2013 12 15 Duke Old Mans Friend No More v02

The Old Man’s Friend No More:Disability & Cognitive Decline

After Acute Infection

Theodore J. Iwashyna, MD, PhDUniversity of Michigan

Ann Arbor VA Center for Clinical Management Research

5 December 2013 – DuPRI Seminar Series

Disclosures•Key Funding:

•U.S. NIH K08 HL091249 (TJI)•U.S. NIH U01 AG09740 (HRS)•U.S. VA HSR&D IIR 11-109 (TJI)

•This work does not necessarily represent the views of the U.S. Government or Department of Veterans Affairs

•I have no relevant financial conflicts of interest to disclose

•I thank the organizers for the opportunity to join you today

http://upload.wikimedia.org/wikipedia/commons/a/ac/PneumonisWedge09.JPG

http://upload.wikimedia.org/wikipedia/commons/a/ac/PneumonisWedge09.JPG

In what sense do acute infections still matter in this era (in the U.S.) of chronic disease of the aged?

Are they common?

Do they cause lingering consequences?

Should they be incorporated into thinking about population health and disability?

Today’s Agenda:

Prologue: When you die with heart disease, what do you die from?

Chapter 1: Sepsis Biology & Epidemiology 101

Chapter 2: Disability & Cognitive Dysfunction

Chapter 3: Life Course Matters

Chapter 4: Population Impact

Epilogue: Summary & What’s Next

Heron et al. (2009) Nat Vital Stat Rep 57:14.

Death certificates are known to have substantial problems with accuracy compared to medical chart review, and there remains substantial uncertainty in how “underlying cause of death” is interpreted

A majority of older Americans die during an inpatient hospitalization

Hospitalization diagnoses are heavily audited for accuracy, with financial penalties for mistakes (unlike death certificates)

So we asked: for older Americans who die during an inpatient stay, how similar are the pictures that emerge from their hospitalization records and their death certificates?

NIA (2007) Growing Older in America.

http://hrsonline.isr.umich.edu/sitedocs/rda/permissions.pdf

Govindan et al. (2013) AJRCCM 187:A5292.

For older Americans who die during an inpatient stay, how similar are the pictures that emerge from their hospitalization records and their death certificates?

Population: Death among HRS-Medicare Cohort where date of death was same as date of discharge from last hospitalization.

Causes of death abstracted from death certificates, then aggregated to National Center for Health Statistics List of 50 Rankable Causes of Death.

Reasons for hospitalization (CMS-DRGs) were manually aggregated into a parallel classification by blinded physician.

Influenza, pneumonia and sepsis combined into “Infections”

Top Three Causes of DeathU.S. National Vital

StatisticsDeath Certificates For

Inpatients1. Heart Disease 1. Heart Disease2. Malignancy 2. Malignancy3. Cerebrovascular

Disease3. Cerebrovascular Disease


N = 2,053 inpatient deaths

Overall Kappa was 0.21

Cause of Death Based on DRGfrom Terminal Hospitalization (#

/ row%)

Same as Death Certificate

StrictAssessment*

Generous Assessment*

Death

Certificate

Heart Disease(n=639) 213 / 33% 421 / 66%

Malignancy (n=319) 120 / 38% 217 / 68%

Cerebrovascular Disease(n=195)

105 / 54% 138 / 71%


N = 2,053 inpatient deaths

Overall Kappa was 0.21

Cause of Death Based on DRGfrom Terminal Hospitalization (# / row%)

Same as Death Certificate

InfectionsStrictAssessment*

Generous Assessment*

Death

Certificate

Heart Disease(n=639) 213 / 33% 421 / 66% 123 / 19%

Malignancy (n=319) 120 / 38% 217 / 68% 54 / 17%

Cerebrovascular Disease(n=195)

105 / 54% 138 / 71% 37 / 19%



Top Three Causes of DeathU.S. National

Vital Statistics

Death CertificatesFor Inpatients

DRGs For Inpatients

1. Heart Disease

1. Heart Disease

1. Infections

2. Malignancy 2. Malignancy 2. Heart Disease

3. Cerebrovascular Disease



Today’s Agenda:







Vincent (2009) “Definition of Sepsis and Non-infectious SIRS” in Cavaillon & Adrie.

Definition: a syndrome that occurs when an infection leads to acute organ dysfunction.

• Profound inflammatory and coagulopathic dysregulation

• Global dysfunction from a locally adaptive process

Wide range of acuity

Angus et al. (2001) Crit Care Med 29:1303.

Annane et al. (2005) Lancet 365:63.

Sepsis as we were taught:• Hospital-Acquired• Procedure-Associated• An ICU Disease• Uniformly Acutely Devastating

The New Data:• Community-Acquired• Common• A Spectrum of Disease

• Most Survive• Dramatic Opportunities for Improvement

Iwashyna, Cooke, Wunsch & Kahn (2012) J Am Geri Soc 60:1070.

Elixhauser et al. (2011) HCUP Statistical Brief #122.

Today’s Agenda:







Q: Is there a residue in sepsis survivors who have had multi-organ failures or dysfunctions?

A: Most people return to normal or near-normal lives even if they have had severe organ failures. … [Persistent problems are] rare. Most surviving patients come back to being normal.

2004 interview with Gordon Bernard, Assistant Vice-Chancellor for Research, Melinda Owen Bass Professor of Medicine and Director, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center.

Frontline (2004) Vol:21 Iss:20 URL: http://www.flonnet.com/fl2120/stories/20041008001708600.htm

Quartin et al. (1997) JAMA 277:1058.

Eikermann et al. (2006) Int Care Med 36:251 as reproduced in Callahan & Supinski (2009) Crit Care Med 37S:S354.

“That which does not kill you, makes you weaker”.

- Christopher Hitchens in Vanity Fair, January, 2012

1998

2000

2002

2004

2006

Worsen

ing

Disabi

lity

If Never Hospitalized

1998

2000

2002

2004

2006

Worsen

ing

Disabi

lity


1998 20

002002

2004

2006

Wors

enin

g Di

sabili

ty

If Hospitalized

Hospitalization Effect:

We estimate these as latent growth curves – that is, using a within-person fixed effectto provide complete control for alltemporally invariant characteristics of patients

1998

2000

2002

2004

2006

Worsen

ing

Disabi

lity


1998 20

002002

2004

2006

Wors

enin

g Di

sabili

ty

If Hospitalized

Hospitalization Effect:

We estimate these as latent growth curves – that is, using a within-person fixed effectto provide complete control for alltemporally invariant characteristics of patients

Is a hospitalization for severe sepsis associatedwith greater disability and cognitive impairmentthan expected by trajectory alone?

Outcome Variables:Disability is measured as self or proxy-reported count of ADLs and IADLs on which help was required due to health

Cognitive impairment is a trichotomous outcome of normal, mildly impaired or moderate / severe impairment, incorporates proxies

Exposure Variable:Severe Sepsis: “Angus” implementation of consensus conference definition• infection + acute organ failure• Defined in ICD-9-CM codes in Medicare

claims• PPV: 71%Crimmins et al. (2011) J Geron B 66(S1):162; Angus et al. (2001) Crit Care Med 29:1303;

Iwashyna et al (2012) Med Care.

Iwashyna et al. (2010) JAMA 304:1787.

n=623Male (%) 45.1%Age at Sepsis 76.9

yearsHospital Length of Stay

10.6 days

Mechanical Ventilation

19.7%

Underwent Major Surgery

30.4%

Used Critical Care 43.2%Organ Dysfunction Score

1.1



Enduring Long-Term Morbidity


Pre-SepsisDisability

Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)

Table 3 (Excerpt):Number of Newly Acquired Disabilities,after regression controls




Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)





Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)





Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)





Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)





Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)





Effect of Sepsis

Severe 0.04 (p=0.93)

Mild/Moderate

1.50 (p<.001)

None 1.57 (p<.001)




Outcome Severe Sepsis

“Generic” Hospitalizati

onCognitive Impairment 3.34 (1.53,

7.25)1.15 (0.80,

1.67)

Disability if None Before

1.57 (0.99, 2.15)

0.48 (0.39,0.56)

Disability if Mild/Mod Before

1.50 (0.87, 2.12)

0.43 (0.22,0.63)

Disability if Severe Before

0.04 (-0.74, 0.81)

-0.47 (-0.83,-0.11)

Semmler, Widmann et al. (2013) J Neurol Neurosurg Psychiatry in press: doi: 10.1136/jnnp-2012-302883.

Normal BrainsPost-Sepsis Brains

Disclosures

Puthucheary et al (2013) JAMA early released 9 Oct 2013.

Today’s Agenda:







Slide courtesy of G. Rubenfeld, from Rubenfeld (2011) ATS International Conference.

• Older Americans frequently have “Geriatric Conditions” – multifactorial conditions that are precipitated by acute illnesses and are associated with frequent problems.

• Development of geriatric conditions is hallmark of aging.

• Biology of geriatric conditions still actively researched.

Inouye et al. (2007) JAGS 55:780.

Condition U.S. Prevalence, 65+Cognitive Impairment 7.3%

Injurious Falls 9.6%Incontinence 12.7%

Low BMI 2.9%Dizziness 13.4%

Vision Impairment 8.0%Hearing Impairment 25.7%

Cigolle et al. (2007) Annals 147:156, Appendix Table 1.

• Hypothesis: Severe sepsis will be associated with an acute increase in the prevalence of geriatric conditions.

Outcomes were self-report using standard language across multiple survey waves of HRS.• augmented with proxies where necessary

Falls: resulting in injuring

Incontinence: requiring pads or diapers

Vision Impairment: despite corrective lenses

Hearing Impairment: despite use of hearing aids

Research Questions (II)Hypothesis: Severe sepsis will be associated with an acute increase in the prevalence of geriatric conditions.

Will the apparent association be similar across 3 alternative study designs?• Prospective cohort vs. age-matched population controls

• Prospective cohort vs. own pre-sepsis baseline

• Prospective longitudinal cohort with extensive pre-sepsis prospective data

Condition General Population

Survivor Cohort

Injurious Falls 9.6% 32% ***Incontinence 12.7% 24%***

Low BMI 2.9% 7% ***Dizziness 13.4% ---Vision

Impairment8.0% 20% ***

Hearing Impairment

25.7% 15% ***

Severe Pain --- 12%*** p < 0.001 for differenceIwashyna et al. (2012) AJRCCM 185:835.

p = 0.029

p = 0.019

p < 0.001

p = 0.975

p = 0.013

p = 0.196

Iwashyna et al. (2012) AJRCCM 185:835.


Pre-Sepsis Trajectory

Effect of Sepsis

OR (per yr) p-value OR p-

valueIncontinence 1.21 0.002 1.02 0.939

Low BMI 1.09 0.607 5.60 0.002Poor Hearing 1.23 0.004 1.32 0.414

Poor Vision 1.25 <0.001 1.16 0.571

Severe Pain 1.15 0.030 0.70 0.217

Fall 1.19 0.002 0.89 0.610Iwashyna et al. (2012) AJRCCM 185:835.

At Risk of Beating A Dead HorseEffect of

Sepsis OR p-value

Incontinence 1.02 0.939 Nothing beyond

trajectoryLow BMI 5.60 0.002Poor Hearing 1.32 0.414 Nothing beyond

trajectoryPoor Vision 1.16 0.571 Nothing beyond

trajectorySevere Pain 0.70 0.217 Nothing beyond

trajectory

Fall 0.89 0.610 Nothing beyond trajectory


Many typical inception cohort study designs would have falsely concluded that severe sepsis had a big association.

Today’s Agenda:








Little Change in Case-Fatality Rate


≥ 3 Year Survivors 637,867

Total Number of Survivors

“New” Survivors, by Year


≥ 3 Year Survivors 637,867

With Cognitive Impairment

*

106,311(95% CI: 79,692,

133,930)

With Functional Disability

*

476,862(95% CI: 455,026,

498,698)

Total Number of Survivors

“New” Survivors, by Year


* These numbers are wrong given the absence of appropriate longitudinal population weights for the HRS-Medicare. But they are probably in the right ballpark.

Today’s Agenda:







In what sense do acute infections still matter in this era (in the U.S.) of chronic disease of the aged?Acute infections are not just acutely life-threatening, but also often life-altering.

Are they common?Yes, both absolutely and as proximal causes of death across diverse underlying causes of death.

Do they cause lingering consequences?Yes, particularly for brains and muscles.

Should they be incorporated into thinking about population health and disability?Probably. There are a lot of survivors out there.

What drives recovery?• Heterogeneity in trajectories within disease

• Effect modifiers (particularly social, organizational and contextual) and positive deviants

• Heterogeneity across acute illnesses

To what extent are apparently continuous “growth curves” for many aging processes really the results of aggregated discontinuous hits?

How important would blunting these acute hits be for long-term morbidity and mortality?• Less bad sepsis vs. rarer sepsis?

The Old Man’s Friend No More:Disability & Cognitive Decline

After Acute Infection

Theodore J. Iwashyna, MD, PhDtiwashyn @ umich . edu

5 December 2013 – DuPRI Seminar Series

Original Slide courtesy of G. Rubenfeld, from Rubenfeld (2011) ATS International Conference, now heavily modified.

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2013 12 15 Duke Old Mans Friend No More v02