Hypothesis-Driven Research (20+ years of burn-related research) - - PowerPoint PPT Presentation

Hypothesis-Driven Research (20+ years of burn-related research)

Craig Crandall PhD

Thermal and Vascular Physiology Laboratory Institute 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 Tissue Muscle

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 Graft Skin Blood Flow (au)

14 16 18 20 22 24 26 28 30

Control Skin Blood Flow (au)

8 9 10 11 12 13 14 15 16

Control Graft ∆CVC (au/mm Hg)

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75

Laser doppler scanner-grafted skin

P < 0.05

Photo Image Flux Image

NORMOTHERMIA

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

∆CVC (au/mm Hg)

0.00 0.25 0.50 0.75 1.00 1.25 1.50

Control Graft

P<0.01

Control Graft ∆SR from Baseline (mg/cm2/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/min)

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 1.8 Control Graft

[ACh] ∆CVC from Baseline (au/mmHg)

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 Graft Control

[SNP] ∆CVC from Baseline (au/mmHg)

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 1.4 Control Graft

[ACh] ∆SR from Baseline (mg/cm2/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 Groups

Control 17-40% >40%

Increase in Internal Temperature (Deg C)

0.0 0.5 1.0 1.5 2.0 2.5

Pre-Acclimation Post-Acclimation

2 way ANOVA Group: P<0.001 Acclimation: P<0.001 Interaction: P=0.073

Pre-Heat Acclimation Post-Heat Acclimation

Schlader et al. J Appl Phyisol 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

Cutaneous Blood Flow (PU)

100 200 300 400 Uninjured Donor

P=0.26 P=0.78

Uninjured Donor

Local Sweat Rate (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

VO2max (ml/min)

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

VO2max (ml/min)

1000 2000 3000 4000

Actual age-related decrease in VO2max in uninjured individuals

Cardiovascular Deconditioning

Age (years)

20 30 40 50 60 70

VO2max (ml/min)

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= 0.008 Pre/Post: P<0.001 Group x Pre/Post: 0.51 Pre-exercise training Post-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

• f 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

Delta Tcore (°C)

0.0 0.4 0.8 1.2 1.6 2.0

R=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

Delta Tcore (°C)

0.0 0.4 0.8 1.2 1.6 2.0

R=0.71; P<0.01

Body Surface Area Available for Heat Dissipation (m2)

0.4 0.8 1.2 1.6 2.0

Delta Tcore (°C)

0.0 0.4 0.8 1.2 1.6 2.0

Control subjects

‡ different from pre-HA (main effect; P=0.05)

* * *

10 20 30 40 50 60 0.0 0.5 1.0 1.5 2.0 2.5

0% burn injury 20% burn injury 40% burn injury 60% burn injury

Elevation in Core Temperature (°C) Time of Exercise (min)

24 °C (75 °F), 20% humidity

10 20 30 40 50 60 0.0 0.5 1.0 1.5 2.0 2.5

0% burn injury 20% burn injury 40% burn injury 60% burn injury

Elevation in Core Temperature (°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 90 5 10 15 20

Percentile Ranking for Maximal Oxygen Uptake Number of Subjects in Each Category

76% in the lowest two categories

Distribution of maximal oxygen uptake in 34 skin graft patients

Ganio, Pearson, Schlader, Brothers, Lucas, Rivas, Kowalske, Crandall, 2014 Percentile rankings for age and sex adjusted maximum oxygen uptake