Subject: RFA HL-90-l2-H.081090
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 09 Aug 90 09:07 EST

Hello,
  This is the second of four items coming to you this morning.
Please post this to the NIH listserver as:
      RFAHL-90-12-H.081090.
  Thanks.
          Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUESTS FOR APPLICATIONS: RFA
 
RFA:  HL-90-12-H
 
MECHANISMS OF DAMAGE CAUSED BY CARDIOPULMONARY BYPASS
 
P.T. 34; K.W. 0715040, 1002004, 0765035
 
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
 
Letter of Intent Receipt Date:  October 15, 1990
Application Receipt Date: December 3, 1990
 
INTRODUCTION
 
The National Heart, Lung, and Blood Institute (NHLBI) invites
applications for grants to support basic research, studies
with animal models, and clinical investigation targeted
toward:  1) obtaining a better understanding of the
mechanisms of multisystem damage seen with cardiopulmonary
bypass and by the often associated technique of profoundly
hypothermic total circulatory arrest, and into the
particular susceptibility to this damage of the very young
and the elderly; and 2) developing methods of preventing or
attenuating this damage.
 
Cardiopulmonary bypass is required for cardiac surgery,
extracorporeal membrane oxygenation, and percutaneously
established circulatory support, resulting in over 375,000
uses annually in the United States alone.  It results in
considerable pulmonary, cardiac, neurologic, and renal
dysfunction, generalized edema, and diffuse bleeding, which
cause important morbidity and mortality, especially in the
very young, the elderly, and the very ill.  Both neonates
and patients over 70 years of age routinely require 48 hours,
and occasionally 3 to 6 weeks, of tracheal intubation after
open heart surgery because of pulmonary dysfunction.
 
The age distribution of patients receiving cardiopulmonary
bypass has changed markedly in recent years.  Ten years ago
1% of cardiopulmonary bypass patients were 1 year old or
less; now this number is 10-20%.  Ten years ago the average
age of a patient having coronary artery bypass graft surgery
was 55-60; now it is close to 70.  With this shift in the
proportion of very young (<1 year) and of elderly (>70
years) patients receiving cardiopulmonary bypass, certain
problems have become more prominent.  Whereas diffuse
bleeding is seen in about 2% of patients overall, it is
about twice as frequent in the very young.  Neurologic
dysfunction after cardiac surgery is seen in about 2% of
patients overall, but in the very young and the elderly the
incidence is about 10%.  Peritoneal or hemodialysis is
required in about 1% of patients overall; but in the very
young and the elderly it occurs in about 5-10%.  Overall
mortality is about 8%, but in the very young and the elderly
it approximates 15%.  Of these, 95% of the very young and
65% of the  elderly die from cardiac dysfunction.  Pulmonary
dysfunction after bypass is probably present in all patients
regardless of age.  These findings suggest a particular
susceptibility of the cardiac, pulmonary, and hemostatic
systems in the very young and of the central nervous system
and kidneys in both the very young and the elderly.
 
One of every 20 adults requires a cardiac support device
after cardiac surgery.  All patients have increased total
body and extracellular fluid as well as an easily
demonstrable hemorrhagic diathesis after cardiopulmonary
bypass, and these may be fatal, particularly in  infants,
the elderly, and the very ill.  This all results in
potentially preventable loss of life, prolonged intensive
care with its high  costs, prolonged hospitalization with
economic disadvantages, and delayed patient rehabilitation.
 
The complex defensive mechanisms of inflammation are
activated during the extracorporeal circulation of blood for
cardiopulmonary bypass, and have been shown to be highly
related to the resultant damage.  Periods of global cardiac,
and at times total systemic, ischemia are required for most
cardiac operations, and even with currently used protective
measures produce an additive inflammatory reaction.
 
BACKGROUND
 
Throughout evolution, circulating blood has traveled only in
endothelial lined channels.  With the advent of
cardiopulmonary bypass for cardiac surgery and other
purposes, circulating blood began to be passed through
foreign pathways.  Considerable evidence indicates that this
contact with artificial surfaces activates the multiple
cascades of inflammation, the complement pathway, and the
hemostatic mechanism.
 
When open heart operations were first performed in the mid-
1950's, patients developed unexplained bleeding, morbidity,
and mortality unlike anything which surgeons had previously
encountered.  The idea soon developed that the large surface
area of a nonbiologic oxygenator was primarily at fault, and
that poor-risk patients and very old patients were
particularly likely to have this kind of morbidity and
mortality. The duration of cardiopulmonary bypass was soon
recognized as an important contribution to bleeding,
morbidity, and mortality.  As operations became more complex
and very long-term cardiopulmonary bypass support began to
be used, thrombosis also became evident.
 
Cohnheim began to develop current concepts of inflammation a
hundred years ago.  As stated by Houck in 1979, "The subtle
kaleidoscopic cascades of interdigitated events which
constitute the reaction of tissues to injury over a variable
time scale is obviously mediated, modulated and
orchestrated by a wide variety of chemical messengers which
influence and determine vascular, extracellular and cellular
sequelae."  Cardiopulmonary bypass initiates the activation
and release of such messengers, resulting in a generalized
inflammatory response.  Injury   begins the moment blood
contacts foreign surfaces, and rapid activation of the
various pathways begins. Although these reactions are
discussed separately for purposes of clarity, the responses
are in fact highly interrelated and the entire process may
be initiated by the almost immediate activation of Factor
XII.
 
The humoral cascades of inflammation are now known to
involve at least the complement, kallikrein, coagulation,
and fibrinolytic cascades; the cellular components involve
at least leukocytes, platelets, and endothelial cells, with
amplification by the arachidonic acid pathway. In addition,
cardiopulmonary bypass is the most powerful known stimulator
of catecholamine response.  Cardiopulmonary bypass is
associated with massive activation of the complement
cascade, and this is reduced by hypothermia and
hemodilution.  Multiple interactions during and soon after
cardiopulmonary bypass have been demonstrated between
complement activation, neutrophil activation, pulmonary,
cardiac, and renal dysfunction, and survival.  The
kallikrein cascade is activated, with the finding of
elevated levels of bradykinin during and soon after
cardiopulmonary bypass.  However, the relation of this and
neutrophil activation to the demonstrated increase in
microvascular permeability produced by cardiopulmonary
bypass is uncertain.  Likewise, the relation of the
vasodilatory effect of bradykinin to the decreased systemic
vascular resistance that characterizes cardiopulmonary
bypass and the early period thereafter is not clear.
 
The coagulation cascade is strongly activated during
cardiopulmonary bypass, although gross clotting is prevented
by heparinization. Platelets are activated during
cardiopulmonary bypass, adhere to synthetic surfaces, lose
their ability to respond to soluble agonists, change shape,
release granular contents, form aggregates, and contribute
to thrombus formation.  Importantly, platelet receptors for
epinephrine and fibrinogen decrease during cardiopulmonary
bypass.  These and other platelet responses and interactions
result in an increased bleeding time and play a major role
in perioperative bleeding.  In addition, activation of the
fibrinolytic cascade during cardiopulmonary bypass may play
a role in perioperative bleeding.  Activation of the
arachidonic acid pathway has been demonstrated by the
finding of increased levels of the inactive degradation
product of the potent platelet aggregating agent thromboxane
A2 which is especially marked in infants and results at
least in part from the action of activated component C5a.
There is also a striking increase in levels of the powerful
inhibitor of platelet aggregation, prostacyclin
(prostaglandin I2;PGI2), during cardiopulmonary bypass.
 
The commonly observed pulmonary dysfunction may be related
to the complement-dependent activation of neutrophils and
monocytes during cardiopulmonary bypass, sequestration of
activated neutrophils in the lung, and oxygen-free radical
generation.  All patients develop at least mild, and some
severe, pulmonary edema after cardiopulmonary bypass.  The
relation between neutrophil activation, the complement and
kallikrein-induced increase in microvascular permeability,
and the whole body increase in water (edema) during and
after cardiopulmonary bypass remains uncertain.
Interleukin-1 production by monocytes is markedly enhanced
within a few hours of cardiopulmonary bypass, and the ratio
of OKT4+ to OKT8+ cells is altered, particularly in patients
who are very ill prior to surgery.  It is clear from this
brief review that many aspects of mechanisms of inflammation
are affected by cardiopulmonary bypass.
 
In addition, hypothermia and periods of total circulatory
arrest importantly affect these pathways.  Reduction and
reversal of body  temperature, by changing the solubility of
gases in blood, may stimulate the formation of microbubbles.
Air inadvertently entering the cardiopulmonary bypass
circuit is a potential cause of air embolism which may cause
clinically significant cerebral or coronary ischemia.  The
contribution of protamine sulfate administration (to
neutralize heparin) and of autologous blood cell salvage,
washing, and transfusion, to the damaging effects of
cardiopulmonary bypass have not been well defined.
Furthermore, certain organ systems have been shown to
manifest "selective vulnerability" to the damaging effects
of cardiopulmonary bypass, hypothermia, and total
circulatory arrest.  For example, the time interval between
onset of ischemia and necrosis is greater in skeletal than
in cardiac muscle and is greater in spinal cord than in
cortical neurons.  Some of these areas of selective
vulnerability show an age dependency.  When total
circulatory arrest results in neurologic damage, in adults
this is almost always manifested at least by intellectual
deficits, but in infants, by seizures and choreoathetotic
movements.  It has recently been shown that following total
circulatory arrest, levels of glutamate, an excitatory
neurotransmitter which can lead to metabolic requirements in
excess of substrate supply, increase in areas with a high
concentration of N-methyl-D-aspartate (NMDA) receptors.  A
transient increase in the expression of NMDA receptors in
certain of the basal ganglia has been observed in neonatal
and young subjects.
 
OBJECTIVES AND SCOPE
 
Applicants are encouraged to develop their own approaches
within their areas of expertise to investigating fundamental
mechanisms of the complex humoral, cellular, and other
responses to cardiopulmonary bypass; to developing methods
of preventing or minimizing these responses; or to exploring
and testing in vivo newly developed methods of management.
Cardiopulmonary bypass is a versatile experimental model for
studying fundamental mechanisms since its duration is
controllable and the magnitude of its effect can be varied
by its duration and other conditions.   Promising areas of
investigation include, but are not limited to:
 
o Investigation of the interactions of the various cascades
mentioned in producing the humoral, cellular, and
clinical results observed following bypass; investigation
of a possible single initiating event, for example,
activation of Factor XII
 
o Investigation of differences (compared with the adult age
group) in the function of cardiac, immunologic, hemostatic,
neurologic, renal, and other systems in the very young and
the elderly, which could explain the different
susceptibility of these groups to the problems they
experience following bypass
 
o Investigation of the primacy of neutrophil activation, or
its dependence on the humoral cascades or platelet
activation
 
o Investigation of the contribution of blood-foreign surface
interactions, heparin-protamine interactions, blood
component transfusions, profound hypothermia, and other
aspects of cardiopulmonary bypass to the results observed
 
o Modulation of the humoral and cellular effector systems of
the hemostatic, complement, or inflammatory pathways by
pharmacologic mediators capable of reversibly downregulating
these systems
 
o Reversible blockage of NMDA receptors in the basal ganglia
of neonates and infants prior to cardiopulmonary bypass, as
a means of protecting against important ischemic damage
during profoundly hypothermic cardiopulmonary bypass and
total circulatory arrest.
 
Applicants are encouraged to examine one or more components
or conditions used during cardiopulmonary bypass, and to
study the interactions of the activated pathways.  Studies
of the possible causes of the relation of the problems
observed to age, either in the very young or the elderly or
both, are encouraged.  Such studies could involve
biochemical, physiological, pathological, or other
observations in patients or experimental animals.
 
This RFA is designed to address the problems seen with
conventional cardiopulmonary bypass; however, applications
dealing with extracorporeal membrane oxygenation (ECMO) or
percutaneously established circulatory support will not be
excluded.  Clinical studies may be included if they form
logical extension of a basic investigation proposed.
 
In any studies involving human subjects, women and minority
individuals should be included in the study population;
otherwise a clear rationale for their exclusion must be
provided in the application.  Minority institutions are
encouraged to apply, and other institutions are encouraged
to established collaborative arrangements with minority
institutions.
 
EXCLUSIONS
 
No support will be provided under this Request for
Applications (RFA) mechanism for
large clinical trials.  Support for development of
techniques or devices alone will not be provided.  In
general, funds will not be provided for the purchase and
installation of expensive, new equipment.  Institute staff
should be consulted if an applicant has questions regarding
these limitations.
 
MECHANISM OF SUPPORT
 
The support mechanism for this program will be the
traditional, individual research grant.  Although
approximately $1.2 million for this program is included in
the financial plans for fiscal year 1991, award of grants
pursuant to this RFA is contingent upon receipt of funds for
this purpose. It is anticipated that four to six grants will
be awarded under this program.  The specific amount to be
funded, however, will depend on the merit and scope of the
applications received and the availability of funds.  Since
a variety of approaches would represent valid responses
to this announcement, it is anticipated that there will be a
range of costs among individual grants awarded.  While
multidisciplinary approaches are encouraged, it is not the
intent of this announcement to solicit applications for
large studies encompassing a variety of independent
projects, i.e., program projects.  If collaborative
arrangements involve sub-contracts with other institutions,
the NHLBI Grants Operations Branch should be consulted
regarding procedures to be followed (tel: 301-496-7255).
 
Upon initiation of the program, the Division of Heart and
Vascular Diseases and the Division of Blood Diseases and
Resources will jointly sponsor periodic meetings to
encourage exchange of information among investigators who
participate in this program.  In the budget for the grant
application, applicants should request ADDITIONAL TRAVEL
FUNDS for a one-day meeting each year, most likely to be
held in Bethesda, Maryland.  Applicants should also include
a statement in their applications indicating their
willingness to participate in these meetings.
 
Applicants, who will plan and execute their own research
programs, are requested to furnish their own estimates of
the time required to achieve the objectives of the proposed
research project.  Up to FIVE YEARS of support may be
requested.  At the end of the official award period, renewal
applications may be submitted for peer review and
competition for support through the regular grant program of
the National Institutes of Health (NIH).  It is anticipated
that support for the present program will begin on August 1,
1991.  Administrative adjustments in project period and/or
amount of support may be required at the time of the award.
 
All current policies and requirements that govern the
research grant programs of the NIH will apply to grants
awarded under this RFA.  Awards under this announcement to
foreign institutions will be  made only for research of very
unusual merit, need, and promise, and in accordance with
Public Health Service policy governing such awards.
 
REVIEW PROCEDURES AND CRITERIA
 
Review Method:  Upon receipt, applications will be reviewed
for their responsiveness to the objectives of this RFA.  If
an application is judged unresponsive, the applicant will be
contacted and given the opportunity to withdraw the
application, or have it considered for the regular NIH grant
program.
 
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but has not yet been reviewed,
the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this
RFA that is essentially identical to one that has already been
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
 
Those
applications which are judged to be responsive will be
reviewed for scientific and technical merit by an invited
review group convened by the Division of Extramural Affairs,
NHLBI, composed of mostly nonfederally employed reviewers
with expertise that will include cardiac surgery,
cardiology, pediatrics, immunology, hematology, rheology and
fluid mechanics, materials science, surface chemistry, and
biostatistics.  Applications will be reviewed in competition
with each other on a nation-wide basis.  This RFA
solicitation is a single competition and has one specific
deadline for receipt of applications.
 
Review Criteria:  The factors to be considered in the
evaluation of scientific merit of each application will be
similar to those used in the review of traditional research
project grant applications, including:
 
o  the novelty, originality, and feasibility of the approach,
and the adequacy of the experimental design
 
o  the competence of the principal investigator and
collaborator to accomplish the proposed research, and the
commitment and time they will devote to this project
 
o  the suitability of the facilities to perform the proposed
research, including laboratories, instrumentation, and
data management systems
 
o  of the appropriateness of the requested budget for the
work proposed.
 
METHOD OF APPLICATION
 
Letter of intent:  Prospective applicants are asked to
submit a letter of intent to apply to this RFA.  This letter
should include the names of any participating institutions
and all investigators, together with a descriptive title.
Such a letter of intent is not binding and it will not enter
into the review of any application subsequently submitted,
nor is it a necessary requirement for application.  Letters
of intent are requested solely for planning purposes.  The
NHLBI Staff will not provide responses to such letters.
Letters of intent to apply to this RFA should be received no
later than October 15, 1990, and should be addressed to:
 
Dr. Charles L. Turbyfill
Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
National Institutes of Health
Westwood Building, Room 553
Bethesda, MD  20892
 
Format for Applications:  Submit applications on form PHS-
398 (revised 10/88), the application form for the
traditional NIH research project grant.  Copies of this form
are available in the applicant institution's office of
sponsored research, or may be obtained from the following:
 
Office of Grants Inquiries
Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
Bethesda, MD  20892
 
Use the conventional format for research project grant
applications and ensure that the points identified in the
section above on "Review Procedures and Criteria" are
fulfilled.  To identify the application as a response to
this RFA, CHECK "YES" on item 2 of page 1 of the application
and enter the title "Mechanisms of Damage Caused by
Cardiopulmonary Bypass" and the RFA number HL-90-12-H in
the space provided.
 
THE RFA LABEL FOUND IN THE FORM PHS 398 APPLICATION KIT MUST
BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL
COMPLETED APPLICATION FORM PHS 348.  FAILURE TO USE THIS
LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION
SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR
REVIEW.
 
Application Procedure:  Send or deliver the completed,
signed application and four (4) completed photocopies of it
to the following, making sure that the original application
with the RFA label attached is on top:
 
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD  20892**
 
SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. CHARLES
TURBYFILL AT THE ADDRESS LISTED UNDER "LETTER OF INTENT".
IT IS IMPORTANT TO SEND TWO COPIES AT THE SAME TIME AS THE
ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF
RESEARCH GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT
THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS
RFA.
 
Applications must be received by December 3, 1990.  An
application not received by this date will be considered
ineligible.
 
Timetable:
 
Letter of Intent:                 October 15, 1990
Application Receipt Date:         December 3, 1990
Review by National Heart, Lung,
and Blood Advisory Council:       May 1991
Anticipated Award Date:           August 1, 1991
 
Inquiries regarding this announcement may be directed to the
following:
 
Paul Didisheim, MD               Diane Lucas, PhD
Devices and Technology Branch    Blood Diseases Branch
Division of Heart and Vascular   Division of Blood Diseases
Diseases, NHLBI                  and Resources, NHLBI
Federal Building, Room 312       Federal Building, Room 5A12
NIH                              NIH
Bethesda, MD  20892              Bethesda, MD  20892
Telephone:  (301) 496-1586       Telephone:  (301) 496-5911
Fax:   (301) 480-6282            Fax:   (301) 496-9940
 
This program is described in the Catalog of Federal
Domestic Assistance number 13.837, Heart and Vascular
Diseases.  Awards will be made under the authority of the
Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CFR
Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order
12372, or to Health Systems Agency Review.