RR&D Center of Excellence
for the
Medical Consequences
of Spinal Cord Injury
William A. Bauman, M.D.
Director
Ann M. Spungen, Ed.D
Co-Director
January 21, 2010
Rancho Los Amigo National Rehabilitation Hospital
Program Lines of Study
1. Endocrine Program
William A. Bauman, MD
2. Pulmonary Program
Gregory J. Schilero
3. Automomic Program
Jill M. Wecht, EdD
4. Gastrointestinal Program
Mark A. Korsten, MD
5. Molecular Program
Christopher P. Cardozo, MD
Endocrine Program
 Disuse Osteoporosis
 Anabolic Hormones
 Carbohydrate Metabolism
 Lipid Metabolism
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
Calcium Metabolism in Chronic SCI
• 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
Bauman et al. Metabolism. 44:1612-1616, 1995.
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
Absolute Deficiency < 16 ng/ml
Relative Deficiency < 30 ng/ml
No Deficiency ≥ 30 ng/ml
8
7
Number of Subjects
6
5
4
3
2
1
0
Baseline
Month 1
Bauman et al., Unpublished observation.
Month 3
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
Characteristics of Subjects for the
Testosterone Replacement Study
Count
Age (yrs)
Height (cm)
Weight (kg)
BMI (kg/m2)
Duration of Injury
Para/Tetra
Complete/Incomplete
Control
9
37±9
174±4
83.2±6.0
27.4±2.2
11±9
2/6
7/2
TRT
6
43±5
180±7
87.8±15.7
26.8±3.1
13±10
2/9
4/2
Testosterone Replacement Therapy
Design:
TRT for 12 mo
Washout for 6 mo
Testosterone
Control
TOTAL BODY LTM (kg)
P<0.05
60
58
56
54
52
50
48
46
44
42
40
P<0.05
54.8
52.2
52.7
REE (Kcal/d)
Baseline
Bauman et al., Unpublished observation.
1700
1600
1500
1400
1300
1200
1100
1000
900
800
55.0
53.4
51.1
Testosterone
Washout
P<0.05
 122 Kcal/d
1,508
1,386
1,341
Baseline
1,349
Testosterone
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
TOTAL BODY % LEAN
95
85
AB slope (-0.175, P<0.0001)
75
65
55
45
35
25
10
20
30
40
50
AGE (y)
Spungen et al., J Appl Physiol. 95:2398-2407, 2003.
60
70
80
Cross-Sectional Study: Chronic SCI
P<0.0001
Total Body Percent Fat
40
35
30
25
*
*
20
Control
15
SCI
10
5
0
< 40 y
* P<0.05 for Control vs. SCI
Spungen et al., J Appl Physiol. 95:2398-2407, 2003.
 40 y
Body Mass Index Criteria for
Normal, Overweight and Obesity
Underweight
Normal
Overweight
Obese
BMI (m/kg2)
<18.5
18.5-24.9
25-29.9
>30
Expert Panel on the Identification , Evaluation and
Treatment of Overweight and Obesity in Adults. NIH
NHLBI. 1998
The Relationship of Percent Fat
With Body Mass Index
Total Body% Fat
60
50
40
30
20
SCI
Control
10
0
10
15
20
25
30
35
40
45
Body Mass Index (kg/m2)
Spungen et al., J Appl Physiol 95:2398-2407, 2003.
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
Complete Paraplegia
6%
23%
27%
18 %
76%
50%
NL
IGT
DM
Incomplete Tetraplegia
14 %
20%
24%
Incomplete Paraplegia
56%
Bauman et al., Spinal Cord. 37:765-771, 1999.
17 %
69%
Frequency of Impaired Glucose Tolerance and/or
Diabetes Mellitus by Neurological Deficit
Neurological Subgroup
Complete Tetra
Percent
73*
Incomplete Tetra
44
Complete Para
24
Incomplete Para
31
*p<0.0001
Bauman et al., Spinal Cord. 37:765-771, 1999.
Frequency of Hyperinsulinemia
Group
Percent
Tetra
53*
Para
37
*P<0.05
Bauman et al., Spinal Cord. 37:765-771, 1999.
Serum Glucose Results from a 75 g
OGTT in SCI
Serum Glucose (mg/dL)
250
225
200
175
150
DM
125
IGT
100
NGT
75
50
25
0
0
30
Bauman et al., Unpublished observation.
60
90
Time (minutes)
120
Plasma Insulin (U/ml)
Plasma Insulin Results from a
75
g
OGTT
in
SCI
180
160
140
120
DM
100
IGT
80
NGT
60
40
20
0
0
30
Bauman et al., Unpublished observation.
60
90
Time (minutes)
120
Percent of Subjects by SCI
Group and FPI Category
40
TETRA
35
PARA
30
25
20
15
10
5
0
0-5
5-9
10-14
15-19
FPI Category
Bauman et al., Unpublished observation.
20-100
Percent of Subjects by Group &
2-Hour Insulin Category
After a 75 g OGTT
45
TETRA
40
PARA
35
30
25
20
15
10
5
0
0-49
50-99
100-150
> 150
Two-Hr Insulin Category
Bauman 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
Relationships between Insulin Sensitivity with
VO2 max & HDL Cholesterol
Bauman et al., Metab. 43:749-756, 1994.
HDL as a Risk Factor in Persons with SCI
Decreased plasma HDL cholesterol
Elevated Total Cholesterol : HDL ratio
HDL cholesterol < 40 mg/dL: 63%
HDL cholesterol < 35 mg/dL: 44%
HDL cholesterol < 30 mg/dL: 19%
HDL Cholesterol (mg/dL)
50
Morbidity risk ratio
(age-adjusted)
2.0
45
Average Risk
40
1.0
35
0
20
30
40
60
80
HDL (mg/dl)
Tetra
Complete
Tetra
Incomplete
Para
Complete
Para
Incomplete
Bauman et al., Spinal Cord, 1998
Bauman et al., Metabolism, 1994
Bauman et al., Spinal Cord, 1999
Bauman et al., Topics in Spinal Cord Injury Rehab, 2008
HDL-Cholesterol & CHD Risk
(Men in Framingham, MA)
HDL Cholesterol by Ethnicity
Bauman et al., Arch Phys Med Rehabil. 79:176-180, 1998.
Guidelines for Assessment of Risk for CHD
National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation and Treatment
Of High Blood Cholesterol in Adults
» 1988 Adult Treatment Panel (ATP) I
» 1993 ATP II
» 2001 ATP III
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 cholesterol
have become more conservative.
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
Subjects:
41 subjects with paraplegia
• ASIA A & B: T6 to L1
• Age: 34±11 years
Main Outcome Measure:
% of subjects qualifying for intervention
• Based on ATP III guidelines
Nash MS, et al. Arch Phys Med Rehabil. 88:751-757, 2007
Results:
63% of subjects qualified for intervention
» 76% had HDL cholesterol <40 mg/dL
» ~1/3 had hypertension
» 34% had the metabolic syndrome
Conclusion:
A high percentage of young, healthy
persons with SCI are at risk for CVD
& qualify for lipid-lowering intervention.
Nash 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.
Major Risk Factors for CHD
Tetra (n=103)
Para (n=119)
Table 2
Bauman et al. Topics in Spinal Cord Inj Rehabil. 12:35-53, 2007.
Ten-Year Risk Assessment
Table 3
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 antihypertensive 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:
1000 mg
30
1500 mg
Percent Change
↑ HDL (24.5%)
↓ LDL
↓ TC
↓ TC:HDL
↓ LDL:HDL
500 mg
20
2000 mg
10
0
-10
-20
HDL
LDL
Conclusion: Extended-release niacin is safe,
tolerated, and effective for most persons with
chronic tetraplegia.
Unpublished observation.
Supported by NIDRR, Department of Education
TC
Emerging Risk Factors For
Coronary Heart Disease
● 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
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 artery
calcification by electron beam computerized tomography
in persons with chronic spinal cord injury: evidence
for 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
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).
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.
Questions to be Addressed
● Are persons with SCI at increased risk for CHD?
Is there a study that has determined CHD in persons
with SCI compared with matched, able-bodied controls?
● 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 SCI
for risk of CHD on evidenced-based guidelines?
● What factors best predict 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 inflammation
Inhibition of lung nitric oxide &
effects on airway tone
Fitted Values for FVC Percent Predicted by
Vertebral Level for Complete Motor Lesions
Percent Predicted FVC
120
Normal Range
100
80
60
49
40
55
99 100
97
96
94
91 93
89
88
86
83
81
76 79
73
67 70
64
60
42
20
0
C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4
Lin & Spungen et al., Spinal Cord. 2001; 39:263-268.
LUNG VOLUMES
Normal
Tetraplegia
FVC
FRC
Restrictive Findings
Slight  TLC
  FVC
  ERV
 RV
IC
TV
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 noninvasive 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
● 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.
*
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
● 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
105
24-hour Heart Rate
100
95
90
85
controls
paraplegic
tetraplegic
80
75
70
65
8am
noon
4pm
8pm
midnight
P<0.001 versus AB & tetraplegic groups
Wecht et al., Unpublished observation.
4am
8am
24 hour Systolic Blood Pressure
135
Control
paraplegic
tetraplegic
24 Hour SBP (mmHg)
130
125
120
115
110
105
100
p<0.05 versus controls
95
8am
noon
4pm
8pm
Wecht et al., Unpublished observation.
midnight
4am
8am
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
LF-RRI 0.04-0.15 Hz
Absolute LF-RRI (msec2/Hz)
7000
6000
5000
4000
3000
ISOMETRIC
COLD PRESSOR
HUT
2000
1000
SUPINE
0
Control
Para
Tetra-Inc
Tetra-Com
Grimm et al. Am J Physiol. 1997.
Parasympathetic Cardiac Control
HF-RRI 0.15-0.40 Hz
Absolute HF-RRI (msec2/Hz)
5000
4000
3000
ISOMETRIC
2000
COLD PRESSOR
1000
HUT
SUPINE
0
Control
Para
Tetra-Inc
Tetra-Com
Grimm et al., Am J Physiol. 1997.
Sympathovagal Balance (LF/HF)
Absolute LF/HF RRI (msec2/Hz)
LF-RRI/HF-RRI
3
2.5
2
1.5
ISOMETRIC
1
COLD PRESSOR
HUT
0.5
SUPINE
0
Control
Para
Tetra-Inc
Tetra-Com
Grimm et al., Am J Physiol. 1997.
Gastrointestinal Program
PI: Mark A. Korsten, MD
Assessment of drug
therapy for treatment of
difficulty with evacuation
Evaluation of elective
colonoscopy
Gastrointestinal Morbidity
Difficulty 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?
Neostigmine and Glycopyrrolate on
Bowel Evacuation in Persons with SCI
*
Percent of Subjects
100
*
Evacuation Rating
None
75
Some
Moderate
50
Most
Complete
25
0
Placebo
Neostigmine
Neo+Glyco
*P < 0.01 compared to normal saline
Korsten et al., Amer J Gastroenterol. 2005.
Elective Colonoscopy 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.
POLYP DETECTION RATE DURING COLONOSCOPY:
ABLE- BODIED CONTROLS vs. SCI PATIENTS
% colonoscopies with polyps
60
51.6
P = 0.02 by Fisher’s exact test
50
40
30
21.9
20
10
0
Able bodied
patients (n=31)
SCI patients
(n=32)
Molecular Program
PI: 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