RR&D Center of Excellencefor the

Medical Consequencesof Spinal Cord Injury

William A. Bauman, M.D.Director

Ann M. Spungen, Ed.DCo-Director

January 21, 2010Rancho Los Amigo National Rehabilitation Hospital

Program Lines of Study

1. Endocrine ProgramWilliam A. Bauman, MD

2. Pulmonary ProgramGregory J. Schilero

3. Automomic Program Jill M. Wecht, EdD

4. Gastrointestinal Program Mark A. Korsten, MD

5. Molecular ProgramChristopher P. Cardozo, MD

Anabolic Hormones

Disuse Osteoporosis

Carbohydrate Metabolism

Lipid Metabolism

Endocrine Program

Coronary Heart Disease

Osteoporosis in SCI

• SCI is a nonweight bearing condition.

• Bone is lost rapidly with acute SCI.– goal is to preserve bone architecture & mass

• Bone continues to be lost years after SCI– goal is to replace bone mass

Endocrine Program

Disuse Osteoporosis• Pharmacological intervention:

Acute SCI: pamidronate & zoledronate Chronic SCI: Hectoral (1-α-hydroxyvitamin D2)

• Low amplitude, high frequency mechanical stimulation

• Evaluation of DXA vs. other imaging modalities

• Vitamin D replacement therapy

Bauman et al. Metabolism. 44:1612-1616, 1995.

• Absolute vitamin D deficiency state:32 of 100 (32%) in SCI 8 of 50 (16%) Cont

In Persons with SCI:

• Negative Correlation: PTH & 25 (OH) vitamin D levels

• Positive Correlation: PTH & 1,25 (OH)2 vitamin D levels

Calcium Metabolism in Chronic SCI

Relationship between Serum PTH and Urinary NTx Levels

Ledger et al., J Clin Endocrinol Metab 80:3304-3310, 1995.

Vitamin D Replacement: 2000 IU per Day for 3 Months

Baseline Month 1 Month 30

1

2

3

4

5

6

7

8Absolute Deficiency < 16 ng/mlRelative Deficiency < 30 ng/mlNo Deficiency ≥ 30 ng/ml

Nu

mb

er

of

Su

bje

cts

Bauman et al., Unpublished observation.

Endocrine Program

Anabolic Hormones• Baclofen to increase IGF-1• Anabolic steroid agents• Testosterone replacement therapy

Testosterone Replacement Therapy (TRT)

Intervention: 12 months of TRT

Endpoints: • Body composition• Muscle strength• Resting energy expenditure• Glucose tolerance• Autonomic function• Psychological assessment

CountAge (yrs)

Height (cm)Weight (kg)BMI (kg/m2)

Duration of InjuryPara/TetraComplete/

Incomplete

TRT 6

43±5180±7

87.8±15.726.8±3.1

13±102/94/2

Control 9

37±9174±4

83.2±6.0

27.4±2.2

11±92/67/2

Characteristics of Subjects for theTestosterone Replacement Study

Baseline Testosterone Washout

4042444648505254565860

TO

TA

L B

OD

Y LT

M (

kg

)

52.2

54.8 55.0

52.753.4

51.1

P<0.05

P<0.05

800900

10001100120013001400150016001700

REE (K

cal/

d)

1,386

Baseline Testosterone

1,508

1,341 1,349

P<0.05

122 Kcal/d

Testosterone Replacement Therapy

Design:TRT for 12 moWashout for 6 mo

Testosterone

Control

Bauman et al., Unpublished observation.

Endocrine Program

Carbohydrate Metabolism• IV GTT• Oral GTT• Relationship to:

- Soft tissue (total & regional)

- Activity (V02max)

Total Body Percent Lean Tissue & Age: Able-Bodied vs. SCI

Spungen et al., J Appl Physiol. 95:2398-2407, 2003.

TO

TAL

BO

DY

% L

EA

N

AGE (y)

25

35

45

55

65

75

85

95

10 20 30 40 50 60 70 80

SCI slope (-0.341, P<0.0001)

AB slope (-0.175, P<0.0001)

Spungen et al., J Appl Physiol. 95:2398-2407, 2003.

Cross-Sectional Study: Chronic SCI

SCI

Control

0

5

10

15

20

25

30

35

40

< 40 y 40 y

Tota

l Bo

dy

Pe

rcen

t F

at

*

P<0.0001

*

* P<0.05 for Control vs. SCI

Body Mass Index Criteria for Normal, Overweight and Obesity

Expert Panel on the Identification , Evaluation and Treatment of Overweight and Obesity in Adults. NIH NHLBI. 1998

UnderweightNormalOverweightObese

BMI (m/kg2)<18.5

18.5-24.925-29.9

>30

Spungen et al., J Appl Physiol 95:2398-2407, 2003.

Tot

al B

ody%

Fat

Body Mass Index (kg/m2)

0

10

20

30

40

50

60

10 15 20 25 30 35 40 45

The Relationship of Percent Fat With Body Mass Index

SCIControl

Ruderman NB, et al. The “metabolically-obese,” normal-weight individual. Am J Clin Nutr 34:1617-1621, 1981

Premise: Persons with metabolic disorders (type 2 DM, HTN, hypertriglyceridemia) who are not obese by standard weight tables or other readily available criteria, but who respond favorably to caloric restriction.

It is proposed that such individuals might be characterized by hyperinsulinism and an increase in fat cell size. Inactivity may be a contributing factor. As such, these individuals may benefit from exercise therapy.

St-Onge MP, et al. Metabolic syndrome in normal-weight Americans: new definition of the metabolically obese, normal-weight individual. Diabetes Care. 27:2222-2228, 2004.

Prevalence rates MONW syndrome were determined in 7,602 adult participants of the Third National Health & Nutrition Examination Survey.

BMI 21-22.9 23-24.9

Men 4.13 5.35

Women 4.34 7.77

Odds ratios (OR) compared with those with BMI=18.5-20.9

Effects of Spinal Cord Injury on the Determinants of Insulin Resistance

Muscle mass ↓Fat mass ↑

Activity ↓

Oral Glucose Tolerance by Neurological Deficit

Complete Tetraplegia

Incomplete Tetraplegia

Complete Paraplegia

Incomplete ParaplegiaDM

IGT

NL

27%

50%

23%

56%24%

20%

69%

76%

17 %

14 %

6 %

18 %

Bauman et al., Spinal Cord. 37:765-771, 1999.

Frequency of Impaired Glucose Tolerance and/orDiabetes Mellitus by Neurological Deficit

Neurological Subgroup

Complete Tetra

Incomplete Tetra

Complete Para

Incomplete Para

Percent

73*

44

24

31*p<0.0001

Bauman et al., Spinal Cord. 37:765-771, 1999.

Frequency of Hyperinsulinemia

Group

Tetra

Para

Percent

53*

37*P<0.05

Bauman et al., Spinal Cord. 37:765-771, 1999.

Ser

um

Glu

cose

(m

g/d

L)

0

25

50

75

100

125

150

175

200

225

250

0 30 60 90 120

NGT

IGT

DM

Time (minutes)

Serum Glucose Results from a 75 g OGTT in SCI

Bauman et al., Unpublished observation.

Pla

sm

a In

sulin

(U

/ml)

0

20

40

60

80

100

120

140

160

180

0 30 60 90 120

NGT

IGT

DM

Time (minutes)

Plasma Insulin Results from a 75 g OGTT in SCI

Bauman et al., Unpublished observation.

Percent of Subjects by SCI Group and FPI Category

0

5

10

15

20

25

30

35

40

0-5 5-9 10-14 15-19 20-100

TETRA

PARA

Per

cen

t

FPI CategoryBauman et al., Unpublished observation.

Percent of Subjects by Group & 2-Hour Insulin Category

After a 75 g OGTT

0-49 50-99 100-150 > 1500

5

10

15

20

25

30

35

40

45 TETRA

PARA

Per

cen

t

Two-Hr Insulin CategoryBauman et al., Unpublished observation.

Endocrine Program

Lipid Metabolism• Descriptive data• Relationship to body fat• Intervention with Niaspan

Protective Effect of HDL Cholesterol

• Reverse cholesterol transport

• Anti-oxidant• Anti-inflammatory• Direct vascular• Anti-platelet• Anti-coagulant

Bauman et al., Metab. 43:749-756, 1994.

Relationships between Insulin Sensitivity with VO2 max & HDL Cholesterol

HDL as a Risk Factor in Persons with SCIDecreased plasma HDL cholesterol Elevated Total Cholesterol : HDL ratioHDL cholesterol < 40 mg/dL: 63%

HDL cholesterol < 35 mg/dL: 44%HDL cholesterol < 30 mg/dL: 19%

Bauman et al., Spinal Cord, 1998Bauman et al., Metabolism, 1994Bauman et al., Spinal Cord, 1999Bauman et al., Topics in Spinal Cord Injury Rehab, 2008

30

35

40

45

50

TetraComplete

TetraIncomplete

ParaComplete

ParaIncomplete

Average Risk

Morbidity risk ratio(age-adjusted)

HDL (mg/dl)

20 40 60 80

0

1.0

2.0

HDL-Cholesterol & CHD Risk(Men in Framingham, MA)

HD

L C

ho

lest

ero

l (m

g/d

L)

HDL Cholesterol by Ethnicity

Bauman et al., Arch Phys Med Rehabil. 79:176-180, 1998.

National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation and TreatmentOf High Blood Cholesterol in Adults

» 1988 Adult Treatment Panel (ATP) I» 1993 ATP II» 2001 ATP III

Guidelines for Assessment of Risk for CHD

2004 Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines

Over the years, the “target values” for LDL cholesterolhave become more conservative.

Subjects: 41 subjects with paraplegia

• ASIA A & B: T6 to L1• Age: 34±11 years

Nash MS, et al. A guideline driven assessment of need for cardiovascular disease risk intervention in persons with chronic paraplegia. Arch Phys Med Rehabil. 88:751-757, 2007

Main Outcome Measure: % of subjects qualifying for intervention • Based on ATP III guidelines

Results: 63% of subjects qualified for intervention » 76% had HDL cholesterol <40 mg/dL » ~1/3 had hypertension » 34% had the metabolic syndrome

Nash et al. Arch Phys Med Rehabil. 88:751-757, 2007.

Conclusion: A high percentage of young, healthy persons with SCI are at risk for CVD & qualify for lipid-lowering intervention.

Nash MS, et al. Arch Phys Med Rehabil. 88:751-757, 2007

Risk Assessment for Coronary Heart Disease in a Veteran Population with Spinal Cord Injury. Topics in Spinal Cord Injury Rehabilitation. 12:35-53, 2007.

Purpose: » To determine the conventional risk factors for CHD & calculate risk for CHD to determine the target level for serum LDL cholesterol.

Population: » 224 outpatients with SCI associated with the VA Medical Center, Bronx, NY

Method: » Conventional risk factors for CHD were defined by the ATP III guidelines.

Characteristics of the Study Group

Bauman et al., Topics in Spinal Cord Inj Rehabil. 12:35-53, 2007.

Table 2

Major Risk Factors for CHD

Tetra (n=103) Para (n=119)

Bauman et al. Topics in Spinal Cord Inj Rehabil. 12:35-53, 2007.

Table 3

Ten-Year Risk Assessment

Bauman et al. Topics in Spinal Cord Inj Rehabil. 12:35-53, 2007.

Major Risk Factors for CHD

• Cigarette Smoking

• Hypertension (>140/90 mm Hg or on anti-hypertensive medications

• Low HDL cholesterol (<40 mg/dL)

• Family history of premature CHD (male first degree relative < 55 years; female first-degree relative < 65 years)

• Age (men > 45 years; women > 55 years

Serum HDL Cholesterol Levels in the ATP III Stratification of Risk for CHD

HDL cholesterol has a dual function:

(1) Counted as a Major Risk Factor that serves to modify LDL goals

(2) Used to estimate the 10-year risk for developing CHD (using the Framingham

risk scoring system)

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Nash MS, et al. Extended-Release Niacin for Treatment of Dylipidemia in Chronic Tetraplegia

Subjects: 54 persons with chronic tetraplegia and low HDL cholestrol

Results: ↑ HDL (24.5%)

↓ LDL

↓ TC

↓ TC:HDL

↓ LDL:HDL

Conclusion: Extended-release niacin is safe, tolerated, and effective for most persons with chronic tetraplegia.

Unpublished observation.Supported by NIDRR, Department of Education

HDL LDL TC-20

-10

0

10

20

30

2000 mg

500 mg

1000 mg

1500 mg

Per

cent

Cha

nge

● High-sensitivity CRP● Interleukin-6● Fibrinogen● Tumor Necrosis Factor-α● Increased concentration of small, dense LDL particles● Lp(a)● Homocysteine● Apolipoprotein A1 and B● Postprandial lipemia● Vitamin D

● Visceral fat

Emerging Risk Factors For Coronary Heart Disease

Lee MY, et al. C-reactive protein, metabolic syndrome, and insulin resistance in individuals with spinal cord injury. J Spinal Cord Injury. 28:20-25, 2004.

C-reactive protein levels and IR C-reactive protein levels and Dyslipidemia

Mortality Ratios for Plasma Homocysteine Levels for Men and Women with SCI

Bauman et al. J Spinal Cord Med. 24:81-86, 2001.

Orakzai SH, et al. Measurement of coronary arterycalcification by electron beam computerized tomographyin persons with chronic spinal cord injury: evidencefor increased atherosclerotic burden. Spinal Cord. 2007

Subjects:

» 91 persons (76 men & 15 women) with chronic SCI matched 3:1 for age, gender, ethnicity & risk factors for CHD

Conclusions:

» Patients with SCI have greater atherosclerotic burden than able-bodied controls. This finding is beyond that explained by the traditional risk factors for CHD.

Results:

» The mean calcium score of the SCI group was significantly greater than the control group (75±218 versus 28±104, P<0.001)

» The prevalence of any CAC score was greater in the SCI population than the control population (51 versus 39%, P<0.05).

● What factors best predict risk for CHD?

Questions to be Addressed

● Are the guidelines for treatment decisions to reduce risk for CHD transferable from the able-bodied population to persons with SCI?

Are there studies that have stratified persons with SCIfor risk of CHD on evidenced-based guidelines?

Is there a study that has determined CHD in personswith SCI compared with matched, able-bodied controls?

● Are persons with SCI at increased risk for CHD?

These questions have not been answered.

Pulmonary Program

PI: Gregory J. Schilero MD

Study of the pathophysiology of spinal cord injury & the lung

Intervention(s) to increase expiratory muscle strength

Markers of lung inflammationInhibition of lung nitric oxide & effects on airway tone

Fitted Values for FVC Percent Predicted by Vertebral Level for Complete Motor Lesions

4249

5560 64 67 70 73 76 79 81 83 86 88 89 91 93 94 96 97 99 100

0

20

40

60

80

100

120

C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4

Pe

rce

nt

Pre

dic

ted

FV

C Normal Range

Lin & Spungen et al., Spinal Cord. 2001; 39:263-268.

LUNG VOLUMES

ICTVERVRV

Normal Tetraplegia

FRC

FVC

Restrictive Findings Slight TLC FVC ERV RV

- Correlates with level of injury

Pulmonary: Obstructive Disease in Individuals with Tetraplegia

Bronchodilators “unmask” obstruction

Increased airway tone

Hyperreactive airways to standard provocative testing

Effects of Nitric Oxide Synthase Inhibition on Levels of Exhaled NO and Airway Tone in Subjects with Chronic Cervical SCI

• Measurement of exhaled levels of nitric oxide offers a non-invasive methodology to indirectly assess the degree of airway inflammation.

Background● Asthma and spinal cord injury have similar findings of

reversible obstructive airway disease.

● In asthma, airway inflammation is present.

● The presence and/or role of airway inflammation in individuals with tetraplegia has not been reported.

● Airway inflammation may be a consequence of: (1) a systemic inflammatory response after acute SCI; (2) chronic underlying systemic inflammation; and/or (3) repetitive pulmonary infections 2º to ineffective cough.

Baseline Values of Exhaled Nitric Oxide (NO)

*P= 0.0109#P= 0.0045

8-Isoprostane Levels in Exhaled Breath Condensate (EBC)

8-isoprostane levels in tetraplegia (n=6), asthma (n=6) and control group (n=6). †p <0.05 vs. control group; *p <0.02 vs. control group

8-Isoprostane Levels

● 8-isoprostane levels represent pathways of inflammation seen in models of inflammation (e.g., COPD and asthma).

● 8-isoprostane is a marker of oxidative stress.

● In the able-bodied population, there is good correlation of 8-isoprostane with small airway function and small airway inflammation.

*

Cardiovascular/Autonomic Program

PI: Jill M. Wecht, EdD

Chronic SCI• 24-hour monitoring of

hemodynamic parameters

• Interventions to reduce orthostatic hypotension

24-hour Heart Rate

65

70

75

80

85

90

95

100

105

24-h

ou

r H

eart

Rat

e

8am noon 4pm 8pm midnight 4am 8am

P<0.001 versus AB & tetraplegic groups

controlsparaplegictetraplegic

Wecht et al., Unpublished observation.

24 hour Systolic Blood Pressure

p<0.05 versus controls

tetraplegicparaplegicControl

95

100

105

110

115

120

125

130

135

24 H

ou

r S

BP

(m

mH

g)

8am noon 4pm 8pm midnight 4am 8am

Wecht et al., Unpublished observation.

Efficacy of Drug or Physical Maneuver on BP and Cerebral Perfusion

Interventions

•α1-agonist (midodrine)

•nocturnal head-up tilt

•nitric oxide synthase inhibitor

Sympathetic Cardiac Control

Grimm et al. Am J Physiol. 1997.

LF-RRI 0.04-0.15 Hz

0

1000

2000

3000

4000

5000

6000

7000

Control Para Tetra-Inc Tetra-Com

SUPINE

HUT

COLD PRESSOR

ISOMETRIC

Ab

solu

te L

F-R

RI (

mse

c2 /H

z)

Parasympathetic Cardiac Control

0

1000

2000

3000

4000

5000

Control Para Tetra-Inc Tetra-Com

SUPINE

HUT

COLD PRESSOR

ISOMETRIC

Grimm et al., Am J Physiol. 1997.

HF-RRI 0.15-0.40 Hz

Ab

solu

te H

F-R

RI (

mse

c2 /H

z)

ISOMETRIC

Sympathovagal Balance (LF/HF)

0

0.5

1

1.5

2

2.5

3

Control Para Tetra-Inc Tetra-Com

SUPINE

HUT

COLD PRESSOR

ISOMETRIC

Grimm et al., Am J Physiol. 1997.

Ab

solu

te L

F/H

F R

RI

(mse

c2 /H

z)

LF-RRI/HF-RRI

Gastrointestinal Program

PI: Mark A. Korsten, MD

Assessment of drug therapy for treatment of difficulty with evacuation

Evaluation of elective colonoscopy

Gastrointestinal MorbidityDifficulty with evacuation, especially

constipation and impaction, is common after SCI.

Bowel care requires regular use of laxatives, enemas and suppositories.

Bowel care is often time-consuming and labor intensive.

Is there a practical pharmacological approach to bowel care on our clinical horizon?

Placebo Neostigmine Neo+Glyco0

25

50

75

100

Complete

Most

Moderate

Some

None

Evacuation Rating

Per

cen

t o

f S

ub

ject

s

* *

*P < 0.01 compared to normal saline

Korsten et al., Amer J Gastroenterol. 2005.

Neostigmine and Glycopyrrolate on Bowel Evacuation in Persons with SCI

» To study the quality of bowel preparation for colonoscopy after oral cleansers, bowel prokinetic agents, mechanical lavage, or a combination.

» To compare polyp detection rates in persons with SCI and able-bodied controls.

Elective Colonoscopy in Persons with SCI

POLYP DETECTION RATE DURING COLONOSCOPY: ABLE- BODIED CONTROLS vs. SCI PATIENTS

Able bodied pa-tients (n=31)

SCI patients (n=32)

0

10

20

30

40

50

60 51.6

21.9

% c

olo

no

sco

pie

s w

ith

p

oly

ps

P = 0.02 by Fisher’s exact test

Molecular ProgramPI: Christopher P. Cardozo, MD

Transcriptional regulation of anabolic/ catabolic factors in muscle

Effect of anabolic/ catabolic agents on muscle after denervation or SCI

Effect of anabolic agents on functional recovery