RFP No. NIH-NHLBI-HR-01-01

"Clinical Centers for the Clinical Network for the Treatment of the Adult Respiratory Distress Syndrome (ARDS)"

Request for Proposal No.: NIH-NHLBI-HR-01-01
Issue Date: March 16, 2000
Issued By: Pamela S. Lew, Contracting Officer
NIH, National Heart, Lung, and Blood Institute
HLVD Contracts Section, Contracts Operations Branch
6701 Rockledge Drive, Room 6104
Bethesda, Maryland 20892-7902
Purchase Authority: Public Law 95-83, as amended
Small Business Set-Aside: No; SIC Code: 8731
Just in Time: Yes
Proposal Intent Due Date: April 21, 2000
Proposal Due Date: May 12, 2000, 4:30 PM (EST)


Ladies and Gentlemen:

The National Heart, Lung, and Blood Institute (NHLBI) is soliciting proposals for clinical centers to participate in the "Clinical Centers for the Clinical Network for the Treatment of the Adult Respiratory Distress Syndrome (ARDS)". The objective of ARDSnet is to test novel therapies for the prevention and treatment of adult respiratory distress syndrome and acute lung injury (ARDS/ALI). The ARDSnet has developed a protocol to test the role of the pulmonary artery catheter (PAC) in the clinical management of ARDS/ALI. The ARDSnet investigators and NHLBI staff have determined that enrollment in this protocol will be challenging and that additional sites are required to complete this protocol in a reasonable time frame. It is anticipated that this solicitation will award up to ten (10) additional Critical Care Treatment Groups (CCTG) to participate in the PAC protocol. Each new CCTG will enroll approximately 30 patients/year during Phase II (24 months).

This Streamlined Technical Request for Proposal (RFP) consists of this combined solicitation form/cover letter and Section I, Technical Information which includes the following four components:

  1. Statement of Work ;
  2. Deliverables/Reporting Requirements ;
  3. Project Information/Background and History ; and
  4. Evaluation Factors for Award, including Technical Evaluation Criteria .

These four components contain the description of the technical information required for the submission of a proposal for this acquisition. In addition, there are two other sections applicable to this RFP. Section II entitled "Specific RFP Instructions and Provisions" contains the address for delivery of your proposal and Section III entitled "Applicable RFP References" lists those items in the Streamlined RFP References directory that apply to this RFP, including forms for submission of the proposal. The URL for this directory is: " http://www4.od.nih.gov/ocm/contracts/rfps/mainpage.htm." The documents listed above represent all of the necessary information required for submission of a proposal.

If you intend to submit a proposal in response to this RFP, it is essential that you immediately notify Pamela S. Lew, Contracting Officer, at the following internet address: lewp@nhlbi.nih.gov

If you do not notify the contracting office of your intent to submit a proposal, you will not receive an individual notice of any amendments to the RFP, if any are issued. However, all amendments will be posted on the NIH web site.

The original and fifteen (15) copies of your technical proposal and the original and four (4) copies of your business proposal must be received by the Contracting Office no later than May 12, 2000, at 4:30 p.m. local time at the address listed in the item entitled "Packaging and Delivery of Proposals". Offers will be valid for 120 days unless a different period is specified by the offeror on the form entitled, "Proposal Summary and Data Record, NIH-2043". Submission of proposals using facsimile or e-mail is not authorized. Finally, please complete the form entitled "Proposal Intent Response Sheet" and send it to the address indicated therein on or before April 21, 2000. This will allow us to expedite preparations for the peer review of proposals.

After reviewing this Request for Proposal, go to " Streamlined RFP References " and select (click on) each section you wish to review:

" Standard RFP Instructions and Provisions " for proposal preparation instructions and other standard provisions,

" Optional RFP Instructions and Provisions " for the special provisions identified in this specific RFP,

" RFP Forms, Formats, and Attachments " to download the forms listed in this specific RFP that you will need to submit a proposal, and

" Sample Contract Format-General " to view some of the clauses that are typical for inclusion in a Research and Development type contract issued by NIH.

If you have any questions regarding this RFP, please contact Pamela S. Lew at (301) 435-0340, facsimile (301) 480-3338. Collect calls will not be accepted.

Sincerely,

Pamela S. Lew

Pamela S. Lew
Contracting Officer


  1. TECHNICAL INFORMATION

    1. STATEMENT OF WORK

      ARTICLE C.l.--STATEMENT OF WORK (Refer to Project Information below for a complete description of Background and History.)

      Independently, and not as an agent of the Government, the contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the statement of work below. Specifically, the contractor shall:

      PHASE II--October 31, 2000 - October 30, 2002

      Train a staff to conduct the Pulmonary Artery Catheter (PAC) study as outlined in the protocol and manual of operations.

      Participate with other study investigators in a clinical study of the PAC in the treatment of Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) according to the protocol and manual of operations. The protocol, manual of operations and any amendments thereto are incorporated herein, by reference, as part of the contract.

      Enroll and treat a minimum of 30 patients, 13 years of age or older, with ARDS or ALI according to the PAC protocol. The patients will have a gender and racial composition similar to the population of patients that are available for study.

      Perform follow-up assessment on the subjects in the manner specified in the manual of operations.

      Collect the subject data as specified by the protocol and forward the data to the Clinical Coordinating Center (CCC) in accordance with procedures in the manual of operations.

      Participate in the Steering Committee to monitor progress on the study.

      Interact with the CCC to provide data and information necessary for data analysis work with other study investigators in the preparation and writing of reports and manuscripts for publication.

      Work with other study investigators in the preparation and writing of reports and manuscripts for publication.

      PHASE III--October 31, 2002 - October 30, 2003

      Interact with the CCC to provide data and information necessary for data analysis. Complete data analysis and publication preparation.

      Work with other study investigators in the preparation and writing of reports and manuscripts for publication.

    2. ARTICLE C.2.--REPORTING REQUIREMENTS

      In addition to those reports required by other terms of this contract, the Contractor shall prepare and submit the following reports in the manner stated below and in accordance with ARTICLE F.1. DELIVERIES of this contract:

      1. Subject Data: Data collected on study subjects shall be submitted to the CCC in accordance with the study protocol and the manual of operations. These data shall be submitted as long as the contractor is participating in the protocol.

      2. Annual Reports: A comprehensive annual report reflecting all activities conducted during the contract year shall be submitted on each anniversary date following contract award. This report shall be written in sufficient detail to allow use as a reference document. The annual reports shall include but not be limited to:

        1. A cover page containing the following information:
          1. Contract number
          2. Contractor's name and address
          3. Principal investigator
          4. Reporting period covered
        2. Description of overall progress.
        3. Current problems that may impede performance and proposed corrective action.
        4. Work to be performed during the next year.

        Each report shall be in a narrative form, concise and informational, and shall include a table of contents, bibliographies, tabular material and exhibits, as necessary. Extensive reference material is not desired, but such references as are necessary to full understanding may be included.

      3. Final Report: This report shall include a summation of the work performed and results obtained for the entire contract performance period. This report shall be in sufficient detail to describe comprehensively the results achieved. The final report shall be submitted on or before the last day of the contract performance period and shall be in the format detailed above under 'Annual Reports'.

      4. Progress Report for Clinical Research Study Populations: During Phase II, as part of data entry, the Contractor shall submit information about the inclusion of women and members of minority groups and their subpopulations. This information shall be submitted in the format indicated in the Attachment entitled "Annual Technical Progress Report Format for Each Study " which is set forth in Section J of this contract.

      5. Financial Reports: Quarterly financial reports that summarize the status of costs incurred under the contract.


        ARTICLE F.1.--DELIVERIES

        Satisfactory performance of this contract shall be deemed to occur upon delivery and acceptance by the Contracting Officer, or the duly authorized representative, of the following items in accordance with the stated delivery schedule.

        The items specified below as described in SECTION C, ARTICLE C.2 shall be delivered F.O.B. destination as set forth in FAR 52.247-35, F.O.B. DESTINATION WITHIN CONSIGNEE'S PREMISES (APRIL 84) and in accordance with and by the dates specified below, and any specifications stated in SECTION D, PACKAGING, MARKING, AND SHIPPING of this contract:

        Item Description Quantity Delivery Schedule
        (a) Subject Data 1 As specified by protocol and
        manual of operations
        (b) Annual Report 2 Annually
        (c) Final Report 3 Completion of contract
        (d) Progress Report for Clinical
        Research Study Populations
        1 Annually
        (e) Financial Report 3 Quarterly

        The above items shall be delivered to the following addressees:

        Addressee Deliverable Item Quantity
        (1) Contracting Officer
        HLVD Contracts Section, COB
        National Heart, Lung, and Blood Institute
        6701 ROCKLEDGE DRIVE, RM 6104
        BETHESDA, MD 20892-7902
        (b) - (d)
        (e)
        1
        3
        (2) Project Officer
        Lung Biology and Disease Program
        Division of Lung Diseases
        National Heart, Lung, and Blood Institute
        6701 ROCKLEDGE DRIVE
        BETHESDA, MD 20892-7952
        (b), (c)


        1


        (3) Clinical Coordinating Center
        Massachusetts General Hospital
        MGH Biostatistics Center
        50 STANIFORD STREET, SUITE 560
        BOSTON, MA 02114-2517
        (a), (d)
        1


    3. SECTION L--PROJECT INFORMATION

      1. Background and History

        ARDS affects approximately 150,000 people in the United States each year. Despite thirty (30) years of research into the mechanisms that cause this syndrome and numerous developments in the technology of mechanical ventilation, the mortality has remained near 40%. Many of the patients are young; and, in addition to the tragic loss of human life, the dollar costs to society are high because these patients spend an average of two weeks in intensive care units and require multiple highly technical procedures. There remain no effective therapies for this disease; care is supportive.

        The NHLBI ARDSnet was initiated on September 30, 1994 with the award of ten (10) CCTGs and a Clinical Coordinating Center. The overall objective of the program was to test novel therapies for the prevention and treatment of adult respiratory distress syndrome (ARDS). Phase I, Protocol Development, involved the planning and development of study protocols. This phase, which has been carried out by the existing ARDSnet clinics and the CCC, has resulted in the development and initiation of five (5) protocols, and development of the PAC protocol which has not been initiated. Phase II involves the screening and randomization of subjects into the various protocols. It is expected that the PAC protocol will be underway at the existing ARDSnet centers prior to award for these additional CCTGs. Phase III involves final data analysis and the preparation of reports and publications.

        The ARDSnet has completed three protocols: 1) Ketoconazole and Respiratory Management in Acute Lung Injury and Adult Respiratory Distress Syndrome (KARMA); 2) Prospective, Randomized Trial of 12ml/kg vs. 6ml/kg Tidal Volume Positive Pressure Ventilation (ARMA); and 3) Phase II/III, Randomized, Double-Blind, Placebo-Controlled Trial of Lysofylline in Patients with Acute Lung Injury and Adult Respiratory Distress Syndrome (LARMA). Two additional protocols are underway: 1) Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome (LASRS) and 2) Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI).

        In 1996, a report published by Connors, et. al., raised issues concerning the clinical effectiveness and safety of right heart catheterization in critically ill patients. This publication raised concerns about "implied harm" associated with PAC use. Implied harm is defined as morbidity and mortality with PAC use, but without a discernible cause and effect relationship to the insertion or pressure of the PAC. As a result of this paper, a conference was convened by NHBLI and the FDA to examine the implications of this work. The Pulmonary Artery Catheterization and Clinical Outcomes (PAACO) conference held in August of 1997 identified ARDS patients as a group in which it would be important to conduct prospective clinical studies of the effectiveness and safety of the PAC. Subsequently, the ARDSnet investigators developed the Prospective, Randomized, Multi-Center Trial of Pulmonary Artery Catheter vs. Central Venous Catheter for Management of Acute Lung Injury and Acute Respiratory Distress Syndrome (PAC) protocol. The additional CCTGs to be awarded under this solicitation are needed to assist with the PAC trial.

      2. Objectives/Description of Requirement/Desired Result

        The objective of this program is to award up to ten (10) additional Critical Care Treatment Groups (CCTG) to participate in an ongoing study being conducted by the NHLBI-sponsored ARDSnet. A protocol has been developed by the ARDSnet Steering Committee to test the efficacy of the pulmonary artery catheter (PAC) in the treatment of ARDS/ALI. Specifically, the ARDSnet will conduct a two-by-two factorial design study to test the effectiveness and safety of PAC. The expectation of this program is that use of the PAC vs. CVC in conjunction with two fluid management strategies (conservative vs. liberal) will improve mortality in patients with ARDS/ALI. The primary endpoint will be mortality at 28 days, with secondary endpoints being duration of assisted ventilation and organ failure. Use of the PAC will also be tested for efficacy and safety.

      3. Study Design

        The protocol consists of 1,000 patients randomly enrolled in a two-by-two factorial design that will test the role of the PAC vs. CVC (central venous catheter) in two fluid management strategies (one "lung protective", one "kidney protective" or conservative vs liberal). The full study protocol is available below.

      4. Phasing

        Phase I, which has been completed, consisted of planning and development of study protocols.

        Phase II--New CCTGs will enter the ARDSnet in Phase II. The PAC study will be underway at the existing ARDSnet CCTGs when the new CCTGs are selected. After selection and award of contracts, there will be training of new CCTG staff in the protocol and data acquisition techniques. Patients will be enrolled into the study and data will be forwarded to the Clinical Coordinating Center (CCC). After completion of protocol activities, the CCTGs will review their data and assist the CCC in closeout of the study. The CCC will support manuscript preparation through data analysis, statistical consultation, editorial tasks, and coordination of meetings. The main results paper for the study will be collaboratively prepared by the investigators and submitted for publication.

        Phase III--Final data analysis and publication preparation will be completed.

      5. Offerors must address in their proposals the following elements relevant to achieving the requirements of the program.

        Offerors shall include in their proposal evidence of 1) the investigators' experience and expertise in treating ARDS, 2) access to and availability of an adequate patient population, 3) experience in multi-center clinical trials and distributed data entry systems, and 4) evidence of IRB approval of the PAC protocol. Specifically:

        • Discuss the principal investigator's clinical expertise in treating ARDS and ALI, and discuss the qualifications and experience of the proposed investigators in clinical research, especially participation in multi-center trials, as evidenced by external support and publications. The offeror must demonstrate an understanding of the scientific and methodological issues that are important in the design and conduct of studies in ARDS patients. Past performance in enrolling patients in multi-center trials will be an important guide in determining the potential of an offeror to successfully fulfill the requirements of this solicitation.

        • Demonstrate ability to enroll 30 patients per year with ARDS/ALI. This should include a discussion of the number of eligible patients screened per year, with an analysis of what fraction could potentially be enrolled in the PAC trial. Patients shall be categorized by gender and race, and patients at-risk shall be categorized according to risk factor. In addition, describe the number and diagnostic category of patients enrolled per year in previous studies. If the offeror has enrolled fewer than 30 patients a year in multi-center trials of ARDS/ALI, a description of how the offeror plans to meet the enrollment goals shall be included in the proposal. Access to patients may include arrangements with physicians outside of the offeror's institution.

        • A description of the patient population, including the number of women, minorities and children (13 years of age or older). A discussion of other studies that would run concurrently with the PAC study and how they would impact patient recruitment. The offeror shall express a commitment to the recruitment goals of the ARDSnet, including the goal of including women and minorities. Provide evidence of physician support where subjects to be recruited are not directly under the care of the PI. Acceptable evidence of such support would be letters from the physicians.

        • Describe the means of communication among various members of the CCTG, including the means of assuring quality control of patient care, plans for day-to-day coordination. Because the PI will be responsible for the entire CCTG, including participating physicians who do not practice at the PI's institution, limiting the CCTG to a greater metropolitan geographic region is encouraged. In no case may an institution participate in more than one CCTG within the ARDSnet.

        • Data collection will require the use of a dedicated computer that can connect to the ARDSnet data network over the Internet using software provided by the ARDSnet Coordinating Center. The connection with the Internet can be continuous (a desktop computer connected to the Internet through a hospital network) or intermittent (connected through an Internet Service Provider). In systems with a firewall this will require that a specified port be open for two-way communication. Describe the system support that is available to establish this type of connection.

        • Offerors shall provide no later than July 3, 2000 documentation from their Institutional Review Board (IRB) that the PAC protocol has been received for review, and by October 31, 2000 documentation of Institutional Review Board (IRB) approval of the PAC protocol. Offerors that do not provide documentation of IRB approval to Pamela S. Lew, Contracting Officer by October 31, 2000 will not be considered for award.

        • Discuss the laboratory/clinical facilities available at each participating institution that will be used to accomplish the statement of work.

        • Offerors 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. In this case, a letter of agreement from either the GCRC Program Director or Principal Investigator shall be included with the proposal.

        • Offerors shall document their willingness, and that of any participating institution, to accept capitation (a fee paid for each patient successfully enrolled and treated).

        • Offerors shall provide a Small Disadvantaged Business (SDB) Participation Program Plan, as part of their business proposal, including the following information:

        A statement, with Standard Industrial Codes (SIC) listed, on the extent of participation of small disadvantaged business concerns in performance of the contract. Participation in performance of the contract includes work expected to be performed by SDB concern(s). This can include small disadvantaged businesses (as prime contractor), joint ventures, teaming arrangements, and subcontracts.

        Include the following information in the SDB participation statement:

        1. Targets, expressed as dollars and as a percentage of total contract value, in each of the applicable, authorized SIC Major Groups.

        2. Total target for SDB participation by the contractor, including joint venture partners and team members.

        3. Total target for SDB participation by subcontractors.

        Each offeror will be evaluated on its demonstrated commitment to use small disadvantaged businesses for the work that it intends to perform as the prime contractor (see Section M). In accordance with FAR 15.304(c)4, the extent of participation of SDB concerns in performance of the contract shall be evaluated in unrestricted acquisitions expected to exceed a total estimated cost of $500,000 subject to certain limitations (see FAR 19.201 and 19.1202). If a SDB concern waives the price evaluation adjustment (PEA) at Subpart 19.11, participation in performance of that contract includes the work expected to be performed by the SDB concern at the prime contract level.

      6. Committees

        The Steering Committee will provide scientific direction to the study at the operational level. The Principal Investigators of the new CCTGs selected as a result of this solicitation will have a vote on issues pertaining to the PAC study.

        A Protocol Review Committee (PRC) has been established to review, prior to initiation, all study protocols for feasibility, efficacy and safety. The PRC reviews protocol amendments as needed.

        A Data and Safety Monitoring Board (DSMB) has been established to monitor study progress, data outcomes and patient safety. The Board periodically reviews study results and evaluates study procedures for beneficial and adverse events and advises the NHLBI when changes should be made. The Board meets twice per year and conducts teleconferences as needed. During the study the DSMB will review study papers prior to publication.

        A Publications Committee has been established to review proposed publications, including those related to issues of patient confidentiality, proprietary information and the final study results. The membership of the committee includes representatives from each CCTG, the CCC and the NHLBI.


    4. SECTION M--EVALUATION FACTORS FOR AWARD WITH TECHNICAL EVALUATION CRITERIA

      1. GENERAL

        The technical evaluation criteria below and all other evaluation factors other than cost or price, when combined are significantly more important than cost or price. The evaluation will be based on the demonstrated capabilities of the offerors in relation to the needs of the project as set forth in the solicitation.

        This research project involves human subjects. NIH policy requires that women, members of minority groups and their sub-populations, and children must be included in the study population of research involving human subjects, unless a clear and compelling rationale and justification is provided with respect to the health of the subjects or the purpose of the research.

        Where inclusion of women, minority populations, and children is not feasible, a detailed rationale and justification for exclusion from the study population must be submitted with the technical proposal. The NHLBI will review the rationale to determine if it is appropriate with respect to the health of the subjects and/or the purpose of the research. If the rationale is not considered acceptable by the Government and you are included in the competitive range, you will be afforded the opportunity to further discuss and/or clarify your position during discussions or include women, minorities, and children in your Final Proposal Revision (FPR). If your exclusion position is still considered unacceptable by the Government after discussions, your proposal may not be considered further for award.

        Awards under this solicitation will be made only to offerors located in the continental United States of America and Canada. Proposals from offerors outside the continental United States of America and Canada will not be considered for award.

        The trade-off process described in FAR 15.101-1 will be employed which will allow the Government to consider award to other than the lowest price offeror or other than the highest technically rated offeror. The Government reserves the right to make an award to the source whose proposal offers the best value to the Government.

      2. MANDATORY QUALIFICATION CRITERIA

        Offerors shall provide no later than July 3, 2000 documentation from their Institutional Review Board (IRB) that the PAC protocol has been received for review, and by October 31, 2000 documentation of Institutional Review Board (IRB) approval of the PAC protocol. Offerors that do not provide documentation of IRB approval to Pamela S. Lew, Contracting Officer by October 31, 2000 will not be considered for award.

      3. TECHNICAL EVALUATION CRITERIA

        Proposals submitted in response to this solicitation will be reviewed by a peer group of scientists under the auspices of the Review Branch, Division of Extramural Affairs, NHLBI, and subsequently by a review group within NHLBI. The evaluation criteria are used by the technical evaluation committee when reviewing the technical proposals. The criteria below are listed in the order of relative importance with weights assigned for evaluation purposes.

        Weight Criterion
        40% Ability to enroll 30 patients with ARDS/ALI per year. Offerors shall describe their previous experience enrolling patients with ARDS or patients at risk of developing ARDS into multi-center treatment trials. If previous enrollment has been less than 30 patients a year, practical procedures must be proposed to identify and screen adequate numbers of prospective subjects.
        30% Adequacy of experience and competence of the professional and technical staff pertinent to the study, including experience in clinical studies of ARDS. In particular, the PI is expected to be expert in the treatment of critically ill patients with ARDS and also to have previously participated in multi-center treatment trials.
        30% Adequacy of laboratory/clinical facilities available, including all participating institutions. Description of the facilities and means of assuring quality control of patient care. Adequacy of plans for study coordination, including quality control of data entry.

      4. PAST PERFORMANCE EVALUATION

        The offeror's past performance will be evaluated after determination of the competitive range. Only those offerors included in the competitive range will be evaluated. The evaluation will be based on information obtained from references provided by the offeror, other relevant past performance information obtained from other sources known to the Government, and any information supplied by the offeror concerning problems encountered on the identified contracts and corrective action taken. Past performance will be considered when determining contractor responsibility using the information required by the "Qualifications of the Offeror" portion of the " Optional RFP Instructions and Provisions " of the RFP References Directory.

        Evaluation of past performance will be a subjective assessment based on a consideration of all relevant facts and circumstances. It will not be based on absolute standards of acceptable performance. The Government is seeking to determine whether the offeror has consistently demonstrated a commitment to customer satisfaction and timely delivery of services at fair and reasonable prices.

        The assessment of the offeror's past performance will be used as a means of evaluating the relative capability of the offeror and other competitors. Thus, an offeror with an exceptional record of past performance may receive a more favorable evaluation than another whose record is acceptable, even though both may have acceptable technical proposals.

        Past performance will not be scored, but the Government's conclusions about overall quality of the offeror's past performance will be highly influential in determining the relative merits of the offeror's proposal and in selecting the offeror whose proposal is considered most advantageous to the Government.

        By past performance, the Government means the offeror's record of conforming to specifications and to standards of good workmanship; the offeror's record of forecasting and controlling costs; the offeror's adherence to contract schedules, including the administrative aspects of performance; the offeror's reputation for reasonable and cooperative behavior and commitment to customer satisfaction; and generally, the offeror's business-like concern for the interest of the customer.

        The Government will consider the currency, relevance and source of the information, context of the data, and general trends in the offeror's performance. The lack of a relevant performance record may result in an unknown performance risk assessment, which will neither be used to the advantage or disadvantage of the offeror.

      5. SMALL DISADVANTAGED BUSINESS PARTICIPATION PROGRAM EVALUATION

        Evaluation of Small Disadvantaged Business (SDB) Participation Plans will be a subjective assessment based on a consideration of all relevant facts and circumstances. It will not be based on absolute standards of acceptable performance. The Government is seeking to determine whether the offeror has demonstrated a commitment to use SDB concerns for the work that it intends to perform as the prime contractor.

        The assessment of SDB Participation Plans will be used as a means of evaluating the relative capability and commitment of the offeror and that of other offerors. Thus, an offeror with higher targets (expressed as dollars or percentages and total target for SDB participation) may receive a more favorable evaluation than another whose targets may be lower, even though both may have acceptable technical proposals.

        SDB participation will not be scored, but the Government's conclusions about overall commitment and realism of the offeror's SDB Participation Plan will be highly influential in determining the relative merits of the offeror's proposal and in selecting the offeror whose proposal is considered most advantageous to the Government.


    1. SPECIFIC RFP INSTRUCTIONS AND PROVISIONS

      Notice to Offerors: This section contains proposal instructions and information which are specifically related to this acquisition. It should be noted that proposals must be in full text. References to URLs will not be accepted. The information provided below is only a portion of the instructions and notices required for the submission of a proposal. References to additional, more general, information and forms regarding proposal preparation are contained under Section III. Applicable RFP References.

      The following specific RFP instructions and provisions apply to this Request For Proposal:

      1. Proposal Intent Response Sheet (Please submit on or before April 21, 2000)
      2. Packaging and Delivery of Proposal
      3. Government Notice for Handling of Proposals
      4. Privacy Act System of Records
      5. SIC Code and Small Business Size Standard
      6. Notice of Price Evaluation Adjustment for Small Disadvantaged Business Concerns
      7. Number and Type of Awards
      8. Estimate of Effort
      9. Travel Requirements for Proposal Preparation Purposes
      10. Service of Protest
      11. Safety and Health
      12. Special Requirements
      13. Other Considerations
      14. Technical Proposal Table of Contents

    1. PROPOSAL INTENT RESPONSE SHEET

      RFP No.: NHLBI-HR-01-01

      TITLE OF RFP: Clinical Centers for the Clinical Network for the Treatment of the Adult Respiratory Distress Syndrome (ARDS)

      Furnish the information requested below and return this page by April 21, 2000. Your expression of intent is not binding but will assist us in planning for proposal evaluation.

      *Please include in your response a listing of all intended collaborators (Investigators) to your proposal by name and institution or organization.


      I INTEND TO SUBMIT A PROPOSAL

      INSTITUTION/ORGANIZATION NAME:

      ADDRESS:

      PROJECT DIRECTOR'S NAME:

      TITLE:

      TELEPHONE & FAX NUMBER:

      E-MAIL ADDRESS:

      * NAMES OF COLLABORATING INSTITUTIONS AND INVESTIGATORS
      (include Subcontractors and Consultants):





      RETURN TO:

      Review Branch
      NIH, NHLBI
      6701 Rockledge Drive MSC 7924
      Bethesda MD 20892-7924
      Attention: Dr. James Scheirer

      or FAX TO: Dr. James Scheirer at
      (301) 480-3541


    1. PACKAGING AND DELIVERY OF THE PROPOSAL

      Your proposal shall be organized as specified in the " Standard RFP Instructions and Provisions ." Shipment and marking shall be as follows:

      EXTERNAL PACKAGE MARKING

      In addition to the address cited below, mark each package as follows:

      "RFP NO. NHLBI-HR-01-01  TO BE OPENED BY AUTHORIZED GOVERNMENT PERSONNEL ONLY"

      NUMBER OF COPIES

      TECHNICAL PROPOSAL: Original* and fifteen (15) copies
      BUSINESS PROPOSAL: Original* and four (4) copies

      DELIVER PROPOSAL TO

      If hand delivered or delivery service:

      Review Branch
      Division of Extramural Affairs
      National Heart, Lung, and Blood Institute
      Rockledge Building, Room 7091
      6701 ROCKLEDGE DRIVE MSC 7924
      BETHESDA, MD 20817-7924

      If using U.S. Postal Service:

      Review Branch, Division of Extramural Affairs
      National Institutes of Health
      National Heart, Lung, and Blood Institute
      6701 ROCKLEDGE DRIVE MSC 7924
      BETHESDA, MD 20892-7924

      * THE ORIGINAL PROPOSAL MUST BE READILY ACCESSIBLE FOR DATE STAMPING.


    1. GOVERNMENT NOTICE FOR HANDLING OF PROPOSALS

      An offeror shall place this notice on top of each copy of its technical proposal:

      "This proposal shall be used and disclosed for evaluation purposes only, and a copy of this Government notice shall be applied to any reproduction or abstract thereof. Any authorized restrictive notices which the submitted places on this proposal shall also be strictly complied with. Disclosure of this proposal outside the Government for evaluation purposes shall be made only to the extent authorized by, and in accordance with, the procedures in HHSAR paragraph 315.608-72."

      (For information regarding authorized restrictive notices, offerors should refer to the "Confidentiality of Proposals" section of the Standard RFP Instructions and Provisions .)


    1. PRIVACY ACT SYSTEM OF RECORDS

      This procurement action requires the contractor to do one or more of the following: design, develop, or operate a system of records on individuals to accomplish an agency function in accordance with the Privacy Act of 1974, Public Law 93-579, December 31, 1974 (5 USC 552a) and applicable agency regulations. Violation of the Act may involve the imposition of criminal penalties. The Privacy Act System of Records applicable to this project is Number 09-25-0200, Clinical, Epidemiology and Biometric Studies of the NIH. The notice was published in the Federal Register, Volume 62, number 66 on April 7, 1997 (http://www.access.gpo.gov/su_docs/aces/PrivacyAct.shtml).


    1. SIC CODE AND SMALL BUSINESS SIZE STANDARD

      NOTE: The following information is to be used by the offeror in preparing its Representations and Certifications, specifically in completing the provisions entitled, SMALL BUSINESS PROGRAM REPRESENTATIONS, FAR 52.219-1:

      The standard industrial classification (SIC) code for this acquisition is 8731, Commercial Physical Research. The small business size standard is 500 employees.

      THIS REQUIREMENT IS NOT SET-ASIDE FOR SMALL BUSINESS. However, the FAR requires in every solicitation (except for foreign acquisitions) the inclusion of the SIC code and corresponding size standard which best describes the nature of the requirement in the solicitation.


    1. NOTICE OF PRICE EVALUATION ADJUSTMENT FOR SMALL DISADVANTAGED BUSINESS CONCERNS

      In accordance with FAR Clause 52.219-23, Notice of Price Evaluation Adjustment for Small Disadvantaged Business Concerns, incorporated in Section I.3., offerors will be evaluated by adding a factor of 10 percent to the price of all offers, except offers from small disadvantaged business (SDB) concerns that have not waived the price evaluation adjustment. In addition, offerors that satisfy the exception requirements under subparagraph (b) of FAR Clause 52.219-23 will not have the price evaluation adjustment factor added to their offers.

      A SDB concern may elect to waive the price evaluation adjustment, in which case the factor will be added to its offer for evaluation purposes. (The agreements in paragraph (d) of FAR Clause 52.219-23 do not apply to offerors that waive the price evaluation adjustment.) If the SDB concern elects to waive the price evaluation adjustment, it will be evaluated under the Small Disadvantaged Business Participation Factor cited in Section M, and participation in performance of the resultant contract shall include the work expected to be performed by SDB 7concerns at the prime contract level. Small businesses, other than SDB concerns, will also be evaluated under the Small Disadvantaged Business Participation Factor cited in Section M. Any targets will be incorporated into and become part of the resulting contract.

      CREDIT UNDER THE SMALL DISADVANTAGED BUSINESS PARTICIPATION FACTOR IS NOT AVAILABLE TO SMALL DISADVANTAGED BUSINESS CONCERNS THAT RECEIVE A PRICE EVALUATION ADJUSTMENT.


    1. NUMBER AND TYPE OF AWARDS

      It is anticipated that ten (10) awards will be made from this solicitation and that award will be made on or before October 31, 2000. It is anticipated that the award from this solicitation will be a multiple-year cost reimbursement, completion type contract with a period of performance of 3 years (thirty-six months), and that incremental funding will be used.


    1. ESTIMATE OF EFFORT

      During the Phase II patient screening process (costs for which are included in the capitation rates) the Principal Investigator or Co-Principal Investigator will review the eligibility of the patient to participate in the study, obtain consent, and supervise the clinical response. Two nurse coordinators will attend a training and certification session at the CCC in Boston, MA. Nurse coordinators will be responsible for the actual screening and recruitment of patients, and for ensuring timely completion of study investigations and data forms. Patient data will be provided to the CCC either by mailing of data forms or by transmission using a microcomputer. Hardware and software needed for data transmission would be provided by the CCC. The PI or Co-PI will be responsible for providing coordination with physicians at other facilities who have agreed to provide patients. The secretary will provide support to the nurse coordinator and help in a variety of functions including typing, performing simple data entry into computer terminals, and liaison with the CCC.

      During Phase III minimal effort will be required for the transmission and interpretation of final data submitted to the CCC. The PIs will participate in producing study manuscripts and publications.

      The Government considers that the personnel and estimated levels of effort identified below will be required for successful completion of the study. Effort is shown as a percentage of FTE (full-time equivalent) labor. The levels of effort listed below are for information only and are not to be considered restrictive for proposal purposes. The levels were formulated by NHLBI staff experienced in the conduct of multi-center clinical trials, utilizing recent experience on other ARDSnet protocols and advice from the existing ARDSnet investigators. It should be noted that these estimates are based on the award to ten (10) CCTGs and assumes an equal distribution of patient randomizations.


      Labor Category
      Phase II
      Core
      Phase II
      Protocol

      Phase III

      Total
      Principal Investigator 5.00% 15.00% 5.00% 25.00%
      Co-Investigators 5.00% 10.00% 0.00% 15.00%
      Nurse Coordinator 50.00% 75.00% 5.00% 130.00%
      Total: 60.00% 100.00% 10.00% 170.00%

      Offerors shall assure that the Principal Investigator and all other personnel proposed will not be committed on Federal grants and contracts for more than a total of 100% of their time. If the situation arises where it is determined that a proposed employee is committed for more than 100% of his or her time, the Government will require action on the part of the offeror to correct the time commitment.


    1. TRAVEL REQUIREMENTS FOR PROPOSAL PREPARATION PURPOSES

      Plans should be made for the following travel.
      Phase II, Year 1: Training Session 1 meeting for 2 days
      2 Nurse Coordinators to Boston, MA
      Phase II, Years 1 and 2: Steering Committee Meetings 3 meetings for 2 days
      2 individuals to Bethesda, MD


    1. SERVICE OF PROTEST (AUG 1996) - FAR 52.233-2

      Protests, as defined in section 33.101 of the Federal Acquisition Regulation, that are filed directly with an agency, and copies of any protests that are filed with the General accounting Office (GAO) shall be served on the Contracting Officer (addressed as follows) by obtaining written and dated acknowledgment of receipt from:
      U.S. Postal Address: Ms. Pamela S. Lew, Contracting Officer
      National Institutes of Health
      National Heart, Lung, and Blood Institute
      Contracts Operations Branch
      ROCKLEDGE 2, RM 6104
      6701 ROCKLEDGE DR
      BETHESDA MD 20892-7902
      Hand Delivery: Ms. Pamela S. Lew, Contracting Officer
      National Institutes of Health
      National Heart, Lung, and Blood Institute
      Contracts Operations Branch
      ROCKLEDGE 2, RM 6104
      6701 ROCKLEDGE DR
      BETHESDA MD 20817


      The copy of any protest shall be received in the office designated above within one day of filing a protest with GAO.


    1. SAFETY AND HEALTH DEVIATION PHS 352.223-70 (AUGUST 1997)

      To help ensure the protection of the life and health of all persons, and to help prevent damage to property, the Contractor shall comply with all Federal, State and local laws and regulations applicable to the work being performed under this contract. These laws are implemented and/or enforced by the Environmental Protection Agency, Occupational Safety and Health Administration and other agencies at the Federal, State and local levels (Federal, State and local regulatory/enforcement agencies).

      Further, the Contractor shall take or cause to be taken additional safety measures as the Contracting Officer, in conjunction with the project or other appropriate officer, determines to be reasonably necessary. If compliance with these additional safety measures results in an increase or decrease in the cost or time required for performance of any part of work under this contract, an equitable adjustment will be made in accordance with the applicable "Changes" Clause set forth in this contract.

      The Contractor shall maintain an accurate record of, and promptly report to the Contracting Officer, all accidents or incidents resulting in the exposure of persons to toxic substances, hazardous materials or hazardous operations; the injury or death of any person; and/or damage to property incidental to work performed under the contract and all violations for which the Contractor has been cited by any Federal, State or local regulatory/enforcement agency. The report shall include a copy of the notice of violation and the findings of any inquiry or inspection, and an analysis addressing the impact these violations may have on the work remaining to be performed. The report shall also state the required action(s), if any, to be taken to correct any violation(s) noted by the Federal, State or local regulatory/enforcement agency and the time frame allowed by the agency to accomplish the necessary corrective action.

      If the Contractor fails or refuses to comply promptly with the Federal, State or local regulatory/enforcement agency's directive(s) regarding any violation(s) and prescribed corrective action(s), the Contracting Officer may issue an order stopping all or part of the work until satisfactory corrective action (as approved by the Federal, State or local regulatory/enforcement agencies) has been taken and documented to the Contracting Officer. No part of the time lost due to any stop work order shall be subject to a claim for extension of time or costs or damages by the Contractor. The Contractor shall insert the substance of this clause in each subcontract involving toxic substances, hazardous materials, or operations. Compliance with the provisions of this clause by subcontractors will be the responsibility of the Contractor.


    1. SPECIAL REQUIREMENTS

      Capitation: A capitation reimbursement system will be used for Phase II protocol activity of this acquisition. CCTG-specific capitation rates will be established during negotiations based on their respective negotiated protocol costs. Reimbursement of these costs would only occur after the CCC has verified to the Contracting Officer that the required study data are complete and accurate for each randomization. Phases II and III core costs will be reimbursed on a cost-incurrence basis.

      The capitated costs will include amounts for investigator(s), nurse coordinator(s), and secretarial support, and for patient care costs that are not a part of usual care. Protocol-related patient care costs that do not fall under usual care are expected to include amounts for laboratory supplies, blood tests, blood gases, and the catheter and its insertion. The offeror is referred to the Schedule of Events page of the PAC protocol for a listing of the required tests/procedures and the frequency of their occurrence. It should be noted, as shown in the Schedule of Events, that only those tests/procedures marked by an "X" are required by the protocol and therefore will be reimbursable under any resultant contract. However, any test/procedure, or specific occurrence of a test/procedure, required by the protocol but otherwise considered routine care by the offeror shall not be included in the offeror's cost proposal. Further, costs shall not be included for the tests/procedures which involve only personnel effort. The estimated protocol FTE levels identified in subparagraph h. above include effort to conduct these tests/procedures.

      IRB Approval: Offerors will be required to document no later than October 31, 2000 that Institutional Review Board (IRB) approval of the PAC protocol has been obtained.

      Conflict of Interest Guidelines for Multi-center Clinical Trials: The following policy was released recently by the NHLBI. Investigators are expected to comply with the PAC protocol, which is incorporated as part of this solicitation, regarding conflicts of interest.

      In 1995, the Department of Health and Human Services released its final rule on "Objectivity in Research" (Federal Register, July 11, 1995). Under this rule, an investigator must disclose to an official in his or her institution "any Significant Financial Interests (and those of his/her spouse and dependent children) that would reasonably appear to be affected by the research proposed for funding by the PHS. The institutional official(s) will review those disclosures and determine whether any of the reported financial interests could directly and significantly affect the design, conduct, or reporting of the research and, if so, the institution must, prior to any expenditure of awarded funds, report the existence of such conflicting interests to the PHS Awarding Component and act to protect PHS-funded research from bias due to the conflict of interest."

      These are minimum requirements. Individual institutions may interpret them and implement them somewhat differently, and investigators may decide to go beyond them. Also, in certain circumstances, these rules may need to be adapted to the specific research program. For example, it would be reasonable for investigators in multi-center clinical trials to come up with a study-wide policy on conflict of interest, as different interpretations of the guidelines by different investigators and their institutions may be inappropriate. Certainly, the credibility of the study might depend on all of the investigators having stronger policies for conflict than are mandated by the PHS. Even if one or two of the investigators have financial interests in a drug or device being evaluated in the trial, or in a competitor of the drug or device, questions may arise as to the validity and interpretation of the trial results. An example of this is TIMI-1, where some of the investigators had considerable financial interest in tPA, leading to Congressional investigation.

      Most, but not all, clinical trial investigator groups have since developed conflict of interest guidelines. These have ranged from disclosure of interests to prohibition against buying or selling stock in a company manufacturing one of the interventions, to having any equity. In some cases, consulting or giving paid talks for the manufacturers has been discouraged.

      It is in the Institute's interest to strongly advise the investigative group to develop guidelines that avoid any perception that the study design, conduct, and data analysis and interpretation might have been biased by investigator conflict. To help investigators comply with the PHS regulations, the Institute Project Officer or Program Scientist and the Principal Investigator(s) must discuss the conflict of interest policy for the study at an early stage in the protocol development process. Although the Institute does not specify exactly what policy a given study should develop, it needs to remind the investigative group that study credibility depends on reasonably strict guidelines. These policies should be clearly spelled out in the protocol. In addition, the Project Officer or Program Scientist should be apprised of conflicts that arise and the corrective actions by the investigator's local institution. As noted in regulations, the Institute "may at any time inquire into the Institutional procedures and actions regarding conflicting financial interests in PHS-funded research, including a requirement for submission of, or review on site, all records pertinent to compliance with this subpart."


    1. OTHER CONSIDERATIONS

      Government Furnished Facilities and Equipment

      No Government furnished material/facilities or Government property will be supplied under this solicitation. The Clinical Coordinating Center will be responsible for acquiring any hardware and software that may be needed for distributed data entry at the clinical sites.

      Cost/Pricing Information

      The offeror's business proposal shall include the basic cost/pricing information specified in the Standard RFP Instructions and Provisions, under the Streamlined RFP References Directory referenced in this RFP. In addition, the Government may require offerors included in the competitive range to submit additional information substantiating their proposed costs or prices. This additional cost/pricing information will be requested after establishment of the competitive range, and potentially includes payroll documentation, vendor quotes, invoice prices, and/or any other information deemed necessary by the Contracting Officer to evaluate the reasonableness of the price or to determine cost realism. The information may also include submission and certification of or pricing data.

      The cost proposal you will prepare in response to this RFP will cover the period October 31, 2000 through October 30, 2003. Costs should be proposed for each year of the contract as follows: October 31, 2000 through October, 2001; October 31, 2001 through October 30, 2002; and October 31, 2002 through October 30, 2003.

      For your convenience, a standard cost proposal spreadsheet in Excel format is available under the Standard RFP References directory in the RFP Forms, Formats, and Attachments file: "http://www4.od.nih.gov/ocm/contracts/rfps/buscost.htm" . Offerors determined to be in the competitive range will be requested to submit a computer disk in Excel format.

      NHLBI Public Use Data Clause - Clinical Center (This clause will be made a part of the contract.)

      Public use data will be released under this clinical trial. After publication of the primary clinical trial results, the coordinating center will prepare the data and deliver it to the NHLBI. The data shall be prepared in a format suitable for use by the public. Such release is expected to occur no later than three years after the primary publication. The coordinating center shall provide the data to the NHLBI within two years of the primary publication so that the NHLBI can check the data before release. This will provide time for NHLBI review, discussion of the data, and opportunity for any changes needed in content or presentation prior to release.

      The public use data set will include the baseline visit, interim visit(s), and outcome data, including laboratory measurements. Inclusion of raw data that has been processed into summary information shall be discussed with the Project Officer prior to submission. Data prepared for release will not contain personal identifiers. Preparation of the data will be coordinated with the NHLBI to assure patient confidentiality.

      The study investigators will be expected to answer basic questions regarding data set characteristics, format and content, during the study. Documentation is expected to be of the highest quality so that such questions will be minimized.

      Data will not be prepared for public use if the investigators and NHLBI believe that they are unreliable or invalid. These exceptions must be justified in writing through the coordinating center to the NHLBI, and will be reviewed and, if the NHLBI concurs, approved in writing by the Director of the Division that sponsored the study.


    1. TECHNICAL PROPOSAL TABLE OF CONTENTS

      Please number each page of text. Type density and size must be 10-12 points. If constant spacing is used, there should be no more than 15 cpi, whereas proportional spacing should provide an average of no more than 15 cpi. There must be no more than six lines of text within a vertical inch.

      The technical proposal should be organized as follows:

      SECTION

      1. TECHNICAL PROPOSAL COVER SHEET ("RFP Forms, Formats, and Attachments")--Page #
      2. TECHNICAL PROPOSAL TABLE OF CONTENTS--Page #
      3. ABSTRACT--Page #
        State the proposal's objectives. Briefly and concisely describe the research design and methods for achieving these goals. DO NOT EXCEED one page in providing the abstract. Identify the RFP Number, Institution and Principal Investigator on the abstract.
      4. TECHNICAL PLAN--Page #
        Refer to Technical Proposal Instructions located in the Standard RFP Instructions and Provisions under Streamlined RFP References for more detail.

        1. Personnel
          1. List of all Personnel in the project including Subcontractors, Consultants/Collaborators, by name, title, department and organization--Page #
            PROVIDE TWO-PAGE BIOSKETCHES FOR INVESTIGATORS AND NARRATIVES, INCLUDING ROLE IN PROGRAM, EXPERTISE, AND RELATED EXPERIENCES, FOR:
          2. Principal Investigator/Project Director--Page #
          3. Other Investigators--Page #
          4. Additional Personnel--Page #

        2. Proposed Approach (no more than 20 PAGES single-spaced)
          1. Objectives--Page #
          2. Approach--Page #
            1. Inclusion of Women and Minorities
            2. Inclusion of Children
          3. Methods and Procedures--Page #
          4. Schedule--Page #

        3. Facilities, Equipment and Other Resources--Page # List/describe all facilities, equipment and other resources available for this project.

        4. Other Considerations/documentation--Page #
          1. Documentation of submission to IRB of protocol and consents

      5. OTHER SUPPORT--Page #
        Complete the Form "Summary of Current and Proposed Activities." All key personnel must be listed on this form.
        The form is located in the Streamlined RFP References under "RFP Forms, Formats, and Attachments."
      6. TECHNICAL PROPOSAL COST INFORMATION--Page #
        The form is located in the Streamlined RFP References under "RFP Forms, Formats, and Attachments."
      7. LITERATURE CITED--Page #
      8. APPENDICES--Page #
        Appendices shall not exceed 40 pages single-spaced. List each Appendix and identify the number of pages for each one. Appendices must be clear and legible, and easily located.


  1. APPLICABLE RFP REFERENCES

    This section identifies the items found in the subdirectory entitled Streamlined RFP References that are applicable to this Request For Proposal (RFP). The files identified below must be retrieved, in whole or in part, in order to submit a proposal in response to this RFP. The entire file entitled " Standard RFP Instructions and Provisions " is applicable to this RFP, except as modified by the inclusion of items from the " Optional RFP Instructions and Provisions " below.

    1. The following items are applicable from the file entitled " Optional RFP Instructions and Provisions ." The full text of the provisions is available in the file. List of provisions which apply to this specific RFP:

      1. Notice: This Requirement is Not Set-Aside for Small Businesses
      2. Human Subjects
      3. Small Business Subcontracting Plan (JAN 1999)
      4. Inclusion of Women and Minorities in Research Involving Human Subjects
      5. Past Performance Information
      6. "Just in Time"
      7. Inclusion of Children in Research Involving Human Subjects


    2. The following items are applicable from the file entitled " RFP Forms, Formats, and Attachments":

      Technical Proposal Forms (with original and every copy of technical proposal)

      1. Technical Proposal Cover Sheet
      2. Summary of Current and Proposed Activities
      3. Technical Proposal Cost Information

      Business Proposal Forms

      1. Proposal Summary and Data Record, NIH-2043
      2. Disclosure of Lobbying Activities, OMB SF-LLL
        This form is not required if there are no lobbying activities to disclose.
      3. Business Proposal Cost Information

      Contract Negotiation Forms/Attachments

      1. DHHS Small, Small Disadvantaged, HUBZone and Woman-Owned Small Business Subcontracting Plan
      2. Certificate of Current Cost or Pricing Data, NIH-1397
      3. Representations and Certifications--Negotiated Contracts
      4. Sample Contract Format-General --R&D Cost Reimbursement

      Contract Forms and Attachments

      1. Invoice/Financing for Cost Reimbursement Type Contracts, NIH(RC)-1
      2. NIH 2706, Financial Report for Individual Project/Contract Instructions
      3. NIH 2706, Financial Report for Individual Project/Contract Form
      4. Research Patient Care Costs, NIH(RC)-11
      5. Annual Technical Progress Report Format for Each Study
      6. NIH Women and Minority Policy
      7. Protection of Human Subjects Assurance/Identification/Certification/Declaration, OF310
      8. NIH Policy for Inclusion of Children as Participants in Research Involving Human Subjects


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Prospective, Randomized, Multi-Center Trial of Pulmonary Artery Catheter (PAC) vs. Central Venous Catheter (CVC) for Management of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).

and

Prospective, Randomized, Multi-Center Trial of "Fluid Conservative" vs. "Fluid Liberal" Management of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).

ARDS Clinical Network
ARDSNet Study 05, Version I

March 14, 2000





PAC Study Version I
ARDSNet Study 05
March 14, 2000


  1. BACKGROUND

    The pulmonary arterial catheter (PAC) was introduced for clinical use in 1970 to provide diagnostic and monitoring information not available from other clinical sources (1). An amendment to the Food and Drug Administration (FDA) act in 1976 charged the FDA with the responsibility for insuring the safety and effectiveness of medical devices. The PAC has been designated as a Class II device, one that requires special controls. Approximately 1.5 million such catheters are sold in the United States annually. Estimates that 30% of PACs are used in cardiac surgery, 30% in cardiac catheterization laboratories and coronary care units, 25% in high risk surgery and trauma, and 15% in medical intensive care units (personal communication, Baxter Healthcare Corporation).

    Observational studies and anecdotal reports of morbidity and mortality associated with and directly related to the catheter (2-8) culminated in a multi-institutional, case matched, statistically sophisticated study of 9 disease categories of patients by Connors et al. (9). The fundamental question raised by the Connors article, as well as by previous reports, relates to "implied harm" that may be associated with use of the PAC. Implied harm is defined as the excess morbidity and mortality found in these reports, but for which there is no discernible cause and effect relationship to the insertion or presence of the PAC. No prospective randomized studies directly relate increased morbidity and mortality to the insertion of the PAC, but a few prior studies infer that operational problems, errors in data interpretation, inappropriate therapeutic responses to catheter data, singly or in combination, result in no benefit to patients and may actually harm them (2-9).

    The PAC provides a wealth of direct and indirect information about circulatory and respiratory systems and intravascular fluid volume over time. Specifically, the PAC allows measurement of central venous and pulmonary arterial pressure, pulmonary artery occlusion pressure (PAOP, or "wedge" pressure), mixed venous blood gases, and indicator-dilution cardiac output. Because the data are quantitative, more information, such as systemic and pulmonary vascular resistance, can be derived. The accuracy of these measurement is high in expert hands (10,11), but is subject to proper placement of the catheter, calibration of transducers and user interpretation of wave forms and data (12, 13). PAC data, properly interpreted, help to assess right and left ventricle function, intracardiac shunts, pulmonary ventilatory function and intra-vascular fluid status (14, 15). Once the PAC is in place and is properly maintained, ongoing monitoring of these data may provide early information regarding trends toward improvement or deterioration (8) in response to therapeutic intervention (15). No other monitoring system provides as much overall information for management of circulatory and respiratory inadequacy or for assessing intravascular fluid volume.

    Direct morbidity and mortality associated with the PAC is related to complications from insertion, passage, and maintenance of the catheter. Such complications include pneumothorax, bleeding (hemothorax, etc), arrhythmias, thromboembolism, pulmonary artery rupture, and infection (17,20). The incidence of these direct complications has been widely reported (17); a consensus of experts estimates that serious complications occur in 0.1-0.5% of monitored surgical patients (15, 17, 18). Ongoing observational studies are expected to better document the incidence of direct complications associated with the use of the PA catheter.

    Morbidity and mortality may also result from misinterpretation or misapplication of data derived from the PAC. The insertion, use and interpretation of data obtained from PACs requires special expertise that is not possessed by all health care professionals (12, 13). Connors et al (9) have also reported significant variability in the prevalence of PAC use across institutions even within patient disease groups that should be relatively homogenous.

    Although there have been multiple calls for investigation (21, 22, 23), no definitive, randomized, prospective clinical trials designed to determine the safety and efficacy of the PAC in medical and surgical patients exist (15, 24). The use of the PAC can be divided into diagnostic and management applications. In most cases, diagnostic applications require the catheter to be inserted for brief periods of time (< 24 hours). The complication rates for these diagnostic studies are well documented and relate primarily to the insertion procedure or the catheter itself (12,15). On the other hand, the management issues related to the PAC are less well investigated.

    The PAC catheter is used commonly in patients with acute lung injury (ALI) and its most severe subset, the acute respiratory distress syndrome (ARDS). ALI is a clinical problem of significant magnitude in terms of incidence (150,000 patients per year), mortality (30%- 60% in most series) and cost (in part due to long stays in intensive care). In patients with ALI, the PAC has been employed widely both to confirm the diagnosis as well as to optimize hemodynamic management. However, there are no prospective data that establish the clinical risk/benefit ratio of use of the PAC in such patients. Although the data obtained from the PAC provides considerable physiologic information about the systemic and pulmonary derangements that occur in patients with ALI (25), it is not clear that such information improves therapy or clinical outcomes. Mitchell and co-workers (26) randomized 52 ARDS patients (already being managed with PAC) to either a extravascular lung water (EVLW) management (based on bedside indicator-dilution measurements) or a "routine" wedge pressure management group. The EVLW management strategy achieved both a lower overall net fluid balance and a lower extravascular lung water, and was associated with improved mortality and shorter ICU length of stay. This study suggests that achieving a lower fluid balance in ARDS patients is associated with improved clinical outcomes. In a retrospective study of 40 ARDS patients, those patients who experienced a reduction of wedge pressure of at least 25 percent during acute management (first 48 hours) were found to have better survival than those patients who did not experience such a reduction in wedge pressure (75% vs. 29% survival, p < 0.02) (27).

    Theoretically, measurement of the PAOP and cardiac output may make it possible for physicians to maintain pulmonary vascular pressures at a lower level, thus reducing the quantity of pulmonary edema that may develop in the presence of an increase in lung vascular permeability (25,28). Also, maintaining a lower pulmonary capillary pressure may prevent or minimize damage ("stress failure") to the capillary wall (29). In normal animals, high pulmonary capillary pressure causes ultrastructural damage to the capillary walls, with a resulting "high permeability" (capillary leak) type of edema (29). Of a high concentration of leukotriene B4 and inflammatory cells is also found in the bronchoalveolar lavage of these animals, suggesting the onset of an inflammatory process (29). Such inflammation may be triggered by exposure of the highly reactive endothelial basement membrane (29).

    Furthermore, the measurement of pulmonary arterial pressure and cardiac output may make it possible for physicians to administer vasoactive agents more skillfully in order to optimize cardiac output, maintain or improve renal function, and increase systemic blood pressure and blood flow to vital organs (25). On the other hand, it is possible that measurement of central venous pressure alone using a central venous catheter (CVC) is adequate to optimize hemodynamics in patients with ALI. The issue can only be resolved with carefully designed prospective studies (30,31). Further, a well designed trial, complete with supporting clinical protocols, could be a model for other interventional studies of ALI specifically and critical care in general. Such a trial also has the advantage of systematically collecting data on the incidence of volume overload pulmonary edema in patients clinically thought to have ALI and evaluating how this information changes clinical management and outcome in prospective randomized trial.

  2. OBJECTIVES
    1. Primary Objectives:

      1. Evaluate the impact of the PAC versus the CVC on mortality, ventilator-free days, and organ failure in patients with ALI.

      2. Evaluate the impact of a fluid conservative management strategy versus a fluid liberal management strategy on mortality, ventilator-free days, and organ failures in patients with ALI.

    2. Primary Hypotheses:

      1. Use of the PAC will be associated with a reduction in 60-day mortality.

      2. Use of the fluid conservative management strategy will be associated with a reduction in 60-day mortality.

    3. Secondary Hypotheses:

      1. Use of the PAC will significantly reduce the duration of assisted ventilation (as measured over 28 days).

        Use of the fluid conservative strategy will significantly reduce the duration of assisted ventilation (as measured over 28 days).

      2. Use of the PAC compared to that of the CVC will reduce the extent of multiple organ system dysfunction including liver function, hematologic function, gastrointestinal function (need for packed red cell transfusion), and an overall organ system dysfunction index (using the Brussels table) by day 7.

        Use of the fluid conservative strategy compared to that of the fluid liberal strategy will reduce the extent of multiple organ system dysfunction including liver function, hematologic function, gastrointestinal function (need for packed red cell transfusion), and an overall organ system dysfunction index (using the Brussels table) by day 7.

      3. Use of the PAC will be associated with a significant reduction in the lung injury score, the PaO2/FiO2 ratio, and/or the oxygenation index on days 1 through 7 after randomization compared to patients with a CVC.

        Use of the fluid conservative strategy will be associated with a significant reduction in the lung injury score, the PaO2/FiO2 ratio, and/or the oxygenation index on days 1 through 7 after randomization compared to patients with a fluid liberal strategy.

      4. The incidence of major complications (pneumothorax, catheter-related infection, and arrhythmias) will be the same for the PAC and the CVC.

  3. ENDPOINTS

    1. Primary Endpoint:

      1. Mortality prior to hospital discharge to day 60.

    2. Secondary Endpoints:

      1. Number of ventilator-free days (VFD) to day 28 after enrollment.
      2. Number of ICU-free days at 7 and 28 days after enrollment.
      3. Number of organ failure-free days at 7 and 28 days after enrollment.
      4. Resource utilization (estimated from event-free days).
      5. Number of complications associated with PAC and CVC (pneumothorax, catheter-related bacteremia or fungemia, and arrhythmias) while the catheters are in place.
      6. Reduction of the PaO2/FiO2 ratio on days 1-7 after catheter insertion.
      7. Improvement in Lung Injury Score on days 1-7 after catheter insertion.
      8. Correlation between the pulmonary artery wedge pressure and the central venous pressure while the PAC and CVC are in place.
      9. Changes in fluid therapy, use of vasoactive agents, and/or diuretics within the first 1-7 days after insertion of a PAC versus a CVC.
      10. Correlation between PAC measure of cardiac output and clinical measures of skin temperature, capillary refill, and skin mottling and relationship to protocol driven interventions.

      VFD to day 28 is defined as the number of days of unassisted breathing to day 28 after randomization, assuming a patient survives for at least two consecutive calendar days after initiating unassisted breathing and remains free of assisted breathing. If a patient returns to assisted breathing and subsequently achieves unassisted breathing prior to day 28, VFD will be counted from the end of the last period of assisted breathing to day 28 unless a period of assisted breathing was < 24 hours and the purpose of assisted breathing was a surgical procedure. If the patient is receiving assisted ventilation at day 28 or dies prior to day 28, VFD will be 0. Unassisted breathing is defined as breathing with face mask or nasal prong oxygen (or room air) following extubation, T-tube breathing, breathing with continuous positive airway pressure (CPAP less than or equal to 5 cm H2O), or tracheotomy mask breathing.

      Organ failure is defined as present on any date when the most abnormal vital signs/abnormal lab value meets the definition of clinically significant organ failure according to the Brussels Organ Failure Table. Patients will be followed for 7 days. Blood tests will be obtained on days 1-7 in order that the presence of clinically significant organ failure can be assessed. Each day a patient is alive and free of a given clinically significant organ failure be scored as a failure-free day. Any day that a patient is alive and free of all 5 organ failures will represent days alive and free of all organ failure. Central nervous system dysfunction is evaluated using the Glasgow Coma Scale.

      Bacteremia and fungemia are defined as isolation from one or more blood cultures of pathogenic bacteria, yeast or fungi with the exception of coagulase negative (or thermonuclease negative) Staphylococci or Corynebacteria. Coagulase negative Staphylococci or Corynebacterium bacteremia require the isolation of these organisms from at least two blood cultures drawn within 24 hours of each other containing the same organism in order to be deemed significant. Bacteremia and fungemia are considered catheter-related if they occur when the same organism is quantitatively cultured (> 15 cfu) from a catheter tip (confirmed) or when, in the opinion of the patient's physician, the infection can only have been caused by the catheter (non-confirmed).

  4. INCLUSION CRITERIA

    Acute Onset of:

    1. PaO2/FiO2 less than or equal to 300. If altitude > 1000m, then PaO2/FiO2 < 300 x (B.P./760).

    2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph. The infiltrates may be patchy, diffuse , homogeneous, or asymmetric.

    3. Requirement for positive pressure ventilation via endotracheal tube.

    4. No clinical evidence of left atrial hypertension.

    Criteria 1-4 must occur together within a 24-hour interval.

  5. EXCLUSION CRITERIA

    1. Absence of current intent or ability on the part of the treating physician(s) to obtain or continue central venous access (that could be used for either CVC or PAC monitoring) as part of regular care of this patient.
    2. Unwillingness or inability to utilize the low tidal volume (6ml/kg PBW) ventilator management protocol.
    3. Presence of a PAC at any time after onset of ALI (meeting of inclusion criteria 1-4).
    4. Forty-eight (48) hours since onset of ALI (meeting of inclusion criteria 1-4).
    5. Age < 13 years.
    6. Burns > 40% body surface area.
    7. Not committed to full support (Exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest).
    8. Bone marrow transplantation.
    9. Acute myocardial infarction within the last 30 days.
    10. Severe chronic respiratory disease:
      • FEV1 < 20 ml/kg PBW (e.g. 1.4 L for 70 kg), or
      • FEV1 /VC < 50% predicted, or
      • Chronic hypercapnia (PaCO2 > 45 mmHg) and/or chronic hypoxemia (PaO2 < 55 mmHg) on FiO2 = 0.21, or
      • Radiographic evidence of chronic over-inflation or chronic interstitial infiltration, or
      • Hospitalization within the past six months for respiratory failure (PaCO2 > 50 mmHg or PaO2 < 55 mmHg or O2-Sat < 88% on FiO2 = .21).
      • Chronic restrictive, obstructive, neuromuscular, chest wall or pulmonary vascular disease resulting in severe exercise restriction, e.g., unable to climb stairs or perform household duties, secondary polycythemia, severe pulmonary hypertension (mean PAP> 40 mmHg), or respirator dependency.
    11. Neuromuscular disease that impairs ability to ventilate spontaneously, such as C5 or higher spinal cord injury, amyotrophic lateral sclerosis, Guillain-Barre Syndrome, and myasthenia gravis.
    12. Morbid obesity (body mass index >40).
    13. Greater than 50% estimated mortality within 30 days due to underlying conditions (e.g., advanced malignancy).
    14. Vasculitis with diffuse alveolar hemorrhage.
    15. Pregnancy (negative pregnancy test required for women of child-bearing potential).

  6. STUDY POPULATION AND ENROLLMENT

    Approximately 1,000 patients will be enrolled over a 3 year interval. Patients with ALI will be sought in the NIH ARDSNet intensive care units. Study Coordinators at each site will visit each intensive care unit daily to identify potential candidates for enrollment. Permission to approach patients/families will be requested from attending physicians. All patients meeting the inclusion criteria will be entered on a screening log. If the patient is not enrolled, the screening log will include information explaining why enrollment did not occur (exclusion criteria, attending physician denial, patient refusal, etc.).

    Enrollment and Study Initiation Time Window: All patients must be randomized within 48 hours of meeting inclusion criterion for ALI (inclusion criteria 1-4). The last inclusion criterion may be met at either the Network hospital or a referring hospital. Following randomization, the low tidal volume protocol for mechanical ventilation must be initiated within one hour (if not already being utilized). The appropriate catheter (PAC or CVC, based upon randomization) must be in place within four hours of randomization. Finally, initiation of the fluid management protocol (fluid liberal or fluid conservative, based upon randomization) must begin within two hours of the time of placement of the PAC or CVC.

    Informed Consent: Informed consent will be obtained from each patient or surrogate prior to enrollment in the trial.

    Randomization: After obtaining informed consent, the Clinical Coordinating Center will be called and an assignment will be made by computer-generated randomization to either the PAC or CVC and to either the fluid conservative or fluid liberal management strategies. The randomization system will be based on Interactive Voice Response (I.V.R.) technology. Each research coordinator will have a unique Personal Identification Number (PIN). He or she will call the system and be asked to supply the PIN. A treatment assignment and a patient ID number will be assigned. A confirmation will follow to the site.

    Minorities/Women: Gender and racial patient subsets were considered by the NHLBI in selecting the Network Centers. The demographic profiles of the Centers selected for the Network show that the aggregate patient population contains representative proportions of minorities (28%) and women. Recruitment of minorities and women will be monitored by the Network Coordinating Center. If necessary, additional recruitment efforts will be made at specific centers to ensure that the aggregate patient sample contains appropriate gender and minority subsets.

  7. DATA COLLECTION AND SITE MONITORING

    Data Collection: Each site will have one or more computers. The research coordinator will be responsible for maintaining a database using a custom designed database application. Data will be stored in this computer and transferred to the Clinical Coordinating Center on a prescribed basis.

    Site Monitoring: Site visits will be performed on a regular basis by the Data Coordinating Center, to ensure that all regulatory requirements are being met and to monitor the quality of the data collected. Records of IRB approvals and patient charts will be examined on a spot check basis to evaluate the accuracy of the data entered into the database.

  8. PROCEDURES

    Insertion of the Catheter and Acquisition of Data

    The patient will be randomized to receive either PAC (which includes the CVC port) or a CVC alone. At the time of enrollment, patients will have either central venous access (CVC but not PAC) or it will be the prior intent of the attending physician to attain such access. For patients with no central access at the time of enrollment, central access will be obtained via an internal jugular, subclavian, antecubital, or femoral vein (if the physician is willing to use this site for CVC or PAC). For patients with an existing central venous catheter who are randomized to PAC, the CVC will be changed over a wire to PAC for subsequent PAC placement. Alternatively, a PAC introducer may be placed using a new access site.

    The type of CVC or PAC catheter used in this trial will be those already in clinical use in the study ICUs. The minimum requirement for PAC will be the availability of right atrial and distal PA ports as well as a capability to measure thermodilution cardiac output. PACs with continuous cardiac output monitoring capabilities can be used. The type of catheters (number of ports, continuous cardiac output, etc), antibiotic coating of catheter/introducer, the site of insertion, the date and duration of insertion will all be recorded on the case report form.

    Catheters will be inserted using aseptic technique and full barrier precautions. Catheters will be prefilled with heparinized saline solutions and the distal balloon will be tested with the injection of 1.5 cc of air followed by passive deflation. The PAC will then be inserted through the PAC introducer and the typical wave forms of the right atrium, right ventricle, pulmonary artery, and PAOP observed on the bedside monitor. The balloon will then be passively deflated and reinflated to confirm the PAOP. An acceptable PAOP waveform should produce a tracing that is compatible with a left atrial wave form when assessed in reference to a simultaneously recorded electrocardiogram on a strip chart recording and the mean PAOP should be equal to or lower than the PA diastolic pressure. The insertion site will then be secured and dressed per local hospital policy. A chest radiograph will be performed immediately thereafter to confirm proper placement of the CVC and PAC. Location of the catheter tip with the balloon deflated will be as close to the pulmonic valve as possible to avoid technical problems.

    Right atrial pressure, PA systolic pressure, PA diastolic pressure, and PAOP will all be measured in reference to the midthorax at the 4th intercostal space. Catheter transducer systems will be electronically zeroed to this reference point. Pressure measurements will be made on a 2channel strip chart recorder that allows simultaneous display of the electrocardiogram and PA or RA wave form. The mean right atrial pressure and mean PAOP will be measured at end expiration. Cardiac output will be measured by thermodilution technique with either iced saline or room temperature saline as per the study ICU's procedures. Thermodilution cardiac outputs will be measured in triplicate and the average of the three injections will be recorded. No attempt will be made to time the injection to the respiratory cycle.

    Hemodynamic measurements will be obtained at least every four hours by the nursing personnel in the study intensive care units and the strip chart recordings kept in the ICU. At a randomly selected time each day, the strip chart recording will be reviewed with a member of the study team to confirm accurate measurement of pressure and timing of respiration of the respiratory cycle. Study personnel and the critical care nurses in the study ICUs will have the Pulmonary Artery Catheter and Clinical Outcomes (PACCO) educational materials and PACCO pre and posttests available for training at each site.

    Material will also be distributed to each site providing standard instructions for assessing capillary refill time, cutaneous "mottling" of the skin over the knees, and skin temperature at the knees.

    Infection Monitoring

    The catheter insertion site will be inspected daily. The presence of purulence alone, or erythema with one of the following; tenderness, and increased warmth, induration, lymphangitis, or probable thrombosed vein, will constitute local site inflammation and the catheter will be removed and a new insertion site selected. For patients with fever and other clinical signs of infection, the PAC introducer or the CVC introducer will be changed to a new line or introducer over a wire and the tip quantitatively cultured. For febrile patients with septic shock, the PAC or CVC will be removed and a new insertion site selected unless there is clearly a likely cause of septic shock other than the catheter.

    Clinical Management

    Hemodynamic management of patients in each of the 4 groups (PAC-fluid conservative; PAC-fluid liberal; CVC-fluid conservative; CVC-fluid liberal) will be conducted according to protocol, as provided in Appendix I.

    Treatment Algorithm Validation

    Compliance with the hemodynamic protocol instructions and safety of the protocol instructions will be monitored by the PAC committee daily for the first sixty patients (15 in each treatment cell) as part of the protocol evaluation process. During this period, the protocol rules may be refined through iterative application and evaluation in the ARDS Network Sites. The goals for this refinement phase will be to achieve approximately 90% compliance with instructions with no safety concerns.

    Protocol performance data will include percent compliance with the protocol instructions and adverse events. Summary data for the first sixty patients and the revised hemodynamic management protocols will be reviewed by the Steering Committee and the Data and Safety Monitoring Board. The iterative refinement process will continue during Steering Committee and DSMB review. The Steering Committee or the DSMB may ask that the detailed iterative refinement continue beyond sixty patients or recommend that the study proceed with the refined protocol.

    Duration of Protocol

    The fluid management strategy (fluid liberal or fluid conservative) will be carried out for 7 days or until unassisted ventilation is achieved, whichever occurs first.

    The PAC will be maintained for at least 3 days, and thereafter until a 24 hour period of hemodynamic stability occurs (defined as the absence of instructions for any of the following interventions by the fluid management strategy: fluid bolus, pressors, inotropes, diuretic) up to a maximum of 7 days or until unassisted ventilation is achieved, whichever occurs first. If the PAC is removed between day 3 and day 7 by the protocol defined stability criterion, a CVC will be maintained and will be utilized to continue the fluid management strategy (conservative vs. liberal) that the patient was initially randomized to.

    The CVC will be maintained for 7 days or until unassisted ventilation is achieved, whichever occurs first.

    For the purpose of determining the endpoint of protocol application, unassisted ventilation must be continuously achieved for at least 8 consecutive hours, or until discharge of the patient from the intensive care unit, whichever occurs first.

    Schedule of Hemodynamic Management Events

    The data that serves as "input" for the fluid management protocol will be obtained at least every 4 hours. In all patients, this includes blood pressure, urine output, clinical assessment of the effectiveness of the arterial circulation, and central venous pressure. In patients with PAC, this additionally includes measurement of pulmonary artery occlusion pressure and cardiac index. Based upon this data, the appropriate protocol "output" (maintenance fluid, bolus fluid, inotrope, diuretic, pressor) will be implemented.

    If, prior to the next scheduled 4 hour assessment, a change in one of the data inputs occurs (e.g., decrease in urine output), then the investigator shall have two options. First, it can be determined whether this change would cause a new output instruction, based upon the most recent available full set of data inputs (occlusion pressure, etc) carried forward. If so, then a full set of data inputs must be obtained (unless < 30 minutes have elapsed since a particular measurement was last obtained), and then the appropriate output instruction is implemented based upon this new full set of data. Alternatively, the investigator may elect to measure the data inputs at anytime, based upon clinical judgement. In any event, in all circumstances, output instructions will be carried out only based upon an updated full set of data inputs (each element obtained within 30 minutes or less of the output instruction).

    Ventilator Management

    (VENTILATOR MANAGEMENT FOR ALL PATIENTS WILL BE ACCORDING TO THE 6 ml/kg PROTOCOL OF ARMA) - See Appendix II

    Data Collection

    1. Background Assessments including pregnancy test (serum or urine) for women of child-bearing potential
    2. Demographic and admission data
    3. Pertinent medical history and physical examination
    4. Height; calculated predicted body weight (PBW)
    5. Time on ventilator prior to enrollment
    6. Type of admission
      1. Medical
      2. Surgical scheduled
      3. Surgical unscheduled
    7. Risk factors for ALI/ARDS (sepsis, trauma, pneumonia, drug overdose, other)
    8. Presence of following chronic diseases:
      1. Metastatic cancer
      2. Hematologic malignancy
      3. AIDS

      Baseline Assessments

    9. Vital signs: heart rate (b/min), systemic systolic and diastolic blood pressure (mm Hg), body temperature (°C)
    10. Ventilator mode, rate, minute ventilation, tidal volume, FiO2, PEEP, plateau, peak, and mean airway pressures.
    11. Arterial PO2, PCO2, pH, and SpO2
    12. Central venous pressure
    13. Mixed venous PO2, PCO2, pH, and SPO2 as well as central venous sample (simultaneous when PA inserted).
    14. Urinary output (most recent 24 hour value) or mean hourly value for most recently available period
    15. Serum electrolytes, BUN, creatinine, glucose, albumin, and total protein
    16. Blood hematocrit/hemoglobin, WBC, and platelets
    17. Glasgow Coma Score
    18. Frontal chest radiograph
      1. Radiographic lung injury score (# of quadrants)
      2. Presence or absence of barotrauma
        Pneumothoraces (R/L)
        Pneumomediastinum
        Pneumatoceles > 2 cm minimum diameter (R/L)
        Subcutaneous emphysema
    19. Administration of following medications:
      1. Vasopressors
      2. Inotropic agent
      3. Diuretics
    20. Presumed site of infection, if sepsis is the etiology of ALI/ARDS.
    21. Results of special diagnostic studies performed to assess hemodynamic status (e.g. cardiac echocardiogram)
    22. Signs of the effectiveness of the arterial circulation (e.g. capillary refill time, knee mottling, skin temperature, etc.)
    23. Intake and output for 24 hours on that calendar date; intake to include types volumes of various fluids (e.g. blood products, colloids, saline solutions.
    24. Evidence of anasarca (physical exam).

    Assessments During Study

    The following parameters will be measured and recorded daily from 4-10 am using the values closest to 8:00 AM (except where indicated) on days 1-7.

    1. If receiving positive pressure ventilation:
      1. Mode
      2. PEEP level
      3. Peak, plateau, and mean airway pressures
      4. Minute ventilation
    2. FiO2
    3. PaO2, PaCO2, pH, and SpO2
    4. Mixed venous PO2, PCO2, pH, SO2 (not mandated, but entered if recorded)
    5. Central venous PO2 and SpO2 (not mandated, but entered if recorded)
    6. Hemodynamic values (twice daily)
      1. Systemic arterial systolic, diastolic, and mean pressure
      2. Heart rate (b/min)
      3. Central venous, pulmonary artery, PAOP, and end-diastolic pressures, and cardiac output
    7. Intake in past 24 hours; intake to include types and volumes of various fluids (e.g. blood products, colloids, saline solutions).
    8. Urine and other output in past 24 hours
    9. Serum electrolytes, BUN, creatinine
    10. Blood hemoglobin concentration
    11. Administration of following:
      1. Vasopressors
      2. Inotropic agents
      3. Diuretics
    12. Experimental treatment (e.g. nitric oxide)
    13. Frontal chest radiograph
      1. Lung injury score
      2. Presence or absence of barotrauma
    14. Brussels score
      1. Worst PaO2/FiO2 for that date
      2. Worst systolic blood pressure for that date
      3. Worst creatinine, bilirubin, and platelet count for past 24 hours
      4. Use of vasopressors
      5. Glasgow Coma Score
    15. Results of special diagnostic studies performed to assess hemodynamic status in past 24 hours (echocardiogram, etc).
    16. Signs of effectiveness of the arterial circulation (see previously)
    17. Evidence of anasarca (physical exam)
    18. Blood for cytokines, mediators, and markers of lung injury. Plasma obtained from two, 10 ml EDTA anticoagulated blood samples will be divided immediately after centrifugation into 12 equal 1 ml aliquots in specified tubes and frozen at - 70°C. Blood will be collected on Days 0, 1, 3, and 7.

    In addition, the following will be recorded if they occur when a PAC or CVC is in place and up to 3 days thereafter:

    1. Catheter-related fungemia or bacteremia
    2. Arrhythmias
    3. Venous thromboembolism in the veins adjacent to insertion of the CVC or PAC

  9. STATISTICAL CONSIDERATIONS

    This study uses a 2x2 factorial design comparing the use of a liberal fluid management strategy and a conservative fluid management strategy and comparing the use of the PAC to the use of the CVC. The trial will accrue 250 patients in each of the four arms, which will give over 90% power to detect a difference of 10% (from 31% to 21%) in 60 day mortality at hospital discharge in the two primary comparisons using a two sided p=.05 significance level.

    This sample size consideration is based on the results of our earlier study (ARMA). This study found a 31.3% and 39.8% mortality at hospital discharge for 6 ml/kg and 12 ml/kg ventilation.

  10. EARLY STOPPING AND MONITORING

    DSMB meetings will be scheduled when 200, 400, 600, and 800 patients have been treated. A two sided O'Brien-Fleming boundary (32) will be used to determine whether to stop each factor separately. If one factor stops the other randomization may continue. The stopping boundaries correspond to two sided p-values of 0.0000048, 0.0012, 0.0083, 0.0222, and 0.0409.

    At each DSMB meeting a test for interaction will be performed. This test will be controlled for multiple comparisons using a Pocock boundary (33) in order to maximize the chance of early detection of a failure of our assumption that the effects of the two factors are additive. If a significant interaction is found it will be up to the DSMB to determine the best course of action. This may include stopping the trial or dropping one or more of the arms. The Pocock boundary for a trial with five looks at the data would have a two sided p-value of 0.0158.

    The trial will also be monitored by the steering committee for feasibility. Feasibility parameters will include: accrual, the ability to follow the fluid management protocol, separation of the groups based on fluid balance data and the frequency that a PAC is placed in the group that is randomized to CVP. If any of these parameters indicate that the trial is not feasible the trial will be modified or terminated.

    The principal analysis will be by intent-to-treat, based upon randomization assignment. For example, patients who where randomized to receive a CVC, but who receive a PAC sometime during the defined treatment period, will be analyzed as having received the CVC (the treatment that they were randomized to). The rate and timing of "crossovers" will be monitored and will be a feasibility parameter at each interim analysis.

  11. ASSESSMENT OF RISKS

    This study involves randomization of two separate (but potentially interacting) interventions: 1) PAC vs. CVC, and 2) fluid "conservative" strategy vs. fluid "liberal" management strategy. Each of the two randomizations carries with it potential risks (and potential offsetting benefits), and the possible interactions between the two trials may also have risk or benefit.

    The trial of PAC vs. CVC essentially studies the incremental benefit or risk of adding the PAC catheter to the management of an ALI/ARDS patient who otherwise would be treated at least with CVC catheter (see exclusion criteria). Therefore, the risks of participating in this trial do not include those directly attributable to obtaining central venous access, such as pneumothorax, inadvertent arterial puncture, "baseline" infection rate of such catheters, etc. (The probably rare exception would be the patient who when randomized to receive the PAC would require a second central venous access for this purpose, due to a requirement for multiple ports for medication administration, etc.) Rather, the primary risk of participating in this trial relates to the incremental risk of having a PAC vs. having a CVC alone. This would include known "physical risks", such as cardiac arrhythmias, pulmonary artery rupture, pulmonary infarction, etc, as well as physical risks of the PAC that may not yet be known. Furthermore, it is possible that the use of the PAC may lead to erroneous and adverse management, due either to inaccurate acquisition of the primary data (e.g., pulmonary artery occlusion pressure, cardiac output). Conversely, the major risk of not utilizing the PAC is inadequate hemodynamic management that may occur due to the lack of potentially important information provided by the PAC, but not by the CVC (e.g., pulmonary artery occlusion pressure, cardiac output, etc).

    The second trial consists of randomization to either a fluid "liberal" or "conservative" management strategy. Each of these strategies is thought to have potential benefit (such as lung protection in the fluid conservative group, and augmentation of renal and other organ perfusion in the fluid liberal group), but may also have risks (such as inadequate organ perfusion in the fluid conservative group and excessive pulmonary edema and delayed lung recovery in the fluid liberal group). The net balance of these potentially opposing risks and benefits is not known. Furthermore, the actual risks involved with the application of the specific fluid liberal and fluid conservative management strategies posses potential risks, in that these specific strategies have not been tested in patients previously. However, each of the strategies is felt to be clinically reasonable by the collective judgement of experts in the field. Conversely, there may be potential benefit to patients from the specific application of either one or both of these fluid management strategies (relative to "routine" care), in that each of these strategies has been carefully derived by a group of experts. During the early phase of the trial, and for as long as necessary, very close and specific attention will be paid to the safety and clinical "validity" of the specific fluid management strategies.

    It is also recognized that there may be "interaction" between the two trials, which may cause benefit or risk, as well. For example, perhaps the fluid conservative management strategy is superior only when applied with the use of a PAC, but is hazardous when applied only with a CVC. In this hypothetical example, therefore, the patients randomized to receive the PAC with the fluid conservative strategy might have the best outcome among the four groups, whereas the patients randomized to CVC with the fluid conservative strategy might have the worst outcome of the four groups. The potential risks or benefits of such interactions between the two trials will be carefully monitored by the DSMB.

  12. HUMAN SUBJECTS

    All protocols will require that all study participants or a member of a patient's family sign an informed consent. All protocols will require prior IRB approval before any subject is entered into the study. All study participants or their families will be informed about the objectives of the study and the potential risks. All laboratory specimens, evaluation forms, and reports will be identified by a coded number only to maintain patient confidentiality. All records will be kept in a locked/password protected computer. All computer entry and networking programs will be done with coded numbers only. Clinical information will not be released without the written permission of the patient, except as necessary for monitoring by the FDA, National Heart, Lung, and Blood Institute, and the ARDS Clinical Coordinating Center.

  13. PROCEDURES FOR REPORTING ADVERSE EVENTS

    The investigator will determine daily whether any clinical adverse experiences have occurred through study day 21 or ICU discharge, whichever occurs first. The investigator will evaluate any changes in laboratory values and physical signs and make a determine as to whether the change is clinically important and different from what is expected in the course of treatment of patients with ALI or ARDS. If clinically important and unexpected adverse experiences have occurred they will be recorded on the adverse event case report form.

    The investigator will report all serious, unexpected, and study-related adverse events, as defined in Appendix III, to the Data Coordinating Center within 24 hours. The local Institutional Review Board must also be informed in a timely manner. The investigator will then submit a detailed written report to the Clinical Coordinating Center and the Institutional Review Board no later than 5 days after the investigator discovers the event.

    The Clinical Coordinating Center will report all serious, unexpected, and study-related adverse events to the DSMB, by fax or telephone, within 7 calendar days. A written report will be sent to the DSMB within 15 calendar days and these reports will be sent to investigators for submission to their respective Institutional Review Boards. The DSMB will also review all adverse events during scheduled interval analyses. The Clinical Coordinating Center will distribute the written summary of the DSMB's periodic review of adverse events to investigators for submission to their respective Institutional Review Boards in accordance with NIH Guidelines.


Schedule of Events

  Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Days
14,21
Day
28
Randomization X                  
Demographics, History X                  
APACHE III X                  
Physical Exam X X X X X X X X    
Vital Signs X X X X X X X X    
Height X                  
Ventilator Parameters+ X X X X X X X X X X
PAC/CVC Parameters X X X X X X X X    
Blood Tests:                    
   Electrolytes X A A X A A A X    
  BUN/Creatinine¥ X A A X A A A X X X
  Glucose, Albumin, T.Pro X X A X A X A X    
  WBC, Platelets X                  
  Hgb X X X X X X X X    
  HCG (F) X                  
Blood Gas:                    
  Arterial X A A X A A A X    
  Mixed Venous X A A A A A A A    
  Central X A A A A A A A    
Urinary output (24 hr) X X X X X X X X    
Medications:                    
  Vasopressors X X X X X X X X    
  Inotropes X X X X X X X X    
  Diuretics X X X X X X X X    
Fluid Therapy* X X X X X X X X    
I/O (24 hrs) X X X X X X X X    
PAC/CVC
Complications§
X X X X X X X X    
Glasgow Coma Score++ X             X    
Chest X-ray X A A A A A A A    
Diagnostic Tests¤ A A A A A A A A    
Experimental Treatments X X X X X X X X    
Specimen Collection X X   X       X    
Study Completion                   X

+ Vent parameters: Daily until patient achieves 2 consecutive days of unassisted breathing
* Fluid therapy: Blood products, colloids, crystalloid
§ PAC/CVC complications: (pneumothorax, arrhythmias, catheter associated bloodstream infections) will be recorded up to 3 days after PAC or CVC removed to day 10 whichever is sooner.
¤ Diagnostic tests: performed to assess hemodynamic status (e.g., cardiac echocardiogram)
X = required by the protocol
A = record if available
¥ indicate if renal replacement therapy being used
++ and collected at hospital discharge.


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    13. Iberti TJ, Fischer EP, Leibowitz AB, et al. A multicenter study of physician=s knowledge of the pulmonary artery catheter. JAMA 1990; 264:2928-2932.SIS-4. A randomized factorial trial assessing early oral captopril, oral monomitrate, and intravenous magnesium sulfate in 58, 050 patients with suspected acute myocardial infarction. Lancet 1995; 345:669-685.

    14. Tobin MJ. Principles and practice of intensive care monitoring. McGraw Hill, 1998.

    15. Boyd O. To the Editor. JAMA 1997; 277:110.

    16. Task Force on Guidelines for Pulmonary Artery Catheterization. Practice guidelines for pulmonary artery catheterization. Anesthesiology 1993; 78:380-384.

    17. Shah KB, Rao TLK, Laughlin S, El-Etr AA. A review of pulmonary artery catheterization in 6,245 patients. Anesthesiology 1984; 61:271-275.

    18. Connors AF Jr., Castele FJ, Farhat NZ, Tomashefski JF Jr. Complications of right heart catheterization. A prospective autopsy study. Chest 1985; 88:567-572.

    19. Mermel LA, McCormick RD, Springman SR, Maki DG. The pathogenesis and epidemiology of catheter-related infection with pulmonary artery Swan-Ganz catheters: a prospective study utilizing molecular subtyping. Am J Med 1991; 91(Suppl 3B):197S-205S.

    20. Pulmonary Artery Catheter Consensus Conference Participants. Pulmonary artery catheter consensus conference: consensus statement. Crit Care Med 1997; 25:910-925.

    21. Beale RJ, Wyncoll D, McLuckie A. To the Editor. JAMA 1997; 277:110.

    22. Naylor CD, Sibbald WJ, Sprung CL, et al. Pulmonary artery catheterization. Can there be an integrated strategy for guideline development and research promotion? JAMA 1993; 269:2407-2411.

    23. Tuman KJ, McCarthy RJ, Spiess BD, et al. Effect of pulmonary artery catheterization on outcome in patients undergoing coronary artery surgery. Anesthesiology 1989; 70:199-206.

    24. Matthay MA, Broaddus VC. Fluid and hemodynamic management in acute lung injury. Seminars in Respiratory and Critical Care Medicine 1994, 15:271-288.

    25. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis 1992; 145:990-998.

    26. Humphrey H, Hall J, Sznajder I, Silverstein M, Wood L. Improved survival in ARDS patients associated with a reduction in pulmonary capillary wedge pressure. Chest 1990; 97:1176-1180.

    27. Matthay MA, Chatterjee K. Bedside catheterization of the pulmonary artery: risks compared with benefits. Annals of Internal Medicine 1988, 109:826-834.

    28. Dalen JE, Bone RC. Is it time to pull the pulmonary artery catheter? JAMA 1996; 276:916-918.

    29. West JB, Mathieu-Costello O: Stress failure of pulmonary capillaries. In Crystal RG, West JB, et al (eds): The Lung: Philadelphia, Lippincott-Raven, 1997, 1493-1501.

    30. Tuman KJ, Rozien MF. Outcome assessment and pulmonary artery catheterization: why does the debate continue? Anesth Analg 1997; 84:1-4.

    31. Hughes MD. Stopping guidelines for clinical trials with multiple treatments. Statistics in Medicine 1993; 12(10):901-915.

    32. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35:549-556.

    33. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 1997; 64:191-200.


Appendix I


Appendix I

Composite Protocol
Intravascular Pressure MAP
< 60 mm Hg
Consider
correctable causes
of shock first.
MAP Greater Than or Equal To 60 mm Hg
CVP PAOP G Avg. 4 hour UOP < 0.5 ml/kg/hr Avg. 4 hr UOP Greater Than or Equal to 0.5 ml/kg/hr
Conserv-
ative
Liberal Conserv-
ative
Liberal Ineffective
Circulation

C.I < 2.5
OR
Cold & mottled
with capillary refill
> 2 sec
Effective
Circulation

C.I Greater Than or Equal to 2.5
OR
Not cold & mottled or capillary refill
Less Than or Equal to 2 sec
Ineffective
Circulation

C.I < 2.5
OR
Cold & mottled
with capillary refill
> 2 sec
Effective
Circulation

C.I Greater Than or Equal to 2.5
OR
Not cold & mottled
or capillary refill
Less Than or Equal to 2 sec
Range I                 1



Fluid bolus F
Vasopressor F
KVO IV E          3
Dobutamine
A
Furosemide B
KVO IV E         7
Furosemide
B
KVO IV E        11
Dobutamine
A
Furosemide B
KVO IV E         15
Furosemide B
> 13 > 18 > 18 > 24
Range II KVO IV           4
Dobutamine
A
KVO IV            8
Furosemide
B
KVO IV          12
Dobutamine
A
KVO IV             16
Furosemide
B
9-13 15-18 13-18 19-24
Range III                 2



Fluid bolus
F
Vasopressor F
Fluid bolus C     5 Fluid bolus C      9 Fluid bolus C    13 Liberal:
KVO IV E
4-8 10-14 8-12 14-18 Conservative:
Furosemide B
Range IV Fluid bolus C      6 Fluid bolus C    10 Fluid bolus C    14 Liberal:
Fluid bolus
D       19
< 4 < 10 < 8 < 14 Conservative:
KVO IV E           20


FOOTNOTES

  1. Dobutamine:

  2. Furosemide:

  3. Fluid Bolus (Non-shock, except cell #19):

  4. Fluid Bolus (Non-shock, cell #19 only)

    IF CI < 4.5 AND P/F > 75 AND urine output <2.0 ml/kg/hr:

  5. KVO IV:

  6. Choice of either fluid bolus and/or vasopressor therapy (in any order) as follows:

    Fluid Bolus (Shock):

    Vasopressor Therapy:

    Choice of any single agent or any combination of the following:

  7. Invalid PAOP


Appendix II

Ventilator Procedures

  1. Volume Cycled Ventilation

    1.1 Ventilator mode: Volume cycled assist control

    1.2 Tidal Volume and Ventilator Rate Adjustments and Arterial pH Management.

    1. Initial Ventilator Tidal Volume and Rate.

      Tidal Volume
      (In the following procedures, the term "tidal volume " refers to inspired volumes, corrected for gas compression in the ventilator conduits.)

      Initial tidal volumes will be set at 8 ml/kg predicted body weight (PBW). This will be reduced by 1 ml/kg PBW at intervals of less than or equal to 2 hours until tidal volume = 6 ml/kg PBW.

      Predicted weight is calculated from age, gender and height (heal to crown) according to the following equations:

      Males: PBW (kg) = 50 + 2.3 (height (inches) - 60).
      Females: PBW (kg) = 45.5 + 2.3 (height (inches) - 60).

      Ventilator Rate
      Initial ventilator rate will be set to match minute ventilation prior to enrollment, if possible. Maximum rate = 35/min.

    2. Adjustments to Ventilator Tidal Volume and Rate.

      Goals: Ventilator rate and tidal volume will be adjusted to achieve specific goals of arterial pH and end-inspiratory alveolar (plateau) pressure, respectively.

      Arterial pH Goals

      • Arterial pH Goal: 7.30 less than or equal to pH less than or equal to 7.45.
      • Arterial pH will be measured when clinically indicated.
      • Management of alkalemia and acidemia may be according to the following rules:
        1. Alkalemia (pH > 7.45): Decrease ventilator rate, if possible.
        2. Mild acidemia (7.15 less than or equal to pH < 7.30):
          • Increase ventilator rate up to maximum of 35 or until pH > 7.30 or PaCO2 < 25 mm Hg.
          • If ventilator rate = 35 or PaCO2 < 25, then bicarbonate infusion may be given.
        3. Severe acidemia (pH < 7.15):
          • Increase ventilator rate to 35.
          • If ventilator rate = 35 and pH < 7.15 and bicarbonate has been considered or infused, then tidal volume may be increased by 1 ml/kg until pH greater than or equal to 7.15 (under these conditions, the plateau pressure targets described below may be exceeded).

    Plateau Pressure Goal: less than or equal to 30 cm H2O

    • Plateau pressures will be measured at a minimum frequency of q4 hours. Plateau pressures will also be measured and recorded 1-5 minutes after each change in PEEP or tidal volume. For each measurement, patients will be relaxed, not coughing or moving. The pressure corresponding to the first plateau that occurs after initiating a 0.5 second pause will be recorded. The pause will be removed for at least 6 breaths. The plateau pressure measurements will be replicated 3 times with at least 6 "non-plateau" breaths between measurements and the mean of the three values will be calculated. If plateau pressures cannot be measured because of air leaks, then peak inspiratory pressure will be substituted.

    • Tidal volumes will be reduced (if arterial pH > 7.15, see section 2b above) by 1 ml/kg q2-3 hours if necessary to maintain plateau pressures less than or equal to the respective target value.

    • The minimum tidal volume will be 4 ml/kg PBW.

    • Changes in the tidal volume, if indicated above, will be made within five minutes. Tidal volumes will be increased in both groups if plateau pressure << target:
      1. If tidal volume < 6 ml/kg and plateau pressure less than or equal to 25 cm H2O, then tidal volume will be increased by 1 ml/kg until plateau pressure greater than or equal to 25 or tidal volume = 6 ml/kg PBW.

      2. If tidal volume < 8 ml/kg AND Pplat < 30 cm H2O AND airway pressure remains below the PEEP level during inspiration or the ventilator frequent (greater than or equal to 3/minute) double breaths because airway pressure falls below trigger threshold at the end of inspiration, then tidal volume will be increased by 1 ml/kg. If these phenomena persist at tidal volume = 8 ml/kg or with Pplat greater than or equal to 30 cm H2O, then additional sedation or neuromuscular blockade should be considered.

1.3 Inspiratory flow and I:E ratio.

Inspiratory flow rate will be adjusted to maintain the I:E ratio = 1:1.0-1:3.0.

1.4 Oxygenation.

The target range for oxygenation will be:

55 mmHg less than or equal to PaO2 less than or equal to 80 mm Hg
or
88% less than or equal to SpO2 - sat less than or equal to 95%

When both PaO2 and SpO2 are available simultaneously, the PaO2 criterion will take precedence.

Oxygenation will be maintained in the target ranges using the following PEEP/FiO2 combinations: (see table below)

FiO2 .30 .40 .40 .50 .50 .60 .70 .70 .70 .80 .90 .90 .90 1.0 1.0
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18 20-24

    Levels of PEEP in this scale represent levels set on the ventilator, not levels of total PEEP, auto-PEEP, or intrinsic PEEP.

    Arterial oxygenation will be assessed by either SpO2 or PaO2 at a minimum frequency of q4 hours. When SpO2 is used to assess arterial oxygenation, the following measures will be taken if possible to improve accuracy: the SpO2 sensor will be checked to ensure optimal position, cleanliness, and consistent readings with satisfactory waveforms; no position changes or endobronchial suctioning for greater than or equal to 10 minutes; no invasive procedures or ventilator changes for greater than or equal to 30 minutes. SpO2 will be observed for a minimum of 1 minute, and a representative value will be recorded on the appropriate source-document flowsheet.

    If arterial oxygenation is not within the target range, then FiO2 or PEEP will be adjusted within 30 minutes. Following these adjustments, oxygenation will be reassessed within 15 minutes and subsequent adjustments made if necessary.

    If a patient's PEEP/FiO2 is not compatible with the PEEP/FiO2 scale (e.g. immediately after enrollment or after urgent changes in FiO2 or PEEP in response to desaturations, hypotension, etc.), either PEEP or FiO2 (or both) will be adjusted at intervals of 5-15 minutes until the PEEP/FiO2 is compatible with the scale. The procedures for adjusting PEEP and FiO2 to make them compatible with the scale are as follows:

    1.5 Simultaneous changes

    Changes in more than one ventilator setting driven by measurements of PO2, pH, and plateau pressure may be performed simultaneously, if necessary. Arterial blood gases will be obtained after all ventilator changes as clinically indicated.

  1. Weaning
    2.1 Commencement of Weaning.

    Patients will be assessed for the following criteria each day between 0600 and 1000. If a patient procedure, test, or other extenuating circumstance prevents assessment for these criteria between 0600 and 1000, then the assessment and initiation of subsequent weaning procedures may be delayed for up to four hours.

    1. Greater than or equal to 12 hours since initial protocol ventilator changes, if any.

    2. FiO2 less than or equal to .40.

    3. Values of both PEEP and FiO2 less than or equal to values from previous day (comparing Reference Measurement values, section 6.3).

    4. Not receiving neuromuscular blocking agents and without neuromuscular blockade.

    5. Patient exhibiting inspiratory efforts. Ventilator rate will be decreased to 50% of baseline level for up to 5 minutes to detect inspiratory efforts if no efforts are evident at baseline ventilator rate.

    6. Systolic arterial pressure greater than or equal to 90 mm Hg without vasopressor support (less than or equal to 5 mcg/kg/min dopamine or dobutamine or equivalent low dose of another vasopressor will not be considered a vasopressor).

    If criteria 1-6 are met, weaning potential will be assessed during a CPAP trial of less than or equal to 5 minutes at CPAP = 5 cm H2O and FiO2 = .50. If rate remains less than or equal to 35/min during the 5-minute CPAP trial, the patient will have met the commencement of weaning criteria and will enter the Pressure Support Wean Procedure (Section 2). If respiratory rate exceeds 35/min during the 5-minute CPAP trial, the patient will resume A/C ventilation at the most recent settings. The patient will be reassessed for weaning the following day at 0600-1000. (If failure to maintain the respiratory rate less than or equal to 35 during the CPAP trial is attributed primarily to anxiety, then appropriate treatment for anxiety will be given and a second 5-minute CPAP trial initiated within 4 hours).

    2.2 Initial Pressure Support (PS) Setting (for patients whose respiratory rates remain less than or equal to 35/min during 5-minute CPAP trial).

    1. Mode = Pressure Support. Only the following PS levels may be used: 5, 10, 15, and 20 cm H2O.

    2. If respiratory rate less than or equal to 25 during the 5-minute CPAP trial and tolerance criteria (section 3, below) are met then initiate PS = 5 cm H2O. If respiratory rate = 26-35 during the 5-minute CPAP trial then set initial PS = 20 cm H2O and make adjustments in PS within 5 minutes if necessary to achieve respiratory rate = 26-35.

    3. PEEP = 5 cm H2O.

    4. FiO2 = .50.

    2.3 Assessment for Tolerance.

    Patients will be assessed for tolerance using the following criteria:

    1. Total respiratory rate < 35 (less than or equal to 5 min at respiratory rate > 35 may be tolerated).

    2. SpO2 88% (< 15 min at < 88% may be tolerated).

    3. No respiratory distress (two or more of the following):

      1. Heart rate > 120% of the 0600 rate(less than or equal to 5 min at > 120% may be tolerated).
      2. Marked use of accessory muscles.
      3. Abdominal paradox.
      4. Diaphoresis.
      5. Marked subjective dyspnea.

      If any of goals a, b, or c are not met on initial set-up to PS, then the ventilator mode will be changed back to A/C at back-up rate = to most recent A/C settings and the patient will be reassessed the next morning.

    2.4 Subsequent Ventilator Settings.

    1. Reduce PS level by 5 cm H2O q1-3 hours. PS will not be decreased below 5 cm H2O. No decreases in PS will be made after 1900.

    2. If PS = 10, 15 or 20 cm H2O is not tolerated, then return to A/C (patient will remain in previously assigned 12 ml/kg or 6 ml/kg treatment group).

      1. At 0600-1000 of the next day, return to last PS level tolerated and continue with step 1.

    3. If PS level = 5 cm H2O is not tolerated, increase PS by 5 cm H2O to 10 cm H2O, and maintain until the following morning.

      1. If a patient on PS = 5 or 10 must go back to A/C for reasons other than intolerance to weaning (e.g. surgical or other invasive procedures), the weaning sequence will be re-entered with section 2.1.

    4. If PS = 5 cm H2O is tolerated for two or more hours (using tolerance criteria 1-3 in section 2.3 above), assess for ability to sustain unassisted breathing (section 2.5 below).

    2.5 Assess for Ability to Sustain Unassisted Breathing.

    Initiate a trial of spontaneous breathing on CPAP less than or equal to 5 cm H2O, T-piece, or tracheostomy mask with FiO2 less than or equal to .50. Monitor for the following:

    1. SpO2 greater than or equal to 90% and/or PaO2 greater than or equal to 60 mmHg.
    2. Spontaneous tidal volume greater than or equal to 4 ml/kg ideal body weight.
    3. Respiratory Rate less than or equal to 35/min.
    4. pH greater than or equal to 7.30 if measured.
    5. No respiratory distress (2 or more of the following):
      1. Heart rate > 120% of the 0600 rate ( 5 min at > 120% may be tolerated).
      2. Marked use of accessory muscles.
      3. Abdominal paradox
      4. Diaphoresis.
      5. Marked subjective dyspnea.

      If criteria 1-5 are met for > 120 minutes, continue with unassisted breathing (2.6). If any of criteria 1-5 are not met during the 120 minute trial, then resume PS ventilation at 5 cm H2O and assess for tolerance (step 2.3).

    2.6 Definition of Unassisted Breathing.

    1. Extubated with face mask, nasal prong oxygen, or room air, OR
    2. T-tube breathing, OR
    3. Tracheostomy mask breathing, OR
    4. CPAP less than or equal to 5 without PS or IMV assistance.

  2. Completion of Ventilator Procedures

    Patients will be considered to have completed the study ventilator procedures if any of the following conditions occur:

    1. Death.
    2. Hospital discharge.
    3. Alive 28 days after enrollment.

    If a patient requires positive pressure ventilation after a period of unassisted breathing, the study ventilator procedures will resume unless the patient was discharged from the hospital or > 28 days elapsed since enrollment.

  3. Premature Withdrawal from Treatment

    Patients may be removed from the 6 ml/kg tidal volume ventilation protocol if they develop neurologic conditions where hypercapnia would be contraindicated (e.g., intracranial bleeding, GCS less than or equal to 8, cerebral edema, mass effect [midline shift on CT scan], papilledema, intracranial pressure monitoring, fixed pupils).


Appendix III

  1. Procedures for Reporting Adverse Events

    Assuring patient safety is an essential component of this protocol. Each participating investigator has primary responsibility for the safety of the individual participants under his or her care. All adverse events will be evaluated by the Principal Investigator. The Study Coordinator must view patient records for possible adverse events throughout the study period. All adverse events occurring within the study period must be reported in the participants' case report forms.

    The investigator will report all serious, unexpected, and study-related adverse events to the Clinical Coordinating Center within 24 hours. The Institutional Review Board must also be informed in a timely manner. The investigator will then submit a detailed written report to the Clinical Coordinating Center and the Institutional Review Board no later than 5 days after the investigator discovers the event.

  2. Definitions of Adverse Events

    A serious adverse event is any event that is fatal or immediately life threatening, is permanently disabling, or severely incapacitating, or requires or prolongs inpatient hospitalization. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgement, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed above.

    Life-threatening means that the patient was, in the view of the investigator, at immediate risk of death from the reaction as it occurred. It does not include the reaction that, had it occurred in a more serious form, might have caused death. Assessment of the cause of the event has no bearing on the assessment of the event's severity.

    An unexpected event is any experience not identified by type, severity, or frequency in the current study protocol or an event that occurred unexpectedly in the course of treatment for Acute Lung Injury or ARDS.

    Adverse events will be considered to be study-related the event follows a reasonable temporal sequence from a study procedure and could readily have been produced by the study procedure.

    Organ failures related to ARDS or a patient's underlying condition should not be reported as adverse events since they are systemically captured by the protocol data collection.


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