HYPOVOLEMIC CIRCULATORY COLLAPSE: MECHANISMS AND OPPORTUNITIES TO IMPROVE
RESUSCITATION OUTCOMES
RELEASE DATE: February 24, 2003
RFA NUMBER: HL-03-015
National Heart Lung and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov)
United States Army Medical Research and Materiel Command (USAMRMC)
(https://mrmc-www.army.mil/)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.837, 93.838,
93.839, 12.420
LETTER OF INTENT RECEIPT DATE: April 23, 2003
APPLICATION RECEIPT DATE: May 23, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
This initiative is intended to identify novel methods to improve
resuscitation outcomes from severe blood loss and subsequent
hypovolemic circulatory collapse. Applications are sought that propose
innovative research approaches to identify the molecular, cellular, and
pathophysiologic response of the whole organism to hypovolemia and to
apply results of such approaches to the identification of potential,
new approaches to out-of-hospital resuscitation following severe
hypovolemia.
RESEARCH OBJECTIVES
Traumatic injury is the leading cause of death for individuals under
age 44 in the United States. Overall, trauma results in approximately
150,000 deaths per year, and severe hypovolemia due to hemorrhage is a
major factor in nearly half of those deaths. Rapid response and early
intervention are key to improving survival since approximately one
third of trauma deaths occur out-of-hospital and severe blood loss is a
major cause of deaths occurring within 4 hours of injury.
Current resuscitation strategies for hypovolemia due to severe blood
loss typically include the immediate restoration of blood pressure
through the use of intravenous fluids. However, results from recent
animal studies suggest that rapid, high volume replacement during
resuscitation often exacerbates bleeding and may result in increased
mortality compared to either low volume or delayed fluid replacement.
Clinical trial findings indicate that survival is not worsened, and may
be improved, by limiting the initial fluid resuscitation, either by
delaying the initiation or by titrating to a low systolic blood
pressure (70 mmHg), so called permissive hypotensive resuscitation
techniques. Another promising approach to fluid resuscitation appears
to be the use of hypertonic saline solutions that require lower volumes
of fluid and may have beneficial immuno-modulatory effects.
Beyond these relatively straightforward approaches, initial patient
management following severe blood loss is complicated by the fact that
a number of individuals with severe blood loss do not respond to fluid
restoration and/or the use of agents that increase vasomotor activity
and peripheral resistance. These individuals have transitioned from
reversible hypovolemia to hypovolemic circulatory collapse, and their
resuscitation outcomes are dismal.
Although the factors that contribute to the transition from reversible
hypovolemia to circulatory collapse are not known, they likely include
those associated with ischemia and reperfusion injuries. The response
to volume loss consists of biphasic opposing actions that include
activation of sympathetic and parasympathetic neural reflexes and
stimulation of inflammatory and anti-inflammatory cytokine pathways.
Thus there is release of epinephrine and norepinephrine as well as TNF-
alpha and interleukins. These substances, in turn, may induce vascular
decompensation, capillary leak, and organ dysfunction (for example,
induction of severe bradycardia unresponsive to pharmacological
intervention). These cascades of opposing events, and the balance
between them, most likely contribute to development of hypovolemic
circulatory collapse. The relative and direct contribution of
different pathways to the development of circulatory collapse is
unknown. Understanding mechanisms and developing approaches that
improve hypovolemic circulatory collapse resuscitation outcomes is the
primary goal of this initiative. Applications must clearly define the
relationship of the proposed studies to successful out-of-hospital
resuscitation.
Both the National Heart, Lung, and Blood Institute (NHLBI) and United
States Army Medical Research and Materiel Command (USAMRMC) have taken
leadership roles in promoting resuscitation research through the
organization of and continued involvement in the Post-Resuscitation and
Initial Utility in Life Saving Efforts (PULSE) workshop. This research
initiative is one expression of this ongoing partnership and represents
a needed step for improving both civilian and military resuscitation
outcomes.
An understanding is needed of the relative roles of perfusion pressure,
organs and organ systems (including the lung, heart, and vasculature),
as well as neurohumoral and other local and systemic responses to
sudden or severe blood loss that contribute to circulatory collapse and
poor resuscitation outcomes. Studies should focus on relating results
to the whole organism, and should be placed into the context of the
potential for improving resuscitation outcomes. Responsive applications
will include the use of appropriate mammalian models to characterize
the early response to severe blood volume loss and transition to
circulatory collapse. Clinical research of a mechanistic or
observational nature using human subjects may be involved, in
controlled conditions as during surgical procedures associated with
massive blood loss; interventional studies in humans will NOT be
considered responsive.
Research Areas
Examples of research that might address the response to exsanguination
and the failure of fluid replacement resuscitation following severe
hypovolemia and the transition to circulatory collapse are listed
below. This list is not exhaustive and investigators are encouraged to
develop additional approaches. They are encouraged to discuss these
with NHLBI and USAMRMC staff identified in the WHERE TO SEND INQUIRIES
section.
o Use of genomics and proteomics, as well as traditional research
approaches, to characterize the molecular and physiologic alterations
involved in the transition between reversible hypovolemia and
circulatory collapse.
o Identification of factors such as the extent and rate of volume loss,
nature of injury (i.e. blunt versus penetrating trauma), and
environmental determinants (e.g., ambient temperature, 'response'
times) that contribute to the transition between reversible hypovolemia
and circulatory collapse.
o The use of integrated systems biology, or other high-order systems
approaches, to elucidate the influence of individual organs or organ
systems in mediating microcirculatory dysfunction, capillary leak, and
circulatory collapse.
o Identification and evaluation in animal models of novel interventions
to delay or prevent the onset of hypovolemic circulatory collapse.
o The identification of markers for successful out-of-hospital
resuscitation in a setting of severe blood loss.
o Elucidation of autonomic factors contributing to the transition from
reversible hypovolemia to circulatory collapse.
MECHANISM OF SUPPORT
This RFA will use the NIH R01 award mechanism. As an applicant you
will be solely responsible for planning, directing, and executing the
proposed project. This RFA is a one-time solicitation. Future
unsolicited, competing-continuation applications based on this project
will compete with all investigator-initiated applications and will be
reviewed according to the customary peer review procedures. The
anticipated award date is April 1, 2004. Applications that are not
funded in the competition described in this RFA may be resubmitted as
NEW investigator-initiated applications using the standard receipt
dates for NEW applications described in the instructions to the PHS 398
application.
This RFA uses just-in-time concepts. It also uses the modular
budgeting format.
(see https://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in
each year of $250,000 or less, use the modular format. This program
does not require cost sharing as defined in the current NIH Grants
Policy Statement at
https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.
FUNDS AVAILABLE
The NHLBI and USAMRMC each intend to commit approximately $2 million in
FY 2004 to fund 10 to 12 new grants in response to this RFA. An
applicant may request a project period of up to 4 years and a budget
for direct costs of up to $250,000 per year. Because the nature and
scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award
will also vary. Although the financial plans of the NHLBI and USAMRMC
provide support for this program, awards pursuant to this RFA are
contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
Since the total costs for a subcontract or consortium are included in
the direct cost request, one additional module of $25,000 above the cap
may be requested for the facilities and administrative costs associated
with third party agreements. A module requested for this purpose must
be clearly identified in the budget justification section of the
application, and will be restricted for this purpose only at the time
of award.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
o Faith-based or community-based organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
For applications to be considered responsive to this RFA, the proposed
studies must address the transition between reversible hypovolemia and
circulatory collapse following severe blood loss. Studies
investigating the development of multi-organ failure or sepsis will not
be considered responsive and will be returned to the applicant without
further consideration.
Proposed studies may involve human subjects research of a mechanistic
nature and only in a controlled environment (i.e. identification of
biomarkers in surgery with severe blood loss). Clinical trials and
human interventional studies are beyond the scope of this initiative
and will be considered non-responsive. For those studies involving
observational studies with human subjects, a data and safety monitoring
plan is required. More information is available on the NHLBI web site
at http://www.nhlbi.nih.gov/funding/policies/index.htm under the
section entitled NHLBI Clinical Research.
In addition to annual progress reports, the Principal Investigators of
the grants funded under this RFA will be expected to attend and
participate in yearly grantee meetings to present the findings of the
research supported and to suggest future research directions. Funds
for travel to such meetings must be incorporated into the standard NIH
travel allowance for Principal Investigators. For planning purposes,
assume the meetings will be held in Bethesda, MD.
General Clinical Research Centers
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research Resources
may wish to identify the GCRC as a resource for conducting the proposed
research. If so, a letter of agreement from either the GCRC program
director or principal investigator should be included with the
application.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
three areas: scientific/research, peer review, and financial or grants
management issues:
o Direct your questions about scientific/research issues to:
David M. Balshaw, Ph.D.
Division of Heart and Vascular Diseases
National Heart Lung and Blood Institute
6701 Rockledge Dr., Room 9194 (MSC 7940)
Bethesda, MD 20892-7940 (20817 for Courier)
Telephone: (301) 435-0504
FAX: (301) 480-1454
Email: BalshawD@nhlbi.nih.gov
Andrea Harabin, Ph.D.
Division of Lung Diseases
National Heart Lung and Blood Institute
6701 Rockledge Dr., Room 10124 (MSC 7952)
Bethesda, MD 20892-7952 (20817 for Courier)
Telephone: (301) 435-0222
FAX: (301) 480-3557
Email: HarabinA@nhlbi.nih.gov
George Nemo, Ph.D.
Division of Blood Diseases and Resources
National Heart Lung and Blood Institute
6701 Rockledge Dr., Room 10142 (MSC 7950)
Bethesda, MD 20892-7950 (20817 for Courier)
Telephone: (301) 435-0075
FAX: (301) 480-0868
Email: NemoG@nhlbi.nih.gov
Col. Robert Vandre, DDS
Combat Casualty Care Research
United States Army Medical Research and Materiel Command
504 Scott St
Ft. Detrick, MD 21702-5012
Telephone: (301) 619-7919
FAX: (301) 619-7067
Email: Robert.Vandre@det.amedd.army.mil
o Direct your questions about peer review issues to:
Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone: (301)435-0270
FAX: (301)480-0730
Email: ClarkA@nhlbi.nih.gov
o Direct your questions about financial or grants management matters
to:
Robert Vinson
Grants Management Specialist
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive 7156, MSC 7926
Bethesda, MD 20892-7926 (20817 for express)
Telephone: (301) 435-0166
FAX: (301) 480-3310
Email: VinsonR@nhlbi.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to Dr. Anne
Clark at the address listed under WHERE TO SEND INQUIRIES.
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). The PHS 398 is
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications
must be submitted in a modular grant format. The modular grant format
simplifies the preparation of the budget in these applications by
limiting the level of budgetary detail. Applications requesting one
module ($25,000) above the cap due to subcontract or consortium
facilities and administrative costs associated with third party
agreements must also be submitted in modular format and may request up
to $275,000 per year in direct costs. Applicants request direct costs
in $25,000 modules. Section C of the research grant application
instructions for the PHS 398 (rev. 5/2001) at
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on modular grants is available at
https://grants.nih.gov/grants/funding/modular/modular.htm.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three signed,
photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application and
all five collated sets of appendix material must be sent to Dr. Anne
Clark at the address listed under WHERE TO SEND INQUIRIES.
Please note that applications delivered by individuals are no longer
accepted; all applications must either come via courier delivery or the
United States Postal Service
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).
APPLICATION PROCESSING: Applications must be received on or before the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and
funding assignment within 8 weeks.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. However, when a previously unfunded application,
originally submitted as an investigator-initiated application, is to be
submitted in response to an RFA, it is to be prepared as a NEW
application. That is the application for the RFA must not include an
Introduction describing the changes and improvements made, and the text
must not be marked to indicate the changes. While the investigator may
still benefit from the previous review, the RFA application is not to
state explicitly how.
Principal investigators should not send supplementary material without
first contacting the Scientific Review Administrator (SRA). The SRA
will be identified in the letter sent to you indicating that your
application has been received.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NHLBI and the USAMRMC.
Incomplete applications will be returned to the applicant without
further consideration. And, if the application is not responsive to
the RFA, CSR staff may contact the applicant to determine whether to
return the application to the applicant or submit it for review in
competition with unsolicited applications at the next appropriate NIH
review cycle.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NHLBI in accordance with the review
criteria stated below. As part of the initial merit review, all
applications will:
o Receive a written critique
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a second level review by the NHLBI National Advisory Council.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to discuss the
following aspects of your application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these
criteria in assigning your application's overall score, weighting them
as appropriate for each application. Your application does not need to
be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example,
you may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.
(1) SIGNIFICANCE: Does your study address an important problem? If the
aims of your application are achieved, how do they advance scientific
knowledge? What will be the effect of these studies on the concepts or
methods that drive this field?
(2) APPROACH: Are the conceptual framework, design, methods, and
analyses adequately developed, well integrated, and appropriate to the
aims of the project? Do you acknowledge potential problem areas and
consider alternative tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project
challenge existing paradigms or develop new methodologies or
technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to your
experience level as the principal investigator and to that of other
researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your work
will be done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the
following items will be considered in the determination of scientific
merit and the priority score:
o PROTECTIONS: The adequacy of the proposed protection for humans,
animals, or the environment, to the extent they may be adversely
affected by the project proposed in the application.
o INCLUSION: The adequacy of plans to include subjects from both
genders, all racial and ethnic groups (and subgroups), and children as
appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated. (See
Inclusion Criteria included in the section on Federal Citations, below)
o BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: April 23, 2003
Application Receipt Date: May 23, 2003
Peer Review Date: October, 2003
Council Review: February 12, 2004
Earliest Anticipated Start Date: April 1, 2004
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the
policy of the NIH that women and members of minority groups and their
sub-populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided
indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).
All investigators proposing clinical research should read the AMENDMENT
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_
2001.htm. The amended policy incorporates: the use of an NIH definition
of clinical research; updated racial and ethnic categories in
compliance with the new OMB standards; clarification of language
governing NIH-defined Phase III clinical trials consistent with the new
PHS Form 398; and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or
proposals and/or protocols must provide a description of plans to
conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS: The NIH maintains a policy that children (i.e., individuals
under the age of 21) must be included in all human subjects research,
conducted or supported by the NIH, unless there are scientific and
ethical reasons not to include them. This policy applies to all initial
(Type 1) applications submitted for receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should
read the "NIH Policy and Guidelines" on the inclusion of children as
participants in research involving human subjects that is available at
https://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for
research involving human subjects. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June 5, 2000, at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation,
Internet addresses (URLs) should not be used to provide information
necessary to the review because reviewers are under no obligation to
view the Internet sites. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject
to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review. Awards are made under the
authorization of Sections 301 and 405 of the Public Health Service Act
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52
and 45 CFR Parts 74 and 92. Awards by the USAMRMC are made under the
authority of 10 USC 2358. All awards are subject to the terms and
conditions, cost principles, and other considerations described in the
NIH Grants Policy Statement. The NIH Grants Policy Statement can be
found at https://grants.nih.gov/grants/policy/policy.htm.
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.