Theories for Pre-Hospital and In-Hospital Resuscitation

Report
Update on
Hypothermia post Cardiac Arrest.
E Hessel, II, MD, FACS
Strive to Revive:
Improving Cardiac Resuscitation
American Heart Association and
UK HealthCare Gill Heart Institute
Lexington, KY
April 28, 2014
Revised April 28, 2012; 0530 EDST
Disclosures
• I have no disclosures, financial or otherwise.
This is why I am speaking on this topic:
Starting in 2003 therapeutic hypothermia (TH) has been
strongly recommended following some Cardiac Arrests (CA) by
many professional organizations including most recently
by the American Heart Association
• Last year at this meeting I critiqued the use of therapeutic
hypothermia (TH) post cardiac arrest especially post inhospital cardiac arrest (IH-CA)
– Pointed out the limitations of the evidence supporting its use for outof-hospital cardiac arrest (OOH-CA)…
– and the lack of any high level evidence of its benefit following cardiac
arrest associated with non-shockable rhythms and following
in-hospital cardiac arrest (IH-CA).
My Objectives
For this afternoons presentation
• Elaborate and expand on some of the data I presented last
year
• Review important data which have appeared during in the
literature during the past year
• Give you my personal current recommendations regarding the
use of therapeutic hypothermia post cardiac arrest.
I call your attention, and have provided copies for you, of
an article of mine recently published on this topic, largely based on
my presentation at this meeting last year but including some of the new information
which I will present this afternoon.
I am referring you to this paper mainly because it provides references to many of
the studies I will be commenting on this afternoon
J Cardiothoracic and Vascular Anesthesia
Epub ahead of print. April 18, 2014
Outline
•
TH for OOH-CA
–
•
TH for CA associated with non-shockable rhythms
–
•
Recent large observational study
Role of simply preventing hyperthermia post CA
–
•
Recent systematic review and some new data
TH for IH-CA
–
•
A new large observational study with concurrent controls
Recent large RCT 36o versus 33o C
Role of pre-hospital cooling
–
Recent RCT
•
Ongoing Pediatric RCTs
•
Review limitations of TH
•
Selection of candidates for TH
•
Summary
Use Therapeutic Hypothermia (TH) following
Out-of-Hospital Cardiac Arrest (OOH-CA)
• Still no randomized controlled trials since the two major ones
published 12 years ago (2002)
• There have been
– A RCT of benefits of pre-hospital cooling (prior to in-hospital TH)
– A RCT comparing a targeted temperature of 36o C versus traditional
33o C
– I will review these studies subsequently
• In addition the results of a large data registry has been
recently reported (see next.)
Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31
Retrospective cohort study of patients resuscitated from out-of-hospital
Cardiac Arrest using data from the
Cardiac Arrest Registry to Enhance Survival (CARES) [CDC and Emory University]
~ 50 sites
Nov 1, 2010 through Dec 31, 2012
Adults with CA of presumed cardiac etiology with survival to hospital admission;
included shockable and non-shockable l rhythms
Propensity score matching to compare patients receiving
therapeutic hypothermia or not
6369 patients
Shockable 47%; asystole 26%, PEA 20%, other non-shockable 7%
Therapeutic hypothermia in 54% (62% of shockable, 50% on non-shockable)
Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31
Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31
Unadjusted outcomes
(Mader, et al. 2014)
Rhythm
All
– TM
– No TM
Shockable
– TM
– No TM
Non-shockable
– TM
– No TM
n
Survived(%)
Good Neurologic
Outcome(CPC 1 or 2)(%)
3452
2917
40%
39
34%
34
1851
1141
60
65
53
61
1601
1776
17
22
12
16
Note outcome no better or worse with TH
Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31
Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31
Mader TJ, etal.
[Therapeutic Hypoth and Temp management 2013; 4(1): 21-31]
TH following Cardiac Arrest
Associated with Non-shockable rhythms.
• Last year I stated
“Although there are conflicting data, most suggest that TH
is less beneficial, (or perhaps not even beneficial) post nonshockable rhythms following (either out-of-hospital or in-hospital
cardiac arrest)”
• Unfortunately this remains true today
– There have been three new observational studies, and
– Two systematic review and Meta-analyses of this issue
• But the definitive answer awaits large well conducted RCT or
prospective observational studies.
TH following CA associated with
non-shockable rhythms
• Recent observational studies that provide information
– Vaahersalo J, et al. Intensive Care Med 2013; 39: 826-37
– Lindner TW, et al. Critical Care 2013; 17: R147
– Mader, et al. Ther Hypth and Temp Manag 2014; 4: 21-30
• Recent reviews
– Kim Y-M, et al. Resuscitation 2012; 83: 188-96
– Sandroni C, et al. Critical Care 2013:17: 215
A recent Systematic Review and Meta-Analysis
Sandroni C, etal. Critical Care 2013; 17: 217
Death
Bad
neurologic
Outcome
Sandroni, et al
Critical Care
2013; 17:215
TH following CA associated with non-shockable rhythms
My Summary of these data
Studies of effect of therapeutic hypothermia in patients following
Cardiac arrest associated with non-shockable rhythms (PEA or asystole)
Add Mader, et al’s large observational study in 2014
Hessel, EA. J Cardiothoracic and Vascular Anesthesia
Epub ahead of print. April 18, 2014
TH following CA associated with non-shockable rhythms
Summary
• The Studies
– Two small (total of 22 patients in each arm)
– 16 non-randomized observations studies
• Type of controls
– 5 with concurrent controls
– 11 with historical controls
• Patients
– 546 received TH (+ 1601 from Mader, etal 2014)
– 1038 did not (+ 1776 from Mader, etal 2014)
TH following CA associated with non-shockable rhythms
Summary
• The Results
– Impact on survival (13 studies)
• 11 observed no statistically significant difference
• 2 observed an improved survival with TH
• In aggregate: 12% decrease in mortality with TH (No decrease if include Mader, etal, 2014)
– Impact on good neurologic recovery (14 studies)
• 13 observed no statistically significant difference
• 1 observes an improved outcome with TH
• In aggregate: A statistically insignificant 5% increase in good neurologic outcome with TH
(No improvement if include Mader, etal, 2014)
• Conclusion
– There is a suggestion of benefit with use of TH in some studies
– Magnitude much less that seen in patients with shockable rhythms
– Because of the low quality of the evidence (GRADE) there is need for high
quality RCTs to confirm any benefit
Unadjusted outcomes
(Mader, et al. 2014)
Rhythm
Non-shockable
– TM
– No TM
n
Survived(%)
Good Neurologic
Outcome(CPC1 or 2)(%)
1601
17
12
1776
22
16
Worse outcome!
Mader TJ, etal. Therapeutic Hypoth and Temp management 2013; 4(1): 21-31
Mader TJ, etal.
[Therapeutic Hypoth and Temp management 2013; 4(1): 21-31]
In-Hospital Cardiac Arrest
Edelson DP, etal. J Hospital Med 2014 epub ahead of print
(90%)
NEJM 2012; 367: 1912-20
GWTG-R Investigators
374 hospitals 2000-2009
84,625 cardiac arrests
Initial rhythm asystole or PEA in
79% (and increased over time from 69 to 82%)
Survival to discharge
17%
If VF or VT
34%
If Asystole or PEA 10%
Neurologic disability in survivors
30%
Survival to discharge increased over time while neurologic disability decreased
S. Girotra, etal. NEJM 2013.
Therpeutic hypothermia after in-hospital Cardiac arrest
Mikkelsen ME, etal. CCM 2013
Additional comments and observations
• 210,000 in hospitals cardiac arrests (IHCA) annually in USA
• Rate is increasing
• Less than 25% have VF/VT as the initial rhythm (and this appears to be
declining)
• IHCA with initial non-shockable rhythm that transitions to VF/VT is
common and outcomes are dismal (Meaney, etal. CCM 2010; 38: 101)
• No RCT of TH following IH-CA have been reported
TH following In-hospital Cardiac Arrest
• Last year I indicated that there was no high level evidence
(e.g., RCT or large observational studies demonstrating
improved outcome with therapeutic hypothermia when used
following in-hospital cardiac arrest.
• This remains true, however during the past year the largest
retrospective observational study addressing this question
was published. I will review this shortly.
Hessel, EA. J Cardiothoracic and Vascular Anesthesia
Epub ahead of print. April 18, 2014
Nichol G, et al. Resuscitation 2013; 84: 620-25
Retrospective analysis of multi-center prospective cohort of patients
454 hospitals in USA participating in Get With the Guidelines-Resuscitation (TWTG-R) QI
2000-2009
Limited to adult patients with ROSC after in-hospital CA on the ward
(i.e., excluded if arrest in ER, ICU, OR, procedure areas or recovery areas)
8316 patients
214 (2.6%) received hypothermia,
8102 did not
87% had non-shockable rhythms
41% were unwitnessed
1374 (13%) had shockable rhythms (similar rate in both groups)
Nichol G, et al. Resuscitation 2013; 84: 620-25
Primary outcome: Survival to discharge
Secondary outcome: Good neurological status at discharge
(CPC score 1 or 2)
Provided unadjusted and propensity score adjusted Odds Ratios
Results:
Overall non-statistically significant worse outcome in
hypothermia group
In those with shockable rhythms [n 1374 (13%]
non-statistically significant better outcome with hypothermia
Table 2. Effect of hypothermia on survival and favorable
neurologic outcome at discharge in entire population
Nichol G, et al. Resuscitation 2013; 84: 620-25
Table 4. Effect of hypothermia on survival and favorable
neurologic outcome at discharge in patients with shockable rhythms
Nichol G, et al. Resuscitation 2013; 84: 620-25
However only 51% of those receiving hypothermia
were documented to have been cooled to below 34o C
This may explain the lack of benefit
Reasons to anticipate that
therapeutic hypothermia might be less effective for
In-hospital CA (IHCA)
• More than 75% associated with non-shockable rhythms
• IH-CA often due to hemorrhage, respiratory insufficiency or pulmonary
embolism (instead of primary arrhythmias or AMI)
• Victims of In-Hospital CA are often “sicker” and have more co-morbidities
– Girotra, etal NEJM 2013
• 44% respiratory insufficiency
• 29% hypotension
• 20% heart failure
• 17% sepsis
• 15% pneumonia
• 58% in ICU
• 31% on mechanical ventilation
• 29% receiving intravenous vasopressors
Reasons to anticipate that
therapeutic hypothermia might be less effective for
In-hospital CA (IHCA)
• Diagnosis of cardiac arrest often delayed
– Between 12 and 48 % unwitnessed
• These patients may be more prone to the complications of TH
• Poor outcome following IH-CA less likely to be due to
neurologic injury. (See next two slides)
Mode of death after admission to an ICU following cardiac
arrest.
Laver S, etal. Intensive Care Med 2004; 30: 2126-28
Retrospective observational study of 225 patients single ICU in
UK, 1998-2003
N
Mean age (years)
Died (percent)
Cause of death (percent)
Neurologic
Cardiovascular
Multi-organ failure
OOH-CA
IH-CA
113
63
57%
92
72
66%
68%
23
9
23%
26
51
So why might patients who experience CA associated with nonshockable rhythms and In-hospital be resistant to the benefits of TH?
It is reasonable to assume that the pathophysiology of the
neurologic injury (ischemia/reperfusion) is the same regardless
of the rhythm or location of the arrest or these other variables
TH modulates this injury and therefore it is plausible to expect it
to be beneficial in these other circumstances.
However the magnitude of neurologic injury could be much
worse in these scenarios, and thus TH, as currently administered,
may not be adequate [not a high enough “dose” (e.g., timing,
depth and duration), to use the phrase of Dumas, etal
(Circulation 2011)
So why might patients who experience CA associated with nonshockable rhythms and In-hospital be resistant to the benefits of TH?
Possible contributors to worse neurologic injury include:
Delayed diagnosis (not infrequently unwitnessed), longer
delay in ROSC, and more post resuscitation shock.
Since many of these other victims of CA are less likely to
have a cardiogenic cause, and the CA is often
preceded by periods of cardio-respiratory
failure (and associated hypotension and hypoxemia), their
brains may have been somewhat ischemic even before the
arrest occurs, aggravating the brain injury due to the CA per se.
In-hospital Cardiac arrest
• But there may be a unique population of patients who
experience in-hospital cardiac arrest and this may have
implications in our post arrest therapy…
• Specifically peri-operative IH-CA
Ramachandran SK, et al. Anesthesiology 2013; 119: 1322-39
Study of outcome of 2524 adults experiencing Cardiac Arrest in the operating room or
within 24 hours post-operatively. (2.1 % of all in-hospital cardiac arrests)
Obtained from the Get With The Guidelines-Resuscitation (GWTG-R) national
in-hospital resuscitation registry (Perioperative arrests occurred in 234 hospitals
2000-2008
Location of arrest
OR
PACU
ICU
Wards
Telemetry
1458 (57.5%)
536
332
140
58
• Outcome
– ROCS
– Hospital survival
– Neurologically intact( (CPC 1)
57.7%
32%
19%
• (64% of hospital survivors)
•
Factors associated with survival
– Shockable rhythms (better survival)
– Occurrence in PACU and telemetry units (better survival)
– Arrests attributed to arrhythmias and inadequate natural airway
(improved survival)
– Trauma and shock worse survival
– Number of coexisting diseases (survival decrease with number)
– Age (decreases with age)
– Duration of arrest (decreases with increase duration)
– Time to defibrillation and placement of invasive airway (shorter better)
• Factors associated with worse neurologic outcome
–
–
–
–
–
–
Poor pre arrest neurological status
Older age
Inadequate natural airway
Pre-arrest ventilator support
Longer duration of event
NOT the initial CA rhythm
In survivors
Good Neurological Outcome
Among all patients
16.1%
19.9%
27.1%
Comparison of Perioperative with All
In-hospital Cardiac arrests
(Get with the Guidelines-Resuscitation Registry)
All IH-CA@
Periop CA*
• Initial rhythm
– Shockable
– Non-shockable
• Outcome
– Survival to Discharge
– Good neurologic outcome
• All patients
• In survivors
– Survival per initial rhythm
• Shockable
• Non-shockable
@Girotra
21%
79
24%
76
17
32
11
20
67
64
34
10
42
28.5
S, et al. NEJM 2012; 367: 1912-20
*Ramachandran SK, et al. Anesthesiology 2013; 119: 1322-39
Why better outcome following Perioperative cardiac arrest?
Hypotheses
• Shorter time to defibrillation, epinephrine and until invasive
airway placement
• Surgical causes for cardiac arrest are more likely to be
reversible including medication and airway causes
• Immediate availability of skilled physicians
The Authors’ Conclusions
Impact of baseline neurologic status on outcome
% Surv
39.6%
22.6
19.6
6
• Last year I posited that
“Intriguingly, it may be that simply preventing
hyperthermia may be as effective as inducing mild
hypothermia following resuscitation from cardiac
arrest.”
• A recent large RCT has been published that
seems to support this hypothesis.
Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206
Prospective RCT 939 unconscious patients following Out-of Hospital Cardiac Arrest
Note that this included nearly 3 times as many patients as the two prior RCTs of TH combined (350)
36 ICUs in Europe and Australia
Inclusion criteria
≥18 year old, Admitted to hospital
Unconscious (GCS < 8)
after Out-of-Hospital cardiac arrest
of presumed cardiac cause
with any rhythm (but 80% shockable, 12% asystole. 7% PEA
Randomized to temperature target of
-33o or
-36o
Primary outcome: All cause mortality to end of trial
Secondary outcomes:
Neurologic outcome (blinded assessors)
Cerebral Performance Category (CPC) at discharge from ICU, Hospital, and end of trial
Serious adverse events
Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206
• Temperature management
– Cooled to assigned temperature (33o or 36o C) as rapidly
as possible and maintained for 28 hrs
– Then rewarmed at 0.5o/ hour
– Then, if unconscious, kept below 37.5o for 72 hrs post
arrest.
– Sedated until end of intervention.
• Results:
– No difference in any outcome measures between the two
groups.
Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206
Note that by aiming for a temperature of 36o,
temperature was kept below 37.2o in 97.5% of the patients in that group
Nielsen N, et al. NEJM 2013; 369 (23): 2197-2206
Nielsen N, et al.
NEJM 2013; 369 (23):
2197-2206
No difference
in incidence of
Serious Adverse Events
Nielsen N, et al.
NEJM 2013; 369 (23):
2197-2206
Pre-hospital Cooling
Kim F, et al. JAMA 2014; 311(1): 45-52
Note profound effect of rhythm on mortality and neurologic recovery
~65%
~ 20%
Pre hospital cooling (by IV infusion of cold saline) was associated with
more pulmonary edema and lower PaO2 early.
Accompanying Editorial
Granger CB and Becker LB, JAMA 2014; 311(1): 31-32
TH following IH-CA
Even if we don’t know for sure that it will help…
What’s the harm in trying?
• Potential complications of TH
Infection, pneumonia, sepsis, hemodynamic instability,
arrhythmias, hyperglycemia, coagulopathy, bleeding,
electrolyte abnormalities, polyuria, seizures, altered drug
metabolism
• Complicates other care (e.g., angiography, interventional
cardiology )
• Expensive, labor intensive
• Diverts resources (staff, ICU beds, money)
• False sense of hope for family
• Conversely, failure to use may suggest to the family that the
hospital/physicians are not providing optimal care (they have
heard about TH in lay press)
• Inhibits the ability to conduct badly needed RCTs.
Complications of TH
• Recent Reviews:
– Soleimanpour H et al. Review. J CV Thor Res 2013; 6(1): 1-8
– Noyes AM and Lundbye JB. J Intens Care Med 2014, epub ahead of print.
• In Nielsen, et al’s recent RCT comparing 33o with 36oC, found no
significant differences in complication rate.
• One potentially troublesome problem…
Joffe J, et al. Resuscitation 2014, epub ahead of print
Compared stent thrombosis (ST) rate after PCI for AMI
155 without Cardiac Arrest
ST
2.0%
55 with CA (all received TH at 33oC for 24 hours
10.9
Not known if true and if so if related to CA per se or TH, or both
TH could have contributed
Did not receive oral DAT drugs pre procedure
Hypothermia may activate platelets
Hypothermia may inhibit effect of Clopidogrel
Hypothermia may alter pharmacokinetics and dynamics of drugs
Stent thrombosis following PCI post TH
• Penela, D. JACC 2013; 61: 2013
– 31% in TH group (5/11) vs. 0.7 in others
• Ibrahim, K. Eur Heart J 2011, 32: (suppl): 253
– 14.8% in TH (4/27)
• Rosillo SO, et al. JACC 2014; 63(9): 939-49
– 2..3% in TH (2/77)
Furthermore, even if we opt to employ it,
We really don’t know how implement it optimally!
•
•
•
•
•
•
•
•
•
•
•
•
•
Time window of therapeutic effectiveness
Optimal method of inducing and maintaining cooling
Optimal temperature
Optimal duration
How to rewarm
Where/ how to measure temperature
Proper sedation and muscle relaxation
Need for EEG monitoring
Seizure detection and management
Management of shivering, hypotension, hypertension
Neurologic assessment
How to assess neurologic prognosis
Criteria for and when to withdraw
Other’s Assessment
Morrison LJ, et al. Circ 2013; 127: 1538-62
(i.e Kim et al’s pre hospital cooling trial, and
Nielsen etal’s 36o vs 33o C TTM trial)
• Thus I believe there is an increase skepticism being raised
about the benefit of therapeutic hypothermia post cardiac
arrest, if not questions about how it should be applied and to
whom.
Despite what I and some others consider to be limited evidence
supporting the use of Therapeutic Hypothermia post Cardiac Arrest
there are still many (perhaps a majority) who are strong advocates
•
•
•
•
•
•
•
•
Nolan JP. Clin Med 2011, BMJ 2011
Kern KB. JACC Caridvasc Interv 2012
Boutsikaris D Emerg Med Clin NA 2012
Delhaye C etal. JACC 2012
Varon J, et al. Am J Emerg Med 2012
Scirica BM Circulation 2013
Da Silva and Frontera. Cardiol Clinic 2013; 31: 637-55
Perman SM, et al. Chest 2014; 145(2): 386-93
Intra-Arrest Hypothermia
• CBS Sunday Morning, yesterday, April 27, 2014
– “Brought back from the dead” segment
Sam Parnia, MD, PhD. Director of CPR research at Stony Brook
School of Medicine; Director of AWARE
“Today, cooling devices do much the same thing as that icy
stream: it chills people whose hearts have stopped and
preserves their brains until doctors can figure out how to get their
hearts going again.
“Cooling buys us time. So, for example, if somebody were to
suddenly collapse and die at home, what we could do is go into the
freezer and take out our frozen peas, frozen vegetables, put them on
the body, and try to do CPR at the same time, so we can slow down
the rate by which they're getting brain damage.“ !!!
I could find no reference to any published work on Intra-arrest
Hypothermia in PubMed by Dr. Parnia although he has published a book
for the general public on this topic (“Erasing Death”, Harper, 2013)
Scolletta S, et al. Critical Care 2012: 16: R41
Our pediatric colleagues are attempting to answer some of the
questions regarding the efficacy of TH post CA with RCTs
Ongoing Pediatric RCTs
(Children <18 years old)
• THAPCA Trials
– Comparison groups
• Hypothermia (32-34oC) for 48hrs followed by 3 days of “normothermia” (3637.5oC) versus
• 5 days of “normothermia”
– Primary outcome: Neurological outcome at 12 months
– Two studies
• NCT 0080087 (n = 350): In-hospital CA
• NCT 00878644 (n = 500): Out-of-hospital CA
• Two pilot studies
– NCT 00754481 (Phase II, n = 40)
• 48 hours of hypothermia versus 48 hours normothermia
• Primary outcome: Neurological outcome at 12 months
– NCT 00797680 (Phase II, N = 40)
• 72 hours of hypothermia versus 24 hours of hypothermia
• Outcome: Brain injury per plasma biomarkers and MRI
Selection of candidates for TH
Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
Used the GWTG-R Registry
2007-2009
51,240 IHCA in 366 hospitals
Determined which pre-arrest characteristics
predicted good neurologic outcome (CPC 1) at discharge
Then tested in a validation group
Designed to help patients/families make an informed DNR decision
(? Could it also be used to help inform the decision as to
who to utilize aggressive post arrest therapies)
Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
27%
1.4%
Ebell MH, et al. JAMA Intern Med 2013; 173: 1-7
Summary
• The use of TH is based upon the presumed pathophysiology of neurologic
injury (e.g., coma) post cardiac arrest, and animal data suggesting that this
can be ameliorated by hypothermia and two RCTs reported in 2002
• This has led to it to be recommended by many organizations including the
AHA
• Last year at this meeting I indicated that the evidence supporting its use post
OOH CA associated with shockable rhythm's thought to be due to cardiac
disease was weak..
• And that the evidence supporting its use following cardiac arrest associated
with non-shockable rhythms, and following in-hospital cardiac arrest was even
weaker.
• The later may be due to the possibility that these patients have sustained
more severe neurologic injury which is not amenable benefit from TH as
currently practice.
Summary, continued
• As I have just reviewed
– In the past year no new evidence has appeared supporting
the use of TH for any indication
– If anything, new studies have reinforced the skepticism I
expressed last year, and others are voicing similar
concerns.
Summary (continued)
•
Based upon data I presented last year and new information which has become
available during this past year, and until more definitive information becomes
available, I recommend:
– TH following out-of-hospital cardiac arrest TH should be limited to patients
meeting the strict criteria of the original RCTs (witnessed, presenting with
shockable rhythms, and thought to be of cardiac origin)
– TH following in-hospital cardiac arrest TH should be limited to patients with
the best likelihood of benefit (witnessed, shockable rhythms*, due to a
reversible cause, who are without severe pre-existing disease or impaired
neurologic status. (Consider using the GO-FAR score)
*Non-shockable rhythms could be considered if arrest occurred
peri-operatively
– And finally, Instead of cooling to 32-34o, we should instead simply strictly keep
body temperature no higher than 37.0o for the 30 hours after decision to
treat and below 37.5o until 72 or more hours post arrest.
Questions and Comments?

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