aim 2: Assess markers of adaptation – Aim 3: Markers of oxidative stress

  • 2009.5.10: Approval to submit a U34 Application
  • 2009.6.23: U34 proposal submitted to the NIH
  • 2009.11.13: Grant reviewed
  • 2009.12.16: Summary statement received

– Scored “Good”…not good enough

Proposed Model of the Natural Course and Outcome of Acute Liver failure in Children

Alive

urse

Dead Prodrome

TIME

Hours, Days, Weeks Sudden event that alters expected course: bleeding, sepsis, SIRS, etc

Disease Co

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SLIDE 5

4/2/2012 5

Proposed Model of the Natural Course and Outcome of Acute Liver failure in Children

Alive

First Encounter urse

Dead Prodrome

TIME

Hours, Days, Weeks Sudden event that alters expected course: bleeding, sepsis, SIRS, etc

Disease Co Liver Transplant

Proposed Model of the Natural Course and Outcome of Acute Liver Failure in Children

Alive

Event alters expected

urse

A

Patient characteristics and management Cytokine profile/SIRS markers Liver regenerative markers Genetic polymorphisms Immunologic profile Metabolomics Proteomics

Dead Prodrome

TIME

Hours, Days, Weeks expected course: bleeding, sepsis, renal failure

Disease Co B C D

Proteomics Diagnosis

Contributing PALF Investigators

Rob Squires/Ben Shneider‐Pittsburgh Mike Narkewicz‐Denver Estella Alonso‐Chicago (Children’s Memorial) Norberto Rodriguez‐Dallas Simon Horslen/Karen Murray‐Seattle Phil Rosenthal‐San Francisco Girish Subbarao‐Indianapolis Nanda Kerkar‐New York (Mt. Sinai) Jim Lopez‐Ann Arbor Mike Leonis/John Bucuvalas‐Cincinnati David Rudnick‐St. Louis (Wash U) Kathy Loomes/Liz Rand‐Philadelphia (CHOP) Rene Romero‐Atlanta (Emory) Vicky Ng‐Toronto, Canada Anil Dhawan‐London, UK (Kings) Saul Karpen‐Houston (Baylor) D i i D lOli D i d K ll Jim Lopez Ann Arbor Scott Elisofon‐Boston (Harvard) DCC Steve Belle Sharon Lawlor Song Zhang Joy Bowen Stephanie Kelly Denise Vandersal Dominic DelOlio, Deirdre Kelly‐ Birmingham, UK Kathy Schwarz‐Baltimore Steve Lobritto‐New York (Columbia) NIH‐NIDDK Pat Robuck, PhD, MPH Edward Doo, MD Jay Hoofnagle, MD

Thank you to the participating children and their families

Pediatric Acute Liver Failure (PALF) Study Group

  • PALF Study Group (NIH/NIDDK 1 UO1 DK 072146‐01)

– Began in 2000; Independently funded 2005‐2010 – Multi‐center, multi‐national study

  • United States = 17
  • Canada (Toronto)= 1
  • United Kingdom (London Birmingham) = 2
  • United Kingdom (London, Birmingham) = 2

– Data

  • Clinical and Laboratory data, plus serum, daily for 7 days
  • End points: death, transplant, discharge
  • Biological samples: DNA, bile, liver, fibroblasts, urine
  • Treatment trial

– N‐acetylcysteine for non‐acetaminophen ALF (completed)

  • Core and Ancillary studies

Passion versus Equipoise

  • NAC was used routinely in the UK, Canada and

many sites in the US in non‐acetaminophen ALF

  • No prospective data
  • No prospective data
  • Sites committed to test the hypothesis that IV

NAC in non‐acetaminophen ALF improved 1 year outcome

Results Primary Outcome: 1 Year Survival

73% 82% 60% 80% 100%

age Survival

Placebo NAC p-value =0.20

0% 20% 40% 100 200 300 400 Days Following Randomization

  • Cum. Percenta

P

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SLIDE 6

4/2/2012 6

Secondary Outcome: Survival with Native Liver

p-value=0.03 53%

Placebo

60% 80% 100% e Survival 53% 35%

Placebo NAC

0% 20% 40% 60% 100 200 300 400 Days Following Randomization

  • Cum. Percentage

N

Registry Enrollment

400 500 600 700 800

  • f Participants

Pediatric Acute Liver Failure

UTSW to Pittsburgh transition

100 200 300

Number Year Expected Observed

2000 2001 2002 2003 2004 2005 2006

Database as of 10/15/07

2007 2008 2009

NAC Enrollment

80 100 120 140 160 180 200

  • f Participants

Pediatric Acute Liver Failure

UTSW to Pittsburgh transition

20 40 60 80

Number Year Expected Observed

2004 2007 2008

Database as of 10/15/07

2003 2005 2006 2009

Potential Solutions to Improve Enrollment in the NAC trial

  • Be committed to the importance of this study

– We do not know if NAC works for children – Ours is the only randomized trial to answer the question of benefit – If it does not work, we should not confuse management with a placebo – “Failure to complete will make it difficult to compete….”

  • ALF is rare

– Keep talking about the study with GI and ICU colleagues Develop contingency plans for when the PI and coordinator are out – Develop contingency plans for when the PI and coordinator are out – Establish trust with the family through education; this takes time an patience

  • Consent forms

– Know the consent form well, emphasize what is important – Prepare the family – Identify the best person(s) to obtain consent

  • Practice variation

– Educate community physicians about the study – Your commitment to research can inspire others – Get “buy‐in” from other services about the importance of this study

  • There must be other solutions as well, we need each other!

Create a Culture of Clinical Investigation

  • Every child should be in a study
  • Every faculty member should be aware of

every clinical study and promote enrollment ’ l “ di i ” i h f i i

  • Don’t let “tradition” get in the way of curiosity
  • Opportunities for “comparative effectiveness”
  • Quality improvement

PALF Ancillary Studies

Principal Investigator Project Kathy Schwarz (Hopkins) Viral studies in children with ALF Mike Leonis/Estella Alonso (Cincinnati/Chicago) Characterization of APAP induced PALF Lori Holtz (Washington University) Identification of novel viruses in PALF Mike Narkewicz (Denver) Autoimmune hepatitis R S k l (D ) Mit h d i l h t th Ron Sokol (Denver) Mitochondrial hepatopathy David Rudnick (Washington University) Metabolomic analysis Vinay Sundram (University of Pittsburgh) Analysis of Adult Severity Scoring Systems

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4/2/2012 7

Selected Ancillary Studies

  • Acetaminophen (APAP) adducts—Alonso/James

– Determine the frequency of adducts in all PALF – Assess rate of disappearance of adducts in PALF caused by APAP

  • NK cell dysfunction—Bucuvalas

– Patterns are being characterized that will help characterize immune dysregulation in PALF

  • Liver Injury Unit (LIU) score in PALF—Lu/Sokol

– Data currently being analyzed to assess a clinical score for severe liver injury in children developed in Denver

NIH Grant applications utilizing PALF data and biosamples

  • Optimal timing of transplantation in PALF‐ Roberts
  • Neonatal hemochromatosis in PALF‐Whitington
  • Liver regeneration biomarkers in PALF‐Rudnick
  • Can inflammatory and immune markers predict outcome in PALF

Vodovotz

PALF 2010‐15: View from 500 miles

  • Primary Aim: Comprehensively characterize PALF

– Serially collect biochemical, clinical, diagnostic and management profiles – Novel immune, inflammatory, and regeneration markers – Identify dynamic factors that predict outcomes ll bi l ill di – Collect biosamples to support ancillary studies

  • Secondary Aims

– Develop a more comprehensive risk stratification – Develop a data driven decision analysis strategy – Link the PALF phenotype with outcomes and models to develop in silico analogs used to predict long‐term clinical and neurocognitive outcome

  • Clinical Trial

– To assess the safety and efficacy of corticosteroid treatment in children and adolescents with indeterminate ALF

  • Ancillary Study: Hepatic Encephalopathy (Mark Wainwright)

Presentation Disease Severity Diagnosis Identified Unknown Identified Indeterminate Treatable Not treatable Improved No change Outcomes Alive ± morbidities Transplanted y Management Modifying factors Inflammatory milieu End organ damage Immune activation Regeneration g Worse General support Targeted Therapy Δ Inflammatory milieu Δ End organ damage Δ Immune activation Δ Regeneration ± morbidities Death + morbidities

Outcomes and Co‐morbidities

  • Outcomes

– Alive with native liver

  • Without co‐morbidities
  • With co‐morbidities

– Alive with liver transplant

  • Without co‐morbidities
  • Co‐morbidities

– Neurocognitive

  • Intelligence scale (IQ)
  • Health‐related quality of life
  • Visual‐motor integration
  • Attention

Ad i

  • With co‐morbidities

– Dead with native liver

  • Without co‐morbidities
  • With co‐morbidities

– Dead with liver transplant

  • Without co‐morbidities
  • With co‐morbidities
  • Adaptive
  • Post‐traumatic stress disorder
  • Depression

– Hepatobiliary

  • Elevated AST/ALT/GGT/bilirubin
  • Recurrence of disease

– Extra‐hepatic

  • Cytopenias
  • Renal insufficiency

Pre- Post--ICU PICU OP F/U DAILY Int ITEM E D Q D 6 6 D 6 1 Clinical Vitals HR/BP/RR/Temp X X X X X X Weight X X X Length/Height X X X BMI X X X Pulmonary Room air X X X X X O2 supplement X X X X X Intubated Y/N X X Cardiovascular Off pressors X X X

  • Patient identification
  • Patient enrollment
  • Data collection/quality
  • Complete data
  • Correct data
  • Timely
  • Little missing

Off pressors X X X On pressors X X X Neurological Encephalopathy stage X X X X X X Pupilary reactions X X X X X X Components of neuro examination?? X X X X X X Glasgow Coma Score X X X X X X Developmental test X X Neurocognitive test X X Depression X X Post-Traumatic Stress Disorder X X Renal No renal support X X X X X X Medical renal support X X X X X X Renal replacement Y/N TIMES X X X

  • Little missing
  • Processes
  • Serum
  • Urine
  • Liver tissue
  • DNA
  • Prioritization
  • Local commitment
  • Multi‐specialty
  • Colleagues
  • Weekends
  • Vacations
  • Responsive to DCC
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SLIDE 8

4/2/2012 8

PALF and PIFCon PI Retreat

Clinical Research is a Life‐Long Exercise

  • Bloom where you are planted
  • You have to plow the field before you can harvest
  • Have a sense of humor
  • Beware the “God complex” and “co‐dependency”
  • Be curious
  • Maintain equipoise
  • Don’t count
  • Balance “self‐promotion” with “It is amazing what you

can accomplish if you don’t care who gets the credit”

  • Learn to play well in the sandbox

Within the estimated 170 billion galaxies in the universe

“You are here” says the sign, as we hurdle through space Can it be that that point holds the whole human race? It’s all just so big; and we are left to agree That we must focus our vision in order to see. Picture of Earth taken by Voyager 1 from 4 billion miles away as the space craft was leaving the Milky Way. How is it possible that on this blue dot Rest all that has lived and all who have thought. This must be how Horton had felt When sounds of life screamed from that spec on his pelt.

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4/2/2012 9

As we get closer, more comes into focus A beautiful and peaceful and, oh wait, is that Texas? It’s big, yet it’s small so how can it be That water and land move in such harmony. Even closer, ah ha, we find gathering holes Each working together to achieve many goals. All healthy? Not so, for we know to be sure That many are sick and in hope for a cure. Courtesy of David Keljo, MD, PhD We gather resources, and concentrate minds To build a new hospital that’s one of a kind. It’s here we will work, and consult and advise To serve the most vulnerable with hope in their eyes. One child at a time, each one unique Brings such innocence and wonder and trust, that we shriek Charlotte, you see, with eyes bright and blue Expects us and needs us to find new breakthroughs The universe is big too big for my mind Courtesy of Greg and Meghan Squires The universe is big, too big for my mind There are mysteries, and wonders, and

  • nes of a kind.

She is our universe, so innocent and sweet We must strive to collaborate and bring disease to defeat. DORY: Just keep swimming, just keep swimming, just keep swimming!!!!!!