AEROSPACE MEDICINE GRAND ROUNDS
Controlling Cardiovascular Hazards for
Exploration Class Space Missions
May 22nd
2007
Douglas Hamilton MD PhD MSc E Eng P. Eng
Flight Surgeon / Electrical Engineer - Wyle Life Sciences
Objectives
Incid
ence
Severity
MASS
Volu
m
Coste
POWER
1. Describe the Occupational
Medicine approach to
controlling medical Hazards for
Spaceflight
2. Provide a critical appraisal of
the current Cardiovascular
Hazard Controls used for long
duration missions.
3. Describe the operational
research needed to validate the
current cardiovascular hazard
controls for exploration class
missions.
Mission
Design
CV Medical
Requirements
Flight Surgeon
1
Agenda
–
–
–
•
Hazard - Orthostatic
Intolerance
Hazard - Cardiac Atrophy
Hazard – Significant
arrhythmias
Incid
ence
Severity
Volu
m
Coste
MASS
•
Occupational Medicine
Bioastronautics Roadmap
NRC review of NASA’s
Biomedical Research
Program
Treatment of Uncontrolled
CV Hazards
POWER
•
•
•
Mission
Design
CV Medical
Requirements
Flight Surgeon
Discussion/questions
Hazard Controls - Prevention
• Tertiary prevention “the care
of established disease, with
attempts made to restore to
highest function, minimize the
negative effects of disease,
and prevent disease-related
complications. “
• Secondary Prevention –
“those measures that “identify
and treat persons who have
already developed risk factors
or preclinical disease but in
whom the condition is not
clinically apparent.”
• Primary prevention - “those
measures provided to
individuals to prevent the
onset of a targeted condition.”
Treatment
Clinical
Space
Medicine
Countermeasures
Primary Prevention
The U.S. Preventative Services Task Forces’ Guide to Clinical Preventive Services (2d edition, 1996)
2
Occupational Medicine Model
Clinical
Space
Medicine
Tertiary
(Treat)
Secondary
(Countermeasures )
Primary
(Selection, Prevention, Monitoring)
Focused Risk
Mitigation Strategy
Bioastronautics Critical Path
Roadmap SD/CB Input
3
Review of NASA’s Biomedical Research Program
• Committee on Space Biology and Medicine Space Studies Board
• Commission on Physical Sciences, Mathematics, and Applications
• National Research Council
– http://www.nap.edu/catalog/9950.html
FY 1999 funding of
NASA supported
programs in
biomedical research
and
countermeasures.
CRITICAL HAZARD
Any condition which
may cause a nondisabling personnel
injury, severe
occupational illness
4
CATASTROPHIC HAZARD
Any condition which may
cause a disabling or fatal
personnel injury, or loss of
one of the following: Orbiter
or ISS.
Cardiovascular Hazards
• Cardiac hazards are considered to be
controlled for long and short duration
missions since no outstanding waivers in
this area of medicine exists.
• Regardless, cardiac anomalies have been
seen in astronauts within temporal
proximity of space missions.
• To date, the root cause of these cardiac
anomalies has not been proven to be
associated with spaceflight.
5
FY 1999 Review of NASA’s Biomedical Research
Program recommendations for a cardiac summit
1.
2.
3.
4.
5.
6.
7.
Determine if cardiac arrhythmias are a significant
concern and if monitoring is warranted;
Determine if cardiac atrophy is a significant concern
and should be monitored;
Determine if there are pre- and in-flight predictors of
orthostatic intolerance;
Determine which ground-based human and animal
models best reproduce the effects of spaceflight;
Review the data and rationale for current
countermeasures and suggest new countermeasures
on the basis of the existing physiological data;
Determine what level of aerobic fitness should be
maintained in space; and
Determine if countermeasures have been effective
when used as recommended.
http://www.nap.edu/catalog/9950.html
FY 1999 Review of NASA’s Biomedical Research
Program recommendations for a cardiac summit
1.
2.
3.
Determine if cardiac arrhythmias are a significant
concern and if monitoring is warranted;
Determine if cardiac atrophy is a significant concern
and should be monitored;
Determine if there are pre- and in-flight predictors of
orthostatic intolerance
These are clearly Hazards
The “mission design” will determine if they are critical or catastrophic.
Their “incidence” and “severity” will determine if they are controlled.
http://www.nap.edu/catalog/9950.html
6
FY 1999 Review of NASA’s Biomedical Research
Program recommendations for a cardiac summit
These are clearly hazard controls, or the
means to derive them.
4.
5.
6.
7.
Determine which ground-based human and animal
models best reproduce the effects of spaceflight;
Review the data and rationale for current
countermeasures and suggest new countermeasures
on the basis of the existing physiological data;
Determine what level of aerobic fitness should be
maintained in space; and
Determine if countermeasures have been effective
when used as recommended.
http://www.nap.edu/catalog/9950.html
Where are we today?
• Before we can determine if further research is CV
necessary……..
……we need to determine if the absolute risk
(incidence + severity) of a particular cardiovascular
hazard is reduced to acceptable levels.
• If the CV risk is acceptable for the mission
certification of flight readiness, then the suite of
hazard controls which accomplished this must be a
requirement.
7
What is Acceptable?
Risk Matrix
1 in 10 yr
1 in 100 yr
1 in 1000 yr
1 in 10,000 yr
1 in 100,000 yr
L
I
K
E
L
I
H
O
O
D
?
5
4
? ?
?
3
2
?
1
1
4
5
Loss of Life or Mission
Permanent or serious
injury impairment
Long-term or missionimpact injury
impairment DQ
Short-term injury,
illness, or impairment
DNIF
Low
First Aid or minor
injury
Med
?
3
2
Consequence
Risk
High
?
When are we OK?
If the CV hazard risk is
acceptable for flight…..
…. then it should be
considered as the standard
for controlling that hazard.
8
Circa 2007 – What is our risk?
Soooo…….
What is our absolute risk for catastrophic
and critical cardiovascular hazards for
exploration missions?
Do we try to reduce incidence and/or
severity?
Let’s look at “severity”!!!
9
Treatment
Medical event
starts Medical decision
Locate &
extract
to deorbit
3 hr
Stabilize patient
1hr
DeOrbit Burn
Configure Soyuz and safe ISS
1 to 20 hr
Medical event
resolution
“Stand & Fight”
Loiter in Soyuz
>2 hr
Soyuz 3.85 g reentry
Transport to tertiary care center (Germany or Japan)
>6 hr
15 to 33 hours for 1st Primary Landing Site
Acute
Myocardial
Infarction
(AMI)
100%
Yes
3.00E-05
Sudden
Cardiac
Arrest
(SCA)?
19%
50%
Yes
1.50E-05
Asystole?
0.06%
Yes
5.71E-6
No
% of all AMIs
Yes
1.71E-08
Survive?
No
5.69E-06
9.289E-06
12.2%
CAC = 0
Av. Age = 48
AMI = 0.03 per
1000 personyears
Pulseless
Electrical
Activity?
Yes
9.18E-08
Survive?
Perm
Impairment
11.9%
Death
No
5.62E-06
1.24%
V F/VT
EMS
Witnessed?
EMS
Witnessed
VF/VT
Survive?
Yes
3.73E-07
0.47%
0.78%
Death
No
2.33E-07
No
1.5E-05
11.9%
Vfib/Vtach
Bystander
Witnessed?
Perm
Impairment
Yes
1.40E-07
No
5.25E-06
50%
Death
0.31%
Yes
3.67E-6
No
3.58E-06
06JUL06
D. B. Gillis
Event Sequence Diagram
Of AMI, Sudden Cardiac
Arrest and 30 day mortality
in non-Sudden Cardiac
Arrest patients in robust
urban environments.
Perm
Impairment
19%
Yes
3.57E-06
1.43%
Bystander
Witnessed Vt/
VFSurvive?
Yes
4.28E-07
Perm
Impairment
10.5%
No
1.68E-06
Unwitnessed?
Death
No
3.14E-06
5.59%
Unwitnessed
Survive?
Yes
1.68E-06
0.63%
Yes
1.88E-07
Perm
Impairment
4.96%
No
1.45E-06
1.36%
Vtach?
Survive?
1.04%
Yes
4.09E-07
No
1.46E-05
48.64%
1.73%
VFib?
46.9%
0.33%
Yes
5.18E-07
Survive?
1.19%
0.53%
No
1.41E-05
Vtach &
Vfib?
0.64%
Yes
1.91E-07
Survive?
Death
Perm
Impair
ment
Yes
3.11E-07
No
9.81E-08
Death
Perm
Impair
ment
Yes
3.57E-07
No
1.60E-07
0.36%
Yes
1.07E-07
0.28%
No
8.42E-08
Death
Perm
Impair
ment
Death
Assumptions:
46.3%
No
1.39E-05
Survive?
43.5%
2.78%
Yes
1.30E-05
Perm
Impair
ment
No
8.33E-07
Death
• Sex-adjusted hard cardiac event rate of 3 per100,000 person-yrs.
• Age stratum, 40-65 yrs, 50% of AMI present as OOH SCA;
• n = 1,641 OOH SCA for outcomes
• n = 6,450 for hard event rate.
10
Gillis and Hamilton et al 2007
Survival of AMI, SCA and 30 day mortality in
non-SCA patients in
robust after
urbanMIenvironments.
Survival
- SURVIVED
40%
35%
- FATAL
30%
25%
20%
15%
10%
fatal
survived
5%
SCA
SCA
-H
os
p…
VT
No
VT
&
VF
or
VF
-H
os
p…
Ho
sp
.
VF
-H
os
p.
VT
Un
wi
tn
es
se
d.
.
W
itn
es
se
d…
VF
/V
T
W
itn
es
se
d…
.
VF
/V
T
EM
S
PE
A
0%
As
ys
to
le
% ofall
all MI….
% of
events
45%
Non - SCA
Presenting Rythm
Presenting Rhythm
Non-SCA
FY 1999 Review of NASA’s Biomedical Research
Program recommendations for a cardiac summit
1.
2.
3.
Determine if cardiac arrhythmias are a significant
concern and if monitoring is warranted;
Determine if cardiac atrophy is a significant concern
and should be monitored;
Determine if there are pre- and in-flight predictors of
orthostatic intolerance;
These are clearly Hazards
The “mission design” will determine if they are critical or catastrophic.
Their “incidence” and “severity” will determine if they are controlled.
http://www.nap.edu/catalog/9950.html
11
Task 3: Determine if
there are pre- and inflight predictors of
orthostatic
intolerance
Task 3: Determine if there are preand in-flight predictors of orthostatic
intolerance
• Current exercise and fluid loading
countermeasures are an adequate
hazard control.
• Not possible to validate post flight tilttable results to emergency vehicle
egress success.
• Med Ops not convinced orthostasis will
be a problem for lunar surface
operations
• Forward work for Mars needs to be
performed. Only a critical hazard?
• Levine et al has shown initial results of
subjects finishing 5 weeks of bedrest
with an INCREASE in orthostatic
tolerance from rowing/strength training
program + a volume load.
12
FY 1999 Review of NASA’s Biomedical Research
Program recommendations for a cardiac summit
2.Determine if cardiac
atrophy is a
significant concern
and should be
monitored.
1.
2.
3.
Determine if cardiac arrhythmias are a significant
concern and if monitoring is warranted;
Determine if cardiac atrophy is a significant concern
and should be monitored;
Determine if there are pre- and in-flight predictors of
orthostatic intolerance;
http://www.nap.edu/catalog/9950.html
Task 2: Determine if cardiac atrophy is a
significant concern and should be monitored
• Need echo data with
cardiovascular
interventions to better
understand the physiology
and space normal clinical
findings
• In the past astronauts
have not been able to “get
the shot” for retrospective
analysis.
• Pre/Post flight data is high
fidelity because
experience echo
technicians are collecting
the data.
13
• Bed rest deconditioning leads to
physiologic cardiac atrophy
compromises left ventricular filling
during orthostatic stress by reducing
diastolic untwisting and suction.
• Dorfman and Levine used MRI with
myocardial tagging to confirm that
diastolic untwisting is impaired by
head-down tilt bed rest but preserved
by exercise training while confined to
strict bed rest.
T. Dorfman et al “Diastolic Suction is Impaired by Bed Rest: MRI Tagging Studies of
Diastolic Untwisting” Submitted for print
• Dorfman et al performed myocardial tagged MRI
and calculated maximal untwisting rates by
Harmonic Phase Analysis (HARP) before and
after -6° head-down tilt for 18 days with (N=14)
and without exercise (N=10) on previously
sedentary subjects (34.8 ± 9yr.).
• They also measured left ventricular mass and left
ventricular end-diastolic volume using cine MRI.
• The exercise group cycled on a supine ergometer
in a horizontal position for 30 minutes, 3 times a
day at 75% of their maximal heart rate measured
in an upright position.
T. Dorfman et al “Diastolic Suction is Impaired by Bed Rest: MRI Tagging Studies of
Diastolic Untwisting” Submitted for print
14
MRI tagging images using SPAMM
Before Bed Rest
After Bed Rest
Mid-cavity level and short axis image.
This individual’s max midwall untwisting rate prior to bed
rest was -31.8 degrees/sec and it decreased to -25.5 d
degrees/sec following bed rest.
Spatial Modulation of Magnetization (SPAMM)
Untwisting rates versus frame interval
before bed rest and after bed rest.
end-systole
end-systole
Max Untwist
Max Untwist
Before Bed Rest
•
•
After Bed Rest
This individual’s max untwisting rate prior to bed rest was -67.1 degrees/sec.
Untwisting rates are positive during systole and negative during diastole, and a more
negative untwisting rate is indicative of an enhanced diastolic function.
This individual’s max untwisting rate decreased to -42.8 degrees/sec following bed
rest.
T. Dorfman et al “Diastolic Suction is Impaired by Bed Rest: MRI Tagging Studies of
Diastolic Untwisting” Submitted for print
15
Conclusions Dorfman et al
• Diastolic untwisting is impaired following
sedentary short term HDT bed rest.
• Exercise training during bed rest can
prevent the atrophy associated with bed
rest and preserve or even enhance
diastolic suction.
• Exercise appears prevent deleterious
cardiac remodeling during unloading
conditions such as bed rest or perhaps
space flight.
T. Dorfman et al “Diastolic Suction is Impaired by Bed Rest: MRI Tagging Studies of
Diastolic Untwisting” Submitted for print
Next Steps …. Integrated Cardiac
Benjamin D. Levine, M.D. & Michael W. Bungo, M.D.
• In-flight resting echocardiograms with ECG recording followed by
24 to 48 hour Holter/Blood Pressure/Activity Monitoring at FD15
and 30, and every one to two months thereafter with a final
session required 15 days before landing.
• A post-exercise echo as part of the FD90 session.
• Pre- and postflight BDC Cardiac MRIs as well as Exercise
Echo/ECG and Resting Echo/ECG sessions followed by 24 to 48
hour Holter/BP/Activity monitoring.
• Holter/BP/Activity monitoring is also performed on R+0.
• A graded tilt test with echocardiograph, ECG, and BP
measurement is also required pre- and postflight.
• Magnetic Resonance Spectroscopy (MRS) to ground MRI
sessions
• Strain rate imaging for pre/postflight tests
16
FY 1999 Review of NASA’s Biomedical Research
Program recommendations for a cardiac summit
1.Determine if cardiac
arrhythmias are a
significant concern
and if monitoring is
warranted.
1.
2.
3.
Determine if cardiac arrhythmias are a significant
concern and if monitoring is warranted;
Determine if cardiac atrophy is a significant concern
and should be monitored;
Determine if there are pre- and in-flight predictors of
orthostatic intolerance;
http://www.nap.edu/catalog/9950.html
Sources of Cardiac Data
• Detailed Supplemental
Objectives (DSOs)
• Extended Duration Orbiter
Medical Project (EDOMP)
program
• NASA Research
Announcements (NRA)
• National Space Biological
Research Institute
(NSBRI)
• Flight Medicine Clinic
(FMC)
• Shuttle mission medical
records
• ISS mission medical
Records
• Skylab, Apollo-Soyuz, Apollo,
Gemini console logs
• Biomedical Engineer (BME)
Console logs
• Online Data Reduction Center
(ODRC)
• Bld 8 Space Medicine Archives
• Life Sciences Data Archive
(LSDA)
• Longtudinal Study of Astronaut
Health (LSAH)
• Literature review
• NASA internal Technical
Reports
• Astronaut interviews
• Flight Surgeon interviews
17
Cardiac Monitoring Occurrences
• Selection
• Annual physical/FMC
visits
• Parabolic flight
• Preflight
– MRIDs
– NBL
– Chamber
• Inflight
–
–
–
–
PFE
EVA
Contingency Ops
Payload activities
• Postflight
– MRIDs
Incidence of Ectopy in Aviation
24-hour Holter recordings from 303 patients
with normal cardiac catheterization found that
only 11.9% of these patients had no ectopy.
– Of significance was the presence of isolated
atrial and ventricular ectopy, pairs, and
nonsustained SVT
– Results indicate that ectopy in this
asymptomatic cohort with no evidence of
cardiac disease is very common.
• Folarin VA, Fitzsimmons PJ, Kruyer WB. Holter Monitor Findings in Asymptomatic Male Military Aviators
Without Structural Disease. Aviat. Space Environ. Med. 2001;72:836-8.
• Folarin VA, Fitzsimmons PJ, Kruyer WB. Spectrum of Holter Findings in Asymptomatic Male Military Aircrew
Without Structural Heart Disease. Aerospace Medicine Association Meeting. Houston.
18
Incidence of Cardiac Events In Spaceflight Crews
• Apollo 15 was the first U.S.spaceflight in which
cardiac arrhythmias other than the occasional PVC
were observed.
– Lunar module pilot experienced 5 unifocal PVCs within
a 30-second interval
– 1 hour later, the lunar module pilot experienced a 22-beat
run of nodal bigeminy.
– LM pilot recalled experiencing profound fatigue at the
time of this bigeminal rhythm.
• Twenty-one months after the mission he
experienced an myocardial infarction.
• Angiogram revealed diffuse disease
•
•
Rowe W.J. The Apollo 15 Space Syndrome. Circulation 1998;97:119-20.
Mission Medical Archive
Incidence of Cardiac Events In
Spaceflight Crews
• Skylab Space Project also revealed
significant arrhythmias in several of
crewmembers, including
– 3-beat ventricular tachycardia (VT) complex
(triplet) occurring with exercise
– Atrial-ventricular block during LBNP recovery
– Atrio-Ventricular Junctional rhythm at rest
after LBNP
– Multifocal PVCs after an EVA.
• Is this bad?
Johnson RS, Dietlein LF. Biomedical Results from SkyLab. NASA Washington D.C.
1977;SP - 377:313-23.
19
Incidence of Cardiac Events In Spaceflight Crews
• A Holter recording
taken during the
second month on
orbit revealed an
asymptomatic,
non-sustained, 14beat run of VT.
• We now know that this subject experienced a
myocardial infarction 2 years after his flight.
Fritsch-Yelle JM, Leuenberger UA, et al. An Episode of Ventricular Tachycardia During
Long-Duration Spaceflight. Am J Cardiol 1998;81:1391-2.
Circa 2003 EVA
Monitoring system
20
Incidence of EVA related Cardiac Events on
STS and ISS
TDRSS
ISS Airlock EVA –
Joint Ops
EVA EMU (Proprietary OBS)
UHF/S-band
GPIB
STS MPSR BME
DEC Alpha
Streaming Data
Archived
ISS Strip chart recorder
ODRC
ISS MPSR BME
DEC Alpha
FEP
GPIB
*Retrospective data
unable to be retrieved
due to time stamp
problem (except for
shuttle EVA data)
* Cognitive burden for
ECG interpretation and
data management
STS Strip chart recorder
Surgeon
DEC Alpha
New EVA ECG Monitoring System
TDRSS
Front End
Processor
ISP server
Red (Sim)-FRC
GE/Marquette
CIC Monitor
MCC LAN
BioMed
MPSR
ISP Packet Stream
ODRC
Streaming Data Archives
White (STS) -FRC
GE/Marquette
CIC Monitor
Blue (ISS) -FRC
GE/Marquette
CIC Monitor
Rx LAN
BME
GE/Marquette
CIC Workstation
With Full Disclosure
21
How reliable was our EVA ECG data?
Strip Chart Recorder
Red Tag and Critical Anomaly Report
GMT = XXX:15:47:07.000
Triplet, Aberrancy or Artifact?
Flight Surgeon
22
Let’s
CDE
Two
Let’s
Let’s
anomaly
get
now
different
now
getthe
playback
the
playback
ISS
GEMS
was
MPSR
anomalies
and
created
aCIC
STS
amission
hardcopy
mission
ODRC
were
ODRC
20 seconds
backup
created
backup
again
analysis
dump
with
tape
earlier
using
tape–the
–Run
the
Run
anomaly
same
#1#2 data
labeled
Hardcopy from ODRC/CIC
(What really happened on STS)
Hardcopy from ODRC (ISS)
(What really happened on ISS)
Hardcopy from ODRC (STS)
(What really happened on STS)
Hardcopy from MPSR
(Erroneous output at XXX:XX:47:07.000 )
CDE Test Run #1
(Erroneous output at XXX:XX:46:47)
CDE Test Run #2
Original
Anomaly
(Erroneous output at XXX:XX:46:47)
20 seconds
Anomaly at XXX:XX:47:07.000
CDE Playback Anomaly at XXX:XX:46:47.000
• Legacy “hard copy" ECG data is
corrupt – Space Medicine advised not
to use for mission decisions
• EVA telemetry, from April 1983 (STS-6)
until present, was reanalyzed.
• Software developed by Advanced
Projects to convert the digital archives
into telemetry streams for Holter
analysis.
23
AEMS Admin Display
> 20,000 ‘lines of code’ verified for STS 114 “return to flight”
Data Taken From 160 EVA’s STS-006 Thru STS-116
Total STS
Total ISS
Total Joint
Total EVA's Analyzed
104
4
52
160
Total STS
Total ISS
Total Joint
Total EVA's Not Analyzed
Total EVA's
32
4
14
50
210
24
Percent Monitored
Percent of EVA Monitored
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1
21
41
61
81
101
121
141
161
Mission Number
Electrode Failure
Good Electrodes
ODRC Data Taken From 160 EVA’s STS-006 Thru STS-113
• Average Percent Monitored = 72.89%
• Total QRS Complexes = 3,828,826
• Total Ectopic Beats = 11869
SV E
PVC
P V C B i gem
P V C C oup
SV E
B i gem
SV E C o u p
# J unc t i ona l
6787
852
13
3323
1022
25
696
• Total EVA’s with Sinus Arrhythmia = 77 of 160 (48%) Prelim data
• Total Sinus Arrhythmia preflight = 9 of 160 ( 5.6%) Prelim data
• Total Time of 160 Analyzed EVA’s
= 60688 minutes
= 42 Days, 16 Hours and 54 Minutes
• Average EVA length = 300.5 ± 43.1 SD minutes
• Average Heart rate = 86.2 BPM
• Average age at EVA = 45.04 ± 17.63 SD
ODRC Data Taken From 160 EVA’s STS-006 Thru STS-113
25
• The majority of EVA’s had ectopy, which can be
explained by examining pre and post flight medical
data (resting ECG, Treadmill Stress Test,
Electronic Medical Record etc.)
• 1 EVA had ectopy with no terrestrial medical data
to correlate (129 junctional beats over 6 ½ hour
EVA) . Query “Afrin” effect
• 62 had occasional (< 30) PVC’s per EVA
• 62 had no ectopy
• All EVA’s who had “serious” ectopy was diagnosed
with some degree of “Cardiac Disease” within
temporal proximity to the mission.
D'Aunno DS,
Dougherty AH,
DeBlock HF,
Meck JV.
Effect of short- and
long-duration
spaceflight on QTc
intervals in healthy
astronauts.
Am J Cardiol.
2003;91:494-7.
26
Preflight, In-flight and Post flight Data
QTc vs Time After Launch
MIR = 3
550
QTc (ms)
500
450
400
350
300
-300
-250
-200
-150
-100
-50
0
50
100
150
200
250
300
350
400
Time After Launch (days)
D'Aunno, DS, Dougherty, AH, DeBlock, HF, Meck, JV. Effect of short- and long-duration
spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 91:494-7.
Preflight, In-flight and Post flight Data
QTc vs Time After Launch
ISS = 15, MIR = 3,
550
QTc (ms)
500
450
400
350
300
-300
-250
-200
-150
-100
-50
0
50
100
150
200
250
300
350
400
Time After Launch (days)
• D'Aunno, DS, Dougherty, AH, DeBlock, HF, Meck, JV. Effect of short- and longduration spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 91:494-7.
• ISS Mission Archives
27
Preflight, In-flight and Post flight Data
QTc vs Time After Launch
ISS = 15, MIR = 3, SkyLab = 9
550
QTc (ms)
500
450
400
350
300
-300
-250
-200
-150
-100
-50
0
50
100
150
200
250
300
350
400
Time After Launch (days)
• D'Aunno, DS, Dougherty, AH, DeBlock, HF, Meck, JV. Effect of short- and longduration spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 91:494-7.
• ISS Mission Archives
• Skylab Mission Archives
In-flight Data
RUSSIAN DATA?
QTc vs Time After Launch
ISS = 15, MIR = 3, SkyLab = 3
550
QTc (ms)
500
450
400
350
300
0
20
40
60
80
100
120
140
160
Time After Launch (days)
• D'Aunno, DS, Dougherty, AH, DeBlock, HF, Meck, JV. Effect of short- and longduration spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 91:494-7.
• ISS Mission Archives
• Skylab Mission Archives
28
On Orbit Periodic Fitness Exam
Case
8000
CHeCS BP/ECG Kit –
SED46115812-303
Schiller AT-10 ECG
On Orbit Periodic Fitness Exam
•ECG and blood pressure data from 26 on orbit
fitness tests were analyzed.
•All exercise protocols were written to prevent
the crewmember from exceeding 80% of their
prelaunch VO2 max.
•Pre launch exercise stress tests were used as
baselines for comparison.
•ECG's were acquired using the Dower EASI 5
to 10 electrode lead conversion system.
ISS Mission Archives
29
On Orbit Periodic Fitness Exam
• Drew BJ, Adams MG, Pelter MM, Wung SF. ST segment monitoring with a derived 12-lead electrocardiogram is
superior to routine cardiac care unit monitoring. Am J Crit Care. 1996;5:198-206.
• Drew BJ, Adams MG, Pelter MM, Wung SF, Caldwell MA. Comparison of standard and derived 12-lead
electrocardiograms for diagnosis of coronary angioplasty-induced myocardial ischemia. Am J Cardiol.
1997;79:639-44.
• Drew BJ, Koops RR, Adams MG, Dower GE. Derived 12-lead ECG. Comparison with the standard ECG during
myocardial ischemia and its potential application for continuous ST-segment monitoring. J Electrocardiol.
1994;27 Suppl:249-55.
On Orbit Periodic Fitness Exam
Load
250
Load (Watts)
Level 3
200
Level 2
150
100
Recovery
Level 1
50
0
Baseline
11
39.5±6.3*
126
161±14.1*
103±9.8*
151
76
1
39.5±6.3*
101
1
Exercise Stage
* = Mean ± Standard Deviation
ISS Mission Archives
30
On Orbit Periodic Fitness Exam
Heart Rate (BPM)
Actual HR
180
160
140
120
100
80
60
40
20
0
0
25
50
75
100
125
% of Exercise Portion of PFE
ISS Mission Archives
On Orbit Periodic Fitness Exam
Target Heart Rate
% of Max Heart Rate Target
120%
100%
80%
60%
40%
20%
0
25
50
75
100
125
% of Exercise Portion of PFE
ISS Mission Archives
31
On Orbit Periodic Fitness Exam
•26 exercise PFE´s lasting approximately 20 minutes each
were compared to pre launch exercise stress tests.
• No clinically significant ectopy was observed on orbit.
•
•
•
•
•
Resting: Heart rate (mean 68 ±5.7 SD)
PR interval (155 msec ±24 SD)
QRS duration (95 msec ±4.2 SD)
QT interval (389 msec ±1.4 SD)
QTc interval (419 msec ±10.6 SD).
•One clinically significant ST change was observed on orbit.
•One incident of “false positive” ST elevation was observed
when the crew member was pedaling on the cycle
ergometer at the same rate as their heart.
•Will update database to include 54 PFE’s to date
ISS Mission Archives
Summary of Incidence Data
Does Spaceflight Cause Arrhythmias?
• The evidence strongly suggests that preflight
cardiac disease is the main cause of “serious” inflight cardiac arrhythmia and anomalies.
• NO space related risk factors have been validated
to date.
• Until we stop launching cardiac disease…….
…..a prospective study looking at spaceflight induced
arrhythmia (flight surgeon insomnia) will be
impossible.
32
Sooooo…..
…if we think that serious on orbit
arrhythmias are due to cardiac
disease ….
How much ‘disease’ do we fly?
Incidence Of Cardiac Disease in Aviation
Age-specific rates of severe coronary disease among
pilots who were involved in a fatal aviation accident.
R ates per 1000
100
80
63.6
60
89.9
73.9
40
20
22.1
5.8
14.5
0
0
30
14.9
40
50
60
Age
1975 - 1977
1980 - 1982
• A 3 year study of 710 pilot autopsies from airline accidents, 69% had
some degree of heart disease and 2.5% had severe heart disease (Booze
C.F., Staggs C.M., Aviat. Space Environ. Med 1987;58:297-300.)
• These studies give us an idea of the incidence of heart disease which is
present in apparently healthy pilots flying aircraft today
33
Incidence Of Cardiac Disease in Aviation
• A study of 288 military, commercial, and private pilots killed in
aviation mishaps and of 132 healthy males aged 18 to 62 who
died accidentally revealed no significant difference in the
prevalence of coronary artery disease between the aviators and
the control group.
• A study of apparently healthy U.S. Air Force aviators
– reported myocardial infarction, angina, and sudden cardiac death
of 0.02% per year from 1988 to 1992 (20 per 100,000 years)
– the mean age of aviators having a cardiac event was 44 years.
– 61% were myocardial infarction and 21% were sudden cardiac
death.
– Angina only represented 18% of the cardiac events. Does this
suggests that denial or underreporting may be a significant
concern in this population?
Underwood Ground K.E. Prevalance of Coronary Atherosclerosis in Healthy United
Kingdom Aviators. Aviat. Space Environ. Med. 1981;52(11):696-701
Osswald S, Miles R, Nixon W, Celio P. Review of Cardiac Events in USAF Aviators.
Aviat Space Environ Med 1996;67(11):1023-7.
Adapted from Kruyer 2004
20.00
ina
typic
a l Ch
es t p
45 y
/o ♂
,
atypic
o ♂,
45 y/
ymp
toma
tic, H
TN,
al an
g
ain
DM
0.00
0.00
♂ , as
40.00
♂ , as
60.00
45 y
/o
ympto
matic
80.00
Chol,
, no r
isk fa
ctors
100.00
45 y/o
Post-Test Probability of CAD (%)
Bayesian Theory
20.00
40.00
60.00
80.00
100.00
Pre-Test (Clinical) Probability of CAD (%)
34
The sensitivity, specificity, positive predictive value, and
negative predictive values for treadmill, thallium, and CAF for
the presence of SCAD as determined by coronary angiography
100
90
80
Percent
70
60
50
40
30
20
Fluroscopy
10
Thallium
0
Sensitivity
Specificity
Treadmill
PPV
NPV
Fitzsimmons P., Palm-Leis A. Thompson Kruyer W. Comparison of Noninvasive Cardiac Testing
in 759 Military Aviators; Angiographic Correlation and Clinical Follow-up. Aerospace Medicine
Association Meetings 72nd Annual Scientific Meetings; Reno, Nevada. 2001.
Cardiac event rates of aviators (%/year/person) for
2, 5, 10, and 15 years for minimal coronary artery
disease and significant coronary artery disease
CardiacEvent
Event Rates
Cardiac
Rates(%(%)
10
9
8
7
6
5
4
3
2
SCAD (>70%stenosis)
1
SCAD (50-70%stenosis)
0
2 yr
5 yr
MCAD (<50%stenosis)
10 yr
15 yr
Barnett S., Fitzsimmons P. Thompson W. Kruyer W. The Natural History of Minimal and Significant Coronary
Artery Disease in 575 Asymptomatic Male military Aviators. Aerospace Medicine Association Meetings 72nd
Annual Scientific Meetings; Reno, Nevada. 2001.
35
Natural History of CAD
44 military aviators who were diagnosed
with asymptomatic MCAD by
angiography were followed
– Progression of MCAD to SCAD occurred in 25%
of these 11 aviators (63.6%) had a negative
noninvasive test at the time of their recatheterization.
– The group that progressed to SCAD had higher
total and LDL cholesterol and a lower HDL
cholesterol
• Leding C, Fitzsimmons P, Kruyer W. Coronary Artery Disease and Aerospace Medicine - Summary,
Applications and Future Directions . Aerospace Medicine Association Meetings 72nd Annual Scientific
Meetings: Reno, Nevada. 2001.
• Zarr S, Gee M, Fitzsimmons P, et al. Angiographic and Clinical Follow-Up of Military Aviators With Minimal
Coronary Artery Disease and Serial Coronary Angiography . Aerospace Medicine Association Meetings 72nd
Annual Scientific Meetings: Reno, Nevada. 2001.
• Gee MR, Kruyer WB. Progression of Minimal Coronary Artery Disease in USAF Aviators Followed With Serial
Cardiac Catheterizations. Aerospace Medicine Association Meetings: Houston.
Longitudinal Study of Treadmill Tests of
Active and Inactive NASA Astronauts
A review of 2,069 exercise treadmill tests
(TMT’s) using a Bruce protocol conducted
on Active and Inactive astronauts was
conducted from February 1977 until July
2000.
–Age distribution
–Incidence of Positive Tests
–Follow-up of Positive Test
–Incidence of Cardiac Events
FMC and LSAH 133 Inactive Astronauts at 2001
36
Mean Age of Inactive Astronauts by Year
70
65
60
55
50
45
40
35
20
00
19
95
19
90
19
85
19
80
19
75
19
70
19
65
30
FMC and LSAH 133 Inactive Astronauts at 2001
Mean Age of Active Astronauts by Year
50
48
46
44
42
40
38
36
34
32
19
99
19
94
19
89
19
84
19
79
19
74
19
69
19
64
19
59
30
FMC and LSAH 150 astronauts at 2001
37
2,069 Treadmill Tests Administered
to NASA Astronauts
February 1977 - July 2000
51 Positive/Abnormal TMT's
1,941 Negative/Normal TMT's
69 Borderline TMT's
20 Negative/Normal
Thallium Treadmills
24 Negative/Normal
Thallium Treadmills
6 Negative/Normal
Thallium Treadmills
2 Indeterminate/Unclassified
Thallium Treadmills
4 Positive/Abnormal
Thallium Treadmills
1 Unfulfilled
Thallium Treadmill
Recommendation
7 Unfulfilled
Thallium Treadmill
Recommendations
3 Negative
Cardiac Catheterizations
1 Death during the
year of the TMT;
acute myocardial infarction
1 Positive/Abnormal
Thallium Treadmill
1 Negative
Cardiac Catheterization
8 Indeterminate TMT's
1 Unfulfilled
Thallium Treadmill
Recommendation
2 Indeterminate/Unclassified
Thallium Treadmills
1 Referenced
Cardiac Catheterization
(2 years later)
1 Myocardial Infarction
(2 years later)
1,911 TMT's without
Thallium Treadmills
2 Positive
Cardiac Catheterizations
4 Negative
Cardiac Catheterizations
1 Unclassified
Cardiac Catheterization
1 cardiac arrest
(6 months later)
FMC and LSAH 133 Inactive Astronauts at 2001
1,904 Negative TMT's
without either
Thallium Treadmills or
Cardiac Catheterizations
2 Deaths from
Myocardial Infarction
(1 year later and
2 years later)
Longitudinal Study of Treadmill Tests of
Active and Inactive NASA Astronauts
•
•
•
•
Number of Astronauts = 295
Follow up time 1 - 23 years
Total Person Years = 2,240
1941 negative TMT’s
– 2 cardiac events within 4 years of a
negative TMT
– 2 cardiac deaths within 2 years of a
negative TMT
• 51 Positive TMT’s
– 1 Death within the year of the TMT
FMC and LSAH Astronauts at 2001
38
Longitudinal Study of Treadmill Tests of
Active and Inactive NASA Astronauts
• Gross incidence of whole
population
= 0.22%/per person/ year
• 1/51 +TMT lost to follow up
• 2/69 Borderline TMT lost follow up
• Will complete study to include 709
new studies to 12/31/2006
• Will compare to ~5000 LSAH
control population TMT’s
FMC and LSAH Astronauts at 2001
So….. Current circa 2004
selection methods do not
adequately filter out
asymptomatic “Cardiac
Disease” .….
What do we do now?
39
Can we improve the risk factor profile?
male
female
active
inactive
• Wilson, PW, D'Agostino, RB, Levy, D, Belanger, AM, Silbershatz, H, Kannel, WB. Prediction of
coronary heart disease using risk factor categories. Circulation 97:1837-47
• Hamilton DR, Murray JD, Ball CG, Kapoor D, Kirkpatrick A.W. Cardiac Health for Astronauts:
Current Selection Standards and their Limitations. Aviat Space Environ Med. 2005;76:615-26.
• Approximately 25% of patients with
CAD do not have any of the
classically recognized risk factors.
• Presently over 200 new risk factors
and markers (such as C-reactive
protein, homocysteine,4 fibrinogen,
Lp(a), ApoB, ApoA1,urine microalbumin, and some infectious agents)
have been correlated with CAD.
40
Are there other markers which indicate the
presence of cardiovascular disease?
Elevated highly
selective C-reactive
protein is a reliable
risk factor for
helping predict
future cardiac
events that should
warrant primary
prevention but not
necessarily medical
disqualification.
• Ridker, PM, Rifai, N, Rose, L, Buring, JE, Cook, NR. Comparison of C-reactive protein and lowdensity lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J
Med 347:1557-65.
• Hamilton DR, Murray JD, Ball CG. Cardiac health for astronauts: coronary calcification scores
and CRP as criteria for selection and retention. Aviat Space Environ Med 2006; 77:377-387.
Cardiovascular Screening Tests – Stress
Thallium, CAF
• CAF was found to have a PPV of 68% for
any measurable CAD in 613 aviators.
• CAF had a PPV of 81% for all CAD and 34%
for SCAD (mean age of 42.3 years) in 220
male aviators.
• 52% of calcific lesions detected on EBCT
could be seen by fluoroscopy.
Loecker TH, Schwartz RS, Cotta CW, et al. Fluoroscopic Coronary Artery Calcification and
Associated Coronary Disease in Asymptomatic Young Men. J. Am. Coll. Cardiol. 1991;19(6):116772.
Smalley BW, Loecker TH, Collins TR, et al. Positive Predictive Value of Cardiac Fluoroscopy in
Asymptomatic U.S. Army Aviators. Aviat. Space Environ. Med. 2000;71:1197-201.
Wexler L, Brundage B, Crouse J, et al. Coronary Artery Calcification: Pathophysiology,
Epidemiology, Imaging Methods, and Clinical Implications. Circulation 1996;94:1175-92.
41
Coronary Artery
Calcium Score
• Approved by MMOP
for Long Duration
Astronauts
• Astronauts with CACS
< 100 and/or other
significant risk factors
should receive
secondary prevention.
• Astronauts with a
CACS > 100 are
disqualified from long
duration spaceflight.
Hamilton DR, Murray JD, Ball CG. Cardiac
health for astronauts: coronary calcification
scores and CRP as criteria for selection and
retention. Aviat Space Environ Med 2006;
77:377-387.
New selection methods will
start with Increment 16 and
should filter out most
asymptomatic “Cardiac
Disease”…. What is our
risk Circa 2007?
42
LaMonte et al reported CACS and an age stratum of
40-65 years, representing approximately 60% of a
10,746 total population with hard event rates (fatal or
non-fatal AMI) during a 3.5 year follow-up.
Event rates per 100,000 person-years
CACS
0
0 - 100
100 - 400
>400
Rate
3
20
670
1060
LaMonte MJ, FitzGerald SJ, Church TS, Barlow CE, Radford NB, Levine BD, et al.
Coronary artery calcium score and coronary heart disease events in a large cohort of
asymptomatic men and women. Am J Epidemiol 2005 Sep;162(5):421-9.
The very low incidence in the
Church CACS = 0 subgroup may
represent a risk nadir resulting from
exhaustion of the primary CV
pathology in younger individuals and
the nascent risk of CAD in the 4th
decade of life for persons with low
CAC scores and minimal
conventional cardiac risk factors.
43
Med
Low
1 in 10 yr
1 in 100 yr
1 in 1000 yr
1 in 10,000 yr
1 in 100,000 yr
High
Med
Low
L
I
K
E
L
I
H
O
O
D
1
Risk
2
4
2
3
4
Loss of Life or Mission
Permanent or serious
injury impairment
Risk
3
Loss of Life or Mission
High
2
Permanent or serious
injury impairment
1
Long-term or missionimpact injury
impairment DQ
1 in 100,000 yr
Long-term or missionimpact injury
impairment DQ
1 in 10,000 yr
Short-term injury,
illness, or impairment
DNIF
1 in 1000 yr
L
I
K
E
L
I
H
O
O
D
Short-term injury,
illness, or impairment
DNIF
1 in 100 yr
First Aid or minor
injury
1 in 10 yr
First Aid or minor
injury
Risk After Selection
Risk Matrix
5
4
3
2
1
5
Consequence
Acute Myocardial Infarction
Risk Matrix
5
4
3
USAF
NASA - STS
1
Consequence
5
44
Acute Myocardial Infarction
Risk Matrix
1 in 100,000 yr
3
Space flight
2
1
1
Low
First Aid or minor
injury
Med
3
2
4
5
Consequence
Risk
High
NASA
EXP 2007
Loss of Life or Mission
1 in 10,000 yr
NASA
EXP 2004
?
4
Permanent or serious
injury impairment
1 in 1000 yr
?
5
Long-term or missionimpact injury
impairment DQ
1 in 100 yr
L
I
K
E
L
I
H
O
O
D
Short-term injury,
illness, or impairment
DNIF
1 in 10 yr
Is Space Flight a “root cause” for
significant arrhythmias?
• Given that the incidence of all cause
sudden cardiac death or myocardial
infarction in the CACS = 0 astronaut
cohort on Earth…
• What is the evidence that space flight is
responsible other root causes of hard
cardiac events?
• How will we find this out?
45
Yep….Integrated Cardiac…. Again!
Benjamin D. Levine, M.D. & Michael W. Bungo, M.D.
• In-flight resting echocardiograms with ECG recording followed by
24 to 48 hour Holter/Blood Pressure/Activity Monitoring at FD15
and 30, and every one to two months thereafter with a final
session required 15 days before landing.
• A post-exercise echo as part of the FD90 session.
• Pre- and postflight BDC Cardiac MRIs as well as Exercise
Echo/ECG and Resting Echo/ECG sessions followed by 24 to 48
hour Holter/BP/Activity monitoring.
• Holter/BP/Activity monitoring is also performed on R+0.
• A graded tilt test with echocardiograph, ECG, and BP
measurement is also required pre- and postflight.
• Magnetic Resonance Spectroscopy (MRS) to ground MRI
sessions
• Strain rate imaging for pre/postflight tests
Thank You
So now you
know what
keeps the
flight
surgeons up
at night.
Cardiac
Disease
46
Byron Smith
Kelly McFarlin
Ben Voigt
David Gillis
Ashot Sargsyan
Victor Hurst
Kieran Smart
Shannon Melton
Hal Doerr
Scott Dulchavsky Phyllis McCulley
George Beck
Karen Mathis
Kat Garcia
Jack Rasbury
Melisa Rosse
Dave Martin
Don Hagen
Chuck Lloyd
Jack Butler
Tom Goodwin
Jim Locke
Steve Platts
Jon Clark
JD Polk
Ben Levine
Jeff Sutton
Mike Duncan
Jan Meck
Ashkan Moghaddam Gary Gray
Mike Bungo
Bill Kruyer
Terry Guess
Jennifer Fogerty
Steve Nissan
Rick Pettys
Mark Scheutte
Mary Wear
Sonny Belinkie
Peggy Winston
Jocelyn Murray
John Tyberg
ISS Crew
Chad Ball
Cathy Modica
John Charles
Andy Kirkpatrick
HRF team
Mike Barratt
Please excuse me if I missed you
The Team
AEROSPACE MEDICINE GRAND ROUNDS
Questions?
Douglas Hamilton MD PhD MSc E Eng P. Eng
Flight Surgeon / Electrical Engineer - Wyle Life Sciences
47