hypothesis-driven research (20+ years of burn-related
TRANSCRIPT
Hypothesis-Driven Research(20+ years of burn-related research)
Craig Crandall PhDThermal and Vascular Physiology LaboratoryInstitute for Exercise and Environmental Medicine; University of Texas Southwestern Medical Center Dallas
Brown Recluse
11/28/95
12/6/95
12/11/95
THIRD DEGREE BURN
HEALTHY SKIN
Epidermis
Dermis
Subcutaneous TissueMuscle
SPLIT-THICKNESS SKIN GRAFT
Curiosity
How do humans“thermoregulate”?
Question: What are the implications of such an injury and subsequent grafting on skin blood flow and sweating?
Identify a hypothesis and design an experiment to test that hypothesis.
15 seconds
ECG
Gra
ft Sk
in B
lood
Flo
w (a
u)
14
16
18
20
22
24
26
28
30
Con
trol
Ski
n B
lood
Flo
w (a
u)
8
9
10
11
12
13
14
15
16
Control Graft
∆C
VC (a
u/m
m H
g)
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
Laser doppler scanner-grafted skin
P < 0.05Photo Image
Flux Image
NORMOTHERMIA
0 500 1000
Graft Graft
HEAT STRESS
Increases in cutaneous vascular conductance during whole-body heating at control and grafted sites across differing durations post-
graft surgery.
5-9 Months 26-38 Months 50-86 Months
∆C
VC (a
u/m
m H
g)
0.00
0.25
0.50
0.75
1.00
1.25
1.50 Control Graft P<0.01
Control Graft
∆SR
from
Bas
elin
e (m
g/cm
2 /min
)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
P < 0.05
Increase in sweat rate (SR) to whole-body heating
5-9 Months 26-38 Months 50-86 Months
∆SR
(mg/
cm2 /m
in)
0.0
0.5
1.0
1.5
2.0
2.5 Control Graft P<0.01
J Burn Care Res 2009
2-3 Years 4-8 Years
Question: Where are the deficits resulting in impaired increases in skin blood flow and sweating in grafted skin?
Identify a hypothesis and design an experiment to test that hypothesis.
1x10-7 1x10-6 1x10-5 1x10-4 1x10-3 1x10-2 1x10-1
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8ControlGraft
[ACh]
∆C
VC fr
om B
asel
ine
(au/
mm
Hg)
EC50:P=0.003
Dose response curves to exogenous acetylcholine (ACh) in normal and grafted skin
J Burn Care Res 2007
5x10-8 5x10-7 5x10-6 5x10-5 5x10-4 5x10-3 5x10-2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
GraftControl
[SNP]
∆C
VC fr
om B
asel
ine
(au/
mm
Hg)
EC50:P=0.33
Dose response curves to exogenous sodium nitroprusside (SNP) in normal and grafted skin
J Burn Care Res 2007
1x10-7 1x10-6 1x10-5 1x10-4 1x10-3 1x10-2 1x10-1
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4ControlGraft
[ACh]
∆SR
from
Bas
elin
e (m
g/cm
2 /min
)
Increases in sweat rate (SR) to exogenous acetylecholine(ACh) from normal and grafted skin
J Burn Care Res 2007
“We had a new recruit die here last week due to a heat-induced arrhythmia. His core temp was 106° F (~41°C). He died standing in the chow line- and had done very minimal exertion that day (2 mi walk several hours earlier). The guy had burn injuries at age 11- he had skin grafts covering 30% of his trunk- to include one axilla. Our Army medical fitness regulations make no mention of skin grafting/burns as a disqualifier and we are seeking additional knowledge to see if we need to change the regulation. Since so many of our soldiers have recently acquired burn injuries and are subjected to tremendous thermal stress we think that this is a very important question.”
Identify a hypothesis and design an experiment to test that hypothesis.
So what’s next?
Groups• 17-40% BSA grafted; BSA
grafted: 30±7%. 40±13 years.
• >40% BSA grafted; BSA grafted: 54±11%. 34±11 years
• Non-grafted controls. 32±10 years
Skin grafts impair temperature regulation.(40 °C and 30% RH)
Ganio, Schlader, Pearson, Lucas, Gagnon, Rivas, Kowalske, Crandall, 2015
Question: Can impaired thermoregulatory responses be modified?
Identify a hypothesis and design an experiment to test that hypothesis.
Pre-heat acclimation evaluation
Post-heat acclimation evaluation
Heat acclimation: 90 min of exercise (@ 45% VO2max) in 40°C, 30% RH for 7
consecutive days
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Subject GroupsControl 17-40% >40%
Incr
ease
in In
tern
alTe
mpe
ratu
re (D
eg C
)
0.0
0.5
1.0
1.5
2.0
2.5Pre-AcclimationPost-Acclimation
2 way ANOVAGroup: P<0.001Acclimation: P<0.001Interaction: P=0.073
Pre-Heat Acclimation
Post-Heat Acclimation
Schlader et al. J ApplPhyisol 2015
Donor Sites
Question: What questions come to mind regarding donor sites?
Identify a hypothesis and design an experiment to test that hypothesis.
Donor Sites
Pre-Exercise Post-Exercise
Cuta
neou
s Bl
ood
Flow
(PU)
0
100
200
300
400 UninjuredDonor
P=0.26
P=0.78
Uninjured Donor
Loca
l Sw
eat R
ate
(mg/
cm^2
/min
)0.0
0.5
1.0
1.5
Maximal Aerobic Capacity
Serendipitous Findings
J Burn Care Res 2015
ACSM age and sex normative scale: ~75% of burn survivors had a VO2max in the lowest 20th percentile.
American Heart Association Normative Scale: 88% of burn survivors had a VO2max below the age-adjusted normative values
80% of burn survivors had a VO2max in the lowest quartile of the Aspenes database (4631 subjects)
Question: Why are burned individuals generally unfit (consider the variables that influence aerobic capacity)?
Identify a hypothesis and design an experiment to test that hypothesis.
Age (years)20 30 40 50 60 70
VO
2max
(ml/m
in)
1000
2000
3000
4000
Actual age-related decrease in VO2max in uninjured individuals
Cardiovascular Deconditioning
1 day hospitalization per 1% BSA burned
Age (years)20 30 40 50 60 70
VO
2max
(ml/m
in)
1000
2000
3000
4000
Actual age-related decrease in VO2max in uninjured individuals
Cardiovascular Deconditioning
Age (years)20 30 40 50 60 70
VO
2max
(ml/m
in)
1000
2000
3000
4000
Actual age-related decrease in VO2max in uninjured individuals
Cardiovascular Deconditioning
10+ years post-injury
Question: Are these “adverse” responses modifiable?
Identify a hypothesis and design an experiment to test that hypothesis.
Assessments
Steady state followed by maximal oxygen uptake evaluation (X 2)
Assessments of vascular function (FMD, nitro, PWV)
Quality of life surveys
Functional capacity assessments
Cardiac structure/function (MRI and/or echo)
Body composition (DEXA)
Muscle biopsy (citrate synthase & cytochrome C oxidase activity)
Blood volume assessment
Pulmonary function testing
Pre- and post-6 months exercise training
Group: P= 0.008Pre/Post: P<0.001Group x Pre/Post: 0.51
Pre-exercise trainingPost-exercise training
6 month Endurance Exercise Training
GM068865-12; ~$3.5 million W81XWH-15-1-0647; ~$2.0 million
US Army Standards of Medical Fitness, AR 40-501
2-28-(1) Prior burn injury (to include donor sites) involving a total body surface area of
2-28-(2) Prior burn injury involving less than 40 percent total body surface area, which results in a loss or degradation of thermoregulatory function does not meet the standard
Where’s the data to support these guidelines?
Psycho-social
Body Surface Area Grafted (%)10 20 30 40 50 60 70 80
Del
ta T
core
(°C
)
0.0
0.4
0.8
1.2
1.6
2.0R=0.59; P<0.01
108 kg; 195 cm; 2.4 m2 BSA… so he has ~1.6 m2 BSA ungrafted skin available to dissipate heat
70 kg; 175 cm; 1.8 m2; 33% graft = 1.2 m2 for heat dissipation.
Body Surface Area Available for Heat Dissipation (m2)
0.4 0.8 1.2 1.6 2.0
Del
ta T
core
(°C
)
0.0
0.4
0.8
1.2
1.6
2.0R=0.71; P<0.01
Body Surface Area Available for Heat Dissipation (m2)
0.4 0.8 1.2 1.6 2.0
Del
ta T
core
(°C
)
0.0
0.4
0.8
1.2
1.6
2.0
Control subjects
‡ different from pre-HA (main effect; P=0.05)
* * *
0 10 20 30 40 50 600.0
0.5
1.0
1.5
2.0
2.5
0% burn injury20% burn injury40% burn injury60% burn injury
Elev
atio
n in
Cor
e Te
mpe
ratu
re (°
C)Time of Exercise (min)
24 °C (75 °F), 20% humidity
0 10 20 30 40 50 600.0
0.5
1.0
1.5
2.0
2.5
0% burn injury20% burn injury40% burn injury 60% burn injury
Elev
atio
n in
Cor
e Te
mpe
ratu
re (°
C)
Time of Exercise (min)
39 °C (102 °F), 20% humidity
* P<0.01 from 0% burn
**
**
Individuals with significant skin grafts are generally more sedentary.
10 20 30 40 50 60 70 80 900
5
10
15
20
Percentile Ranking for Maximal Oxygen Uptake
Num
ber o
f Sub
ject
s in
Each
Cat
egor
y 76% in the lowesttwo categories
Distribution of maximal oxygen uptake in34 skin graft patients
Ganio, Pearson, Schlader, Brothers, Lucas, Rivas, Kowalske, Crandall, 2014
Percentile rankings for age and sex adjusted maximum oxygen uptake
