Gravity VAP trial

Document Sample
Gravity VAP trial Powered By Docstoc
					  Prospective, Randomized, Multi-Center Trial of
               Lateral Trendelenburg
                       Versus
         Semi-Recumbent Body Position
       in Mechanically Ventilated Patients
                        For
The Prevention of Ventilator-Associated Pneumonia

             Designed by the Gravity-VAP Network
        Prospective, Randomized, Multi-Center Trial of
      Lateral Trendelenburg versus Semi-Recumbent Body
          Position in Mechanically Ventilated Patients
                              For
      The Prevention of Ventilator-Associated Pneumonia
                                   (The Gravity-VAP Trial)

                             Designed by the Gravity-VAP Network

Date: Tuesday, November 02, 2010

Protocol Title: Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg versus
Semirecumbent Position Body Position in Intubated Patients and Ventilator-Associated Pneumonia

Abbreviated Title: The Gravity-VAP Trial.

Identifying words: Ventilator-Associated Pneumonia, Semirecumbent Position, Trendelenburg

Investigators of the American-Italian-Spanish Gravity-VAP network (sorted by last name):

                                      Lorenzo Berra, MD
                                     Massimo Cressoni, MD
                                     Gianluigi Li Bassi, MD
                                      Mauro Panigada, MD
                                      Alberto Zanella, MD

                                      Luciano Gattinoni, MD
                                      Theodor Kolobow, MD
                                       Antonio Pesenti, MD
                                        Antoni Torres, MD
                                   Jeanine Wiener-Kronish, MD




                                                                                            1
Gravity-VAP trial - NCT01138540
Version 1.4.0
Associate Investigators:

    1. Mariano Esperatti, MD

Statistical Analysis:

   1. Dario Consonni
   2. Laura Angelici

Research Contact:
Gianluigi Li Bassi, MD                                           Mauro Panigada, MD

Servei de Pneumologia i Al•lèrgia Respiratòria Hospital Clínic   U.O. Anestesia e Rianimazione Fondazione IRCCS Ospedale
170 Villarroel street, 6/8 2nd floor                             Maggiore Policlinico Mangiagalli e Regina Elena di Milano
08036 Barcelona SPAIN                                            Padiglione Guardia-Accettazione/PS Via F. Sforza 35
Voice/Fax: 0034 932275549                                        20122 Milano
Email: glibassi@clinic.ub.es                                     Voic/Fax: +39 (02) 55033230
Web: www.idibapsrespiratoryresearch.org                          Email: panigadam@gmail.com


Duration of Study: Three years

Number and Type of Subjects:                    Intubated and mechanically ventilated, sedated critical care
patients

Multi-Institutional Project: Yes




                                                                                                                             2
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                      SUMMARY

Précis......................................................................................................................................................... 5
1 Background ............................................................................................................................................ 7
   1.1 Pathogenesis of ventilator-associated pneumonia and rationale for the semi-recumbent position 7
   1.2 VAP and attributable mortality....................................................................................................... 9
   1.3 Economic impact of VAP ............................................................................................................... 9
    1.4 Published human studies on the role of the stomach in the pathogenesis of ventilator-associated
   pneumonia and the semi recumbent position...................................................................................... 11
     1.4a Role of the stomach as a reservoir of pathogenic bacteria:..................................................... 12
     1.4b Role of the oropharynx as a reservoir of pathogenic bacteria: ............................................... 27
     1.4c Efficacy of the semi recumbent position in VAP prevention: ................................................ 28
      1.4d Efficacy of the semi recumbent position in preventing gastric reflux and aspiration of gastric
     content:............................................................................................................................................ 30
     1.4e Efficacy of the semi recumbent position to prevent aspiration of oropharyngeal secretions: 32
     1.4f Feasibility of the semi recumbent position:............................................................................. 32
     1.4g Summary of the role of the semirecumbent position in prevention of VAP: ......................... 33
      1.5 Laboratory animal studies conducted at the National Institutes of Health to assess effects of
   gravity in the pathogenesis of ventilator associated pneumonia......................................................... 34
     1.5a Summary of results from laboratory studies conducted at the National Institutes of Health . 39
2 Rationale of the study .......................................................................................................................... 40
3 Objectives ............................................................................................................................................ 42
4 Study Design ........................................................................................................................................ 42
  4.1 End points ..................................................................................................................................... 42
     Primary end point............................................................................................................................ 42
     Secondary end points ...................................................................................................................... 42
5 Subject Accrual .................................................................................................................................... 44
   5.1 Screening and Research Centers................................................................................................... 44
   5.2 Inclusion Criteria .......................................................................................................................... 44
   5.3 Exclusion Criteria ......................................................................................................................... 44
6 Study procedures.................................................................................................................................. 46
   6.1 Body Positions .............................................................................................................................. 46
     6.1a Semi-recumbent position: ....................................................................................................... 46
     6.1b Lateral Trendelenburg position:.............................................................................................. 46
   6.2 Preventive strategies ..................................................................................................................... 47
   6.3 Respiratory gases humidification.................................................................................................. 47
   6.4 Enteral Nutrition ........................................................................................................................... 47
   6.5 Weaning protocol.......................................................................................................................... 47
   6.6 Ventilator-associated pneumonia diagnosis.................................................................................. 50
   6.7 Data Collection ............................................................................................................................. 50
     6.7a Assessments during enrollment (Appendix C, Baseline Assessment):................................... 50
     6.7b Daily assessments during the study (Appendix C, Daily Assessment) up to 14 days:........... 51
                                                                                                                                                                3
Gravity-VAP trial - NCT01138540
Version 1.4.0
   6.8 Special Clinical and Laboratory Methods (include sample storage) ............................................ 54
     6.8a Bronchoalveolar Lavage ......................................................................................................... 54
     6.8b Blind Bronchoalveolar lavage................................................................................................. 54
     6.8c Nursing evaluation .................................................................................................................. 54
7. Monitoring of Subjects and Criteria for Withdrawal of Subjects ....................................................... 55
   7.1 Stopping Rules .............................................................................................................................. 55
     7.1a Exit criteria:............................................................................................................................. 55
     7.1b Tracheostomy: ........................................................................................................................ 55
     7.1c Follow up: ............................................................................................................................... 56
   8.1 Sample size ................................................................................................................................... 57
   8.2 Randomization .............................................................................................................................. 57
   8.3 Interim analysis............................................................................................................................. 58
   8.4 Statistical analyses ........................................................................................................................ 58
9. Human Subjects Protection................................................................................................................. 59
   9.2 Evaluation of Benefits of the lateral-Trendelenburg position ...................................................... 59
   9.3 Risk assessment of the lateral-Trendelenburg position ................................................................ 59
10. Conflict of Interests........................................................................................................................... 60
11. Adverse events reporting .................................................................................................................. 60
12. Data collection and Site Monitoring plan ......................................................................................... 61
   12.1 Data Collection ........................................................................................................................... 61
   12.1 Site Monitoring ........................................................................................................................... 62
13. Compensations .................................................................................................................................. 62
14. References......................................................................................................................................... 63
APPENDIX A: Laboratory animal studies conducted at the National Institutes of Health to assess
effects of gravity in the pathogenesis of ventilator associated pneumonia............................................. 78
APPENDIX B ......................................................................................................................................... 84
   Figure 1 Lateral-Trendelenburg position............................................................................................ 84
   Figure 2 Lateral-Trendelenburg position............................................................................................ 85
   Figure 3 Semi-Recumbent Position .................................................................................................... 87
APPENDIX C: Data Collection Forms................................................................................................... 88
   BASELINE ..........................................................................................Error! Bookmark not defined.
   DAILY ASSESSMENT ......................................................................Error! Bookmark not defined.
   FINAL EVALUATION.......................................................................Error! Bookmark not defined.
APPENDIX D....................................................................................................................................... 110
   Richmond Agitation Sedation Scale (RASS) * ................................................................................ 110
APPENDIX E: CONSENT FORMS .................................................................................................... 112




                                                                                                                                                        4
Gravity-VAP trial - NCT01138540
Version 1.4.0
Précis
Title: Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg versus Semi-Recumbent
Body Position in Mechanically Ventilated Patients For The Prevention of Ventilator-Associated
Pneumonia
Abbreviated Title: Gravity-VAP trial
Objectives: This study is planned to compare, in patients sedated, intubated and mechanically
ventilated, the efficacy and safety of the Lateral Trendelenburg position in comparison to the
Semirecumbent Position to prevent incidence of ventilator-associated pneumonia.
Study Design: Multicenter, randomized, controlled clinical trial. The enrollment will last
approximately 30 months. The analysis will last approximately 6 months. The entire duration of the
study will be 36 months. The semirecumbent position and the lateral-Trendelenburg position will be
recommended until patient is extubated.
Sample size/Interim Monitoring: This study will enroll a maximum of 800 patients. An interim
analysis will be performed after 40 patients, mainly to assess feasibility and after 400 patients to
determine stop of the study for futility, lack of safety, or proven efficacy
Inclusion Criteria:
   1. Age ≥ 18 years
   2. Patients expected to be oro-tracheally intubated for at least 48 hours or longer
   3. Enrollment time window within 6 hours following intubation
Exclusion Criteria:
   1. Current and past participation in an other intervention trial conflicting with the present study
   2. Previous endotracheal intubation longer than 12 hours during the previous 30 days
   3. Patients with documented bronchiectasis
   4. Cystic fibrosis
   5. Witnessed pulmonary aspiration either prior or at intubation
   6. Patients with increased intracranial pressure, brain edema; or medical conditions that can
       worsen with increase in intracranial pressure
   7. Patients with significant heart failure and activity impairment (Class III-IV of the New York
                                                                                                         5
Gravity-VAP trial - NCT01138540
Version 1.4.0
       Heart Association (NYHA)
   8. Spinal cord injury
   9. BMI > 35, or weight above 300 pound
   10. Grade IV: Intra-abdominal pressure (IAP) > 25 mmHg or abdominal compartment syndrome
       (ACS), defined as a sustained IAP > 20 mmHg that is associated with new organ dysfunction /
       failure
   11. Pregnancy
   12. Orthopedic problems that will not allow the patient to be kept in one of the study positions

Efficacy:
Primary endpoint
       The primary endpoint will be incidence of ventilator-associated pneumonia within the first 14
days of intubation, confirmed by quantitative microbiology analysis of either bronchoalveolar lavage
(BAL) or mini-BAL fluids or secretions collected through protected specimen brush (PSB).
Secondary endpoints
   1. Duration of mechanical ventilation
   2. Duration of intensive care unit stay
   3. Duration of hospital stay
   4. Safety of the Semi-Recumbent and Lateral-Trendelenburg position
   5. Use of Sedatives
   6. Use of Antimicrobials
   7. ICU mortality
   8. Hospital mortality
   9. 28 Days mortality
   10. Assessment of nursing-related issues in the lateral-Trendelenburg position




                                                                                                      6
Gravity-VAP trial - NCT01138540
Version 1.4.0
Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg Body
Position versus Semirecumbent Position in Sedated, Intubated and
Mechanically Ventilated Patients for the Prevention of Ventilator-Associated
Pneumonia

1 Background

1.1 Pathogenesis of ventilator-associated pneumonia and rationale for
     the semi-recumbent position

       Ventilator-associated pneumonia (VAP) is a hospital-acquired pneumonia that develops in
patients receiving mechanical ventilation. VAP is the most common nosocomial infection in patients
requiring mechanical ventilation1, and is associated with prolonged hospitalization, increase in health
care costs and 20%-70% mortality2, particularly when caused by multi-drug resistant bacteria.

       In healthy, non intubated patients, when bacteria gain access into the lower respiratory tract,
colonization is prevented through several defense mechanisms such as cough, mucus clearance and
cellular/humoral immune responses. Critical ill patients are already at high risk of infection for the
underlying critical illness, comorbidities and malnutrition. However, the tracheal tube is the condicio
sine qua non for ventilator-associated pneumonia, because it creates a direct conduit for bacteria to
reach the airways, impairs cough, compromises mucociliary clearance3 and bacterial adhesion to the
airways is facilitated via the cuff-related injury to the tracheal mucosa4. There is still controversy in
regard of the primary source of infection; however, the role of the stomach in the pathogenesis of VAP
has been emphasized. Indeed, the stomach of critically ill patients early becomes colonized with gram-
negative bacteria5;6. Under fasting conditions, gastric sterility is maintained through an acidic pH. In
critically ill patients, use of antacids for stress ulcer prophylaxis and enteral nutrition alkalinize gastric
contents and facilitate bacterial colonization of the stomach6;7. Early reports, using radio-labeled
markers have shown that tracheally intubated patients are at risk of aspiration particularly when are
                                                                                                            7
Gravity-VAP trial - NCT01138540
Version 1.4.0
positioned supine and naso-gastric feeding tube is placed8;9. Conversely, when patients are positioned
supine with the head of the bed elevated 30-45 degrees above horizontal gastro-esophageal reflux is
reduced9. Bacteria aspirated from the stomach into the oropharynx overgrow the normal oropharyngeal
flora; then, leakage across the endotracheal tube (ETT) cuff facilitates bacterial translocation into the
lower airways and leads to lung infection. Indeed, high volume low pressure cuffs of ETTs, commonly
used during prolonged mechanical ventilation, are not leak-proof10 and micro and macro aspiration of
bacteria-laden oropharyngeal secretions often occurs. Following bacterial aspiration and colonization
of the proximal airways, the occurrence of VAP mainly depends on the size of the inoculum, functional
status and defenses of the host. Theoretically, the first hours after the admission into the intensive care
unit are at highest risk for aspiration of colonized oropharyngeal contents since patients are often
deeply sedated and cough reflexes are highly impaired.

       Due to the high morbidity and mortality associated with VAP, and the burden for the healthcare
systems, many efforts have been done in the last decades in order to prevent the disease. Accordingly,
preventive strategies have focused on reducing/avoiding cross transmission, pulmonary aspiration
across the cuff and bacterial load in the oropharynx. Indeed, most of the ETTs used in the ICU
comprise a high volume, low pressure (HVLP) cuffs. The internal volume of standard HVLP cuffs can
exceed by even 40% the internal diameter of the trachea; therefore, when inflated, HVLP cuffs seal the
trachea without being stretched and their internal pressure closely reflects pressure exerted against the
tracheal wall. Nevertheless, longitudinal folds invariably form, hence bacteria-laden oro-pharyngeal
secretions easily leak along these folds, increasing risks for airways infection and pneumonia. Cuffs
made of new materials, i.e. polyurethane, have been developed. Those cuffs during inflation, form
smaller folds and can prevent or highly reduce aspiration of secretions above the cuff11. Reduction of
leakage of oropharyngeal contents across the ETT cuff has been also obtained via a novel endotracheal
tube, which allows continuous aspiration of sub-glottic secretions (CASS Tube). Such strategy has
significantly reduced the incidence of pneumonia, particularly early-onset VAP12.

       Despite those efforts to improve the design of the ETT, most preventive strategies, such as
selective digestive decontamination and semi-recumbent position have generally focused on the theory
that the stomach plays a primary role in the pathogenesis of VAP. The “gastro-pulmonary hypothesis”

                                                                                                         8
Gravity-VAP trial - NCT01138540
Version 1.4.0
emphasizes the role of the stomach in the pathogenesis of VAP and has lead to position patients in the
semirecumbent position. A multivariate analysis of risk factors for VAP13 and a randomized clinical
trial14 have confirmed efficacy of the semi-recumbent position in preventing incidence of VAP.
However, several studies have also questioned whether the gastro-pulmonary route of colonization is
important in the development of nosocomial pneumonia15-18. These studies clearly demonstrated that
gastric acidity influences bacteria colonization of the stomach but not colonization of the upper
respiratory tract or incidence of VAP. Therefore, different sources of lung colonization should also be
considered, particularly the oropharynx. Investigators have clearly demonstrated that the
semirecumbent position is beneficial in preventing gastro-esophageal reflux and bacterial colonization
of the oropharynx14. However, semirecumbent position increases hydrostatic pressure exerted above
the ETT cuff by oropharyngeal secretions, and could be deleterious in patients with oropharyngeal
colonization at admission or at any time during the intensive care stay. Although the role of the
stomach in the pathogenesis of VAP is still under discussion, currently several guidelines recommend
to position all intubated patients with the head elevated 30-45 degrees19-21 (semirecumbent position) to
decrease aspiration of gastric content and colonization of the upper aerodigestive tract by pathogens
from the stomach, irrespective of the patient’s oropharyngeal colonization.


1.2 VAP and attributable mortality

       Crude VAP mortality ranges between 20 to 70 %, depending on comorbidities, severity of
illness, pathogens and quality of antibiotic treatment2. Although mortality rates greatly differ between
studies, it is well recognized that one third to one half of all VAP deaths are directly attributable to the
disease. Late-onset VAP, in comparison to early-onset, has the worst prognosis. Particularly, mortality
can be as high as 65% when VAP is caused by multi-drug resistant pathogens, i.e. Pseudomonas
aeruginosa, Acinetobacter spp. Stenotrophomonas maltophilia22.


1.3 Economic impact of VAP

       Patients who develop VAP during their hospital stay present longer ICU and hospital length of
stay, moreover the increased level of care and need for additional invasive procedures drastically

                                                                                                          9
Gravity-VAP trial - NCT01138540
Version 1.4.0
increase healthcare costs. Each case of VAP significantly increases the duration of ICU care and
associated cost of care. Patients with VAP have a significantly longer periods of mechanical ventilation
(14.3 ± 15.5 d vs 4.7 ± 7.0 d), ICU stay (11.7 ± 11.0 d vs. 5.6 ± 6.1 d), and hospital stay (25.5 ± 22.8 d
vs. 14.0 ± 14.6 d)23. VAP is also associated with increase hospital charges, particularly when cause by
multi-drug resistant bacteria ($104,983 ± 91,080 vs. $63,689 ± 75,030 per patient with or without VAP,
respectively) 22.




                                                                                                       10
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4 Published human studies on the role of the stomach in the
    pathogenesis of ventilator-associated pneumonia and the semi
    recumbent position
       In order to evaluate evidence of the semirecumbent position as preventive strategy for VAP, we
performed a MEDLINE search to first assess role of the oropharynx and stomach in the pathogenesis of
VAP. Moreover, studies on efficacy of the semirecumbent position as preventive strategy to reduce
gastro-esophageal reflux and incidence of VAP were also reviewed. Results were limited to human
studies involving adult subjects.




                                                                                                  11
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4a Role of the stomach as a reservoir of pathogenic bacteria:

       There is clear evidence that in intubated and mechanically ventilated patients the stomach is
often colonized. The main risk factor is the alkalinization of gastric contents due to continuous enteral
nutrition and drugs for stress ulcer prophylaxis. Evidence in favor of the role of the stomach in the
development of VAP can be found mainly from randomized, controlled trials of selective gut
decontamination and stress ulcer prophylaxis in the intensive care unit (ICU), in which reducing the
bacterial burden of the stomach decreases the incidence of nosocomial respiratory infections24.
However, as reported in previous paragraphs, it is important to emphasize that gastro-esophageal reflux
is common in mechanically ventilated patients with naso-gastric feeding tube and, theoretically,
selective digestive decontamination may also affect oropharyngeal colonization. Therefore, in order to
better focus on the role of the stomach as a reservoir of pathogenic bacteria for VAP we only evaluated
studies in which effects of gastric alkalinization on gastric colonization, patterns of colonization and
incidence of VAP were assessed (Table 1). Early studies have clearly shown that in tracheally
intubated patients, gastric pH higher than 4 was consistently associated with gastric colonization5;6.
Most randomized studies compared effects of drugs that alkalinize gastric contents (histamine type 2
blockers, proton pomp inhibitors, antacids) vs. sucralfate16;25-31. Two studies compared either H2-
blockers32 or sucralfate33 vs. placebo. Nine studies assessed gastric pH and colonization and authors
consistently found lower pH and gastric colonization with regular use of sucralfate. Conversely, studies
conducted by Bonten et al.16 and Thomason et al.31 found gastric pH higher than 4 and gastric
colonization, irrespective of the use of sucralfate. Finally Eddlestone et al. did not found differences in
gastric colonization when sucralfate was compared to placebo33. Randomized trials found inconsistent
results regarding incidence of VAP, raising doubts on the gastro-pulmonary theory of colonization. In
particular, early studies found higher incidence of pneumonia in patients with alkalinized gastric
contents26;30;34, more recent studies have not found such association16;25;28;31. Importantly, Cook et al
studied 1200 patients randomized to receive either H2 blockers or sucralfate for stress ulcer
prophylaxis. The study has raised several concerns regarding the role of the stomach in the
pathogenesis of VAP. Indeed, the authors found a VAP incidence of 19.1% and 16.2% in patients
treated with H2 blockers or sucralfate, respectively, despite higher gastric pH and risk for gastric
colonization using sucralfate25. To the best of our knowledge, at least 17 observational studies have
                                                                                                   12
Gravity-VAP trial - NCT01138540
Version 1.4.0
investigated role of the stomach in the pathogenesis of VAP5;6;15;16;18;35-46. Results remain highly
controversial and at least ten studies15;16;18;35;37;38;42-44;46 have not found a relationship with bacteria
causing VAP as originating in the stomach.




                                                                                                         13
Gravity-VAP trial - NCT01138540
Version 1.4.0
Table 1: Studies on gastric alkalinization, gastric colonization, patterns of colonization and incidence of VAP in intubated patients
First Author/              Study type    Methods                          Patients                           Outcome
Journal Year
Driks MR26                 Randomized    Patients received as             130 patients given mechanical      Patients in the sucralfate group had a higher
N Engl J Med. 1987                       prophylaxis for stress ulcer     ventilation in an intensive care   proportion of gastric aspirates with a pH less than or
                                         either sucralfate (n = 61),      unit                               equal to 4 and significantly lower concentrations of
                                         conventional treatment with                                         gram-negative bacilli in gastric aspirates, pharyngeal
                                         antacids, histamine type 2                                          swabs, and tracheal aspirates than did patients in the
                                         (H2) blockers, or both (n =                                         antacid-H2-blocker group. The rate of pneumonia was
                                         69).                                                                twice as high in the antacid-H2 group as in the
                                                                                                             sucralfate group. Gram-negative bacilli were isolated
                                                                                                             more frequently from the tracheal aspirates of patients
                                                                                                             with pneumonia who were receiving antacids or H2
                                                                                                             blockers.
Mahul P29                  Randomized    Patients intubated for more      145 patients intubated for         Sucralfate was not associated with a significantly
Intensive Care Med. 1992                 than 3 days were randomly        more than 3 days                   lower incidence of pneumonia (antacids: 23.6%,
                                         assigned to a double                                                sucralfate: 17.8%), but with a lower increase in the
                                         nosocomial pneumonia                                                colonization rate in subglottic and gastric aspirates,
                                         prevention strategy: 1--                                            from admission to end-point day
                                         Prevention of aspiration by
                                         hourly subglottic secretion
                                         drainage (SSD) with a
                                         specific endotracheal tube
                                         (HI-LO Evac tube,
                                         Mallinckrodt); 2--Prevention
                                         of gastric colonization using
                                         either sucralfate or antacids.




                                                                                                                                                                       14
Gravity-VAP trial - NCT01138540
Version 1.4.0
Apte NM32              Randomized   Sixteen patients received iv     34 tracheotomized patients     Mean gastric pH was higher in the ranitidine group
Crit Care Med. 1992                 ranitidine to increase gastric   with tetanus.                  (median 4.7, range 3.6 to 6.1) than in the control
                                    pH greater than 4 (ranitidine                                   group (median 2.1, range 1.2 to 4.9; p less than .05).
                                    group), while 18 patients                                       Gastric colonization occurred in 15 (94%) of 16
                                    received no prophylaxis for                                     patients who received ranitidine, 2 days (median;
                                    upper gastrointestinal                                          range 1 to 5) after intubation; gastric colonization also
                                    bleeding (control group).                                       occurred in all control patients (median 4 days, range
                                                                                                    1 to 9; p less than .05). Pneumonia occurred in 13
                                                                                                    (81%) of 16 patients who received ranitidine, 3 days
                                                                                                    (median, range 1 to 5) after intubation and in nine
                                                                                                    (50%) of 18 control patients (p less than .01) 5 days
                                                                                                    after tracheal intubation (median, range 3 to 14; p less
                                                                                                    than .01). Prior gastric colonization by the pathogen
                                                                                                    that caused pneumonia was demonstrable in nine
                                                                                                    (56%) of 16 patients who received ranitidine vs. eight
                                                                                                    (44%) of 18 control patients (p greater than .05).
                                                                                                    Pharmacologically increasing gastric pH increased the
                                                                                                    risk for developing pneumonia in intubated critically
                                                                                                    ill patients. The pneumonia occurs earlier than in
                                                                                                    untreated control patients
Prod’hom G30           Randomized   At intubation, patients were     244 Medical and surgical ICU   The incidence of early-onset pneumonia was not
Ann Intern Med 1994                 randomly assigned to receive     patients                       statistically different among the three treatment
                                    one of the following: antacid                                   groups (P > 0.2). Among the 213 patients observed
                                    (a suspension of aluminum                                       for more than 4 days, late-onset pneumonia was
                                    hydroxide and magnesium                                         observed in 5% of the patients who received
                                    hydroxide), 20 mL every 2                                       sucralfate compared with 16% and 21% of the
                                    hours; ranitidine, 150 mg as                                    patients who received antacid or ranitidine,
                                    a continuous intravenous                                        respectively (P = 0.022). Patients who received
                                    infusion; or sucralfate, 1 g                                    sucralfate had a lower median gastric pH (P < 0.001)
                                    every 4 hours. The incidence                                    and less frequent gastric colonization compared with
                                    gastric colonization, early-                                    the other groups (P = 0.015). Using molecular typing,
                                    onset pneumonia, and late-                                      84% of the patients with late-onset gram-negative
                                    onset pneumonia was                                             bacillary pneumonia were found to have gastric
                                    assessed in patients intubated                                  colonization with the same bacteria before pneumonia
                                    for more than 24 hours.




                                                                                                                                                                15
Gravity-VAP trial - NCT01138540
Version 1.4.0
Eddleston JM33               Randomized   Patients were randomized to        26 intubated adult patients.   The frequency of gastric colonization with aerobic
Crit Care Med. 1994                       receive either sucralfate (2 g                                    Gram-negative bacilli was 25.6% in group 1 and
                                          every 8 hrs) (group 1) via the                                    28.6% in group 2. Only one retrograde nosocomial
                                          nasogastric tube (flushed                                         pneumonia developed.
                                          with 10 mL of sterile water)
                                          or 20 mL of sterile water
                                          every 8 hrs (group 2) via the
                                          nasogastric tube.
Bonten MJ16                  Randomized   Patients were stratified on        141 patients                   Continuous intragastric pH monitoring was performed
Am J Respir Crit Care Med.                initial gastric pH. Intragastric                                  in 112 patients (58 antacids, 54 sucralfate). Using
1995                                      acidity was measured with                                         predetermined criteria, colonization of stomach,
                                          computerized, continuous                                          oropharynx, and trachea, and the incidence of VAP
                                          intragastric monitoring. The                                      were assessed. Altogether, 141 and continuous
                                          diagnosis of VAP was                                              intragastric pH monitoring was performed in 112
                                          established with protected                                        patients, with a mean of 75 h per patient. The median
                                          specimen brush and/or                                             pH and the percentage of time with a pH < 4.0 were
                                          bronchoalveolar lavage.                                           calculated from each measurement. No significant
                                          After stratification on initial                                   differences in median pH values (4.7 +/- 2.2 and 4.5
                                          intragastric pH into two                                          +/- 2.0 for antacids and sucralfate, respectively) were
                                          groups, patients from both                                        observed. Median pH values were higher in patients
                                          groups were randomly                                              with gastric bacterial colonization than in no
                                          assigned to receive either                                        colonized patients (5.5 +/- 2.1 and 3.3 +/- 2.0, p <
                                          antacids (a suspension of                                         0.01), but colonization of oropharynx and trachea was
                                          aluminum hydroxide and                                            not related to intragastric acidity. Thirty-one patients
                                          magnesium hydroxide), 30                                          (22%) developed VAP, with a similar incidence in
                                          mL every 4 h, or sucralfate,                                      both treatment groups. In addition, antibiotic use,
                                          1 g every 4 h. 74 patients                                        duration of hospitalization, and mortality rates were
                                          received antacids, 67                                             similar in both groups. Enteral feeding did not change
                                          sucralfate                                                        intragastric acidity significantly but increased gastric
                                                                                                            colonization with Enterobacteriaceae, without
                                                                                                            influencing oropharyngeal and tracheal colonization.
                                                                                                            Antacids and sucralfate had a similar effect on
                                                                                                            intragastric acidity, colonization rates, and incidence
                                                                                                            of VAP. Intragastric acidity influenced gastric
                                                                                                            colonization but not colonization of the upper
                                                                                                            respiratory tract or the incidence of VAP.




                                                                                                                                                                       16
Gravity-VAP trial - NCT01138540
Version 1.4.0
Thomason MH31          Randomized   Patients were randomized:        242 trauma patients   There was no statistically significant difference in
J Trauma. 1996                      sucralfate, n = 80; antacid, n                         pneumonia rates among the treatment groups (p =
                                    = 82; and ranitidine, n = 80.                          0.875). Pneumonia occurred more frequently in
                                                                                           patients with gram-negative retrograde colonization
                                                                                           from stomach to trachea (p = 0.02), but this accounted
                                                                                           for only 13% of all pneumonias in the study
                                                                                           population. Mean gastric pH was > 4 in 95% of the
                                                                                           study population, including 88% of patients receiving
                                                                                           sucralfate. The death rate in the antacid group was
                                                                                           significantly higher (p = 0.046) but not because of
                                                                                           increased gastrointestinal bleeding or pneumonia.
                                                                                           Results show no difference in the incidence of
                                                                                           nosocomial pneumonia in mechanically ventilated
                                                                                           trauma patients during the first 4 days of stress ulcer
                                                                                           prophylaxis with sucralfate, antacid, or ranitidine.
                                                                                           There is a trend toward decreased pneumonia in the
                                                                                           sucralfate group after study day 4.
Cook D25               Randomized   Authors compared sucralfate      1200 patients         In the ranitidine group, 114 of 596 patients (19.1
N Engl J Med 1998                   with the H2-receptor                                   percent) had ventilator-associated pneumonia, as
                                    antagonist ranitidine Patients                         compared with 98 of 604 (16.2 percent) in the
                                    received either nasogastric                            sucralfate group (relative risk, 1.18; 95 percent
                                    sucralfate suspension (1 g                             confidence interval, 0.92 to 1.51; P=0.19).
                                    every six hours) and an
                                    intravenous placebo or
                                    intravenous ranitidine (50
                                    mg every eight hours) and a
                                    nasogastric placebo.




                                                                                                                                                     17
Gravity-VAP trial - NCT01138540
Version 1.4.0
Ephgrave KS27                 Randomized      Baseline cultures of gastric     140 patients entered this study   Gastric pH was affected by the form of stress ulcer
Arch Surg. 1998                               and pulmonary secretions to      before major elective surgery,    prophylaxis throughout the study, and this pH effect
                                              be obtained intraoperatively.                                      affected the number of new gastric organisms
                                              Postoperatively, the patients                                      appearing in the 2 different groups. Colonization of
                                              were treated with standard                                         the airway with new gastric organisms occurred more
                                              doses of either sucralfate or                                      frequently in the antacid than in the sucralfate group,
                                              antacids, plus a sham of the                                       and colonization of the airway with organisms of
                                              other drug. Cultures were                                          gastric origin was associated with occurrence of
                                              repeated twice daily for 3                                         postoperative pneumonia. In association with the
                                              days. Molecular                                                    drug's effects on gastric pH, more new pathogens
                                              epidemiological typing was                                         appeared in the gastric contents of antacid-treated
                                              used to track the appearance                                       than sucralfate-treated patients
                                              of specific microbes and
                                              their transmission from site
                                              to site, and clinical end
                                              points were compared.
Kantorova I28                 Randomized      3 prophylactic regimens          287 patients with trauma and      The gastric pH (p>0.001) and gastric colonization
Hepatogastroenterology 2004                   (proton pump inhibitor--         after major surgery ventilated    (p<0.05) was significantly higher in the patients who
                                              omeprazole 40 mg i.v. once       for more than 48 hours            received pH increasing substances when compared
                                              daily, n=72; H2 antagonists--                                      with the other 2 groups. Nosocomial pneumonia
                                              famotidine 40 mg twice a                                           occurred in 11% of patients receiving omeprazole, in
                                              day, n=71; and sucralfate 1 g                                      10% of famotidine patients, in 9% of sucralfate
                                              every 6 hours, n=69) with                                          patients and in 7% of controls (p>0.34).
                                              placebo (n=75) No
                                              statistically significant
                                              differences were found for
                                              days on ventilator, length of
                                              ICU stay, or mortality
                                              among all the 4 groups.
Hillman KM6                   Observational   Cimetidine administration to     28 ventilated patients in the     Cimetidine increased gastric pH above 4. Quantitative
Crit Care Med 1982                            all patients and daily gastric   ICU                               and qualitative bacteriological examination of daily
                                              aspirates                                                          gastric aspirates showed that when the pH was above
                                                                                                                 4, there was rapid colonization with high counts of
                                                                                                                 organisms, predominantly coliforms.




                                                                                                                                                                           18
Gravity-VAP trial - NCT01138540
Version 1.4.0
Donowitz LG5           Observational   Serial gastric pH               153 critical care patients with   47% of gastric fluid cultures from 153 patients were
Infect Control 1986                    determinations and semi         documented cimetidine and         positive for gram negative bacteria (GNB), 24% were
                                       quantitative gastric fluid      antacid use                       sterile and 29% positive for mixed oropharyngeal
                                       cultures.                                                         flora. 59% of the cultures at a pH of 4 or greater were
                                                                                                         positive for GNB. In contrast, only 14% of cultures at
                                                                                                         a pH of less than 4 were positive for GNB.
Reusser P43            Observational   During the 7-day study          40 neurosurgical patients         66.7% contained microorganisms at a mean quantity
J Infect Dis 1989                      swabs from the nose and         requiring mechanical              of 10(7) cfu/ml. Nosocomial pneumonia occurred in
                                       oropharynx were cultured at     ventilation for greater than 48   15 patients. The stomach was the evident source of
                                       admission, and aspirates        h.                                infection in only 1 patient with pneumonia.
                                       from the stomach and
                                       trachea were cultured daily
Garvey BM39            Observational   Authors studied the             25 critically ill ICU patients    All patients had bacterial colonization of NG contents
Crit Care Med 1989                     incidence of gastric                                              within 4 days of ICU admission and 10 had Candida
                                       colonization and its relation                                     colonization within 8 days. There were 70 NG isolates
                                       to other infections and                                           and the same isolates were found in tracheobronchial
                                       antibiotic therapy in. All                                        secretions (n = 46), blood (n = 4), urine (n = 4), and
                                       patients received 12-h NG                                         wounds (n = 8). Tracheobronchial colonization was
                                       Mylanta II and 15 received                                        preceded by NG colonization with the same organism
                                       an H2-receptor antagonist.                                        in 12 instances (11 patients), was concurrent with NG
                                                                                                         colonization in 20 instances (14 patients), was
                                                                                                         followed by NG colonization in 14 instances (11
                                                                                                         patients), and had no similar NG isolate in 18
                                                                                                         instances (11 patients). NG culture of the same
                                                                                                         organism preceded four of eight positive blood
                                                                                                         cultures. In 35 of 70 NG isolates and five of 11
                                                                                                         subsequent tracheobronchial isolates, colonization
                                                                                                         occurred despite concurrent appropriate antibiotics.




                                                                                                                                                                   19
Gravity-VAP trial - NCT01138540
Version 1.4.0
Simms HH44             Observational   Trauma patients admitted to      92 Trauma patients               Patients receiving antacids had a significantly greater
J Trauma 1991                          the SICU were randomized                                          pH than those receiving cimetidine. However, there
                                       to receive antacids (n = 27),                                     was no significant difference between the overall
                                       continuous IV cimetidine (n                                       incidence of pneumonia, the percentage of NGT
                                       = 32), or sucralfate (n = 30).                                    isolates greater than 10(6)/ml, or the % GSP. The
                                       Quantitative nasogastric tube                                     gastric bacteriology of the three subgroups was nearly
                                       (NGT) cultures were                                               identical, with Candida albicans, Enterococci, and
                                       obtained biweekly and                                             beta-hemolytic Streptococci being the most frequently
                                       correlated with gastric pH,                                       isolated organisms. Gastric growth of organisms
                                       the incidence of pneumonia,                                       preceding their appearance in the blood occurred in 5
                                       and the incidence of                                              of 89 (5.6%) patients.
                                       pneumonia caused by an
                                       organism previously isolated
                                       from the stomach
                                       (percentage of gastric source
                                       of pneumonia--% GSP).
Eddleston JM36         Observational   Patients in the intensive care   104 mechanically ventilated      The incidence of pneumonia was 45.5% (25 patients)
Crit Care Med. 1991                    unit who were receiving                                           in the cimetidine group and 26.5% (13 patients) in the
                                       sucralfate (n = 49) or                                            sucralfate group (95% confidence interval 0.98 to
                                       cimetidine (n = 55) for stress                                    6.97; odds ratio 2.61; p = 0.0549). The mean pH
                                       ulcer prophylaxis.                                                values of gastric aspirates were significantly lower in
                                                                                                         patients treated with sucralfate than in patients
                                                                                                         receiving cimetidine (p = 0.044). The number of
                                                                                                         colony-forming units of Enterobacteriaceae in gastric
                                                                                                         aspirates was also significantly lower in the sucralfate
                                                                                                         group (p = 0.0037)sucralfate group (p = 0.0037)
Kappstein I41          Observational   Patients receiving sucralfate    104 mechanically ventilated      The incidence of pneumonia was 45.5% in the
Am J Med. 1991                         (49) or cimetidine (55) for      patients in the intensive care   cimetidine group and 26.5% in the sucralfate group
                                       stress ulcer prophylaxis.        unit                             (95% confidence interval 0.98 to 6.97; odds ratio
                                                                                                         2.61; p = 0.0549). The mean pH values of gastric
                                                                                                         aspirates were significantly lower in patients treated
                                                                                                         with sucralfate than in patients receiving cimetidine (p
                                                                                                         = 0.044). The number of colony-forming units of
                                                                                                         Enterobacteriaceae in gastric aspirates was
                                                                                                         significantly lower in the sucralfate group (p =
                                                                                                         0.0037)




                                                                                                                                                                    20
Gravity-VAP trial - NCT01138540
Version 1.4.0
Torres A45               Observational   Gastric, pharyngeal, and       36 patients with nosocomial     Mean gastric colonization was similar in both patients
Am Rev Respir Dis.1993                   endotracheal sampling for      pneumonia acquired during       with VAP and control subjects. In the former group
                                         quantitative cultures was      mechanical ventilation and 27   there was an increase in coincident microorganisms
                                         performed upon all patients,   mechanically ventilated         isolated from gastric, pharyngeal, and EA samples in
                                         as well as fiberoptic          control subjects without        relation to PSB samples compared with control
                                         bronchoscopy with protected    pulmonary infection             samples. Among the different quantitative cultures
                                         specimen brush (PSB)                                           analyzed, only those obtained from endotracheal
                                         sampling.                                                      aspirates significantly correlated with PSB cultures in
                                                                                                        patients with pneumonia.
Bonten MJ15              Observational   Microbiologic cultures of      64 patients admitted to ICU     Eleven patients developed 14 episodes of nosocomial
Chest. 1994                              serially taken samples of      for at least 5 days, 59 were    pneumonia, yielding 20 species of microorganisms.
                                         gastric aspirates,             intubated                       Seventeen of 20 species (85 percent), associated with
                                         oropharyngeal swabs, and                                       pneumonia, were cultured, previous to or on the day
                                         tracheal aspirates were                                        of diagnosis, from tracheal aspirates, and 6 of 20 (30
                                         performed at the time of ICU                                   percent) species were cultured from gastric samples.
                                         admission and subsequently                                     A sequence of colonization from the stomach to the
                                         twice a week. Diagnosis of                                     upper respiratory tract eventually leading to
                                         pneumonia was based on                                         pneumonia was not observed in any of the six species.
                                         quantitative cultures from                                     Initial colonization with Pseudomonas aeruginosa and
                                         bronchoalveolar lavage                                         Enterobacter species was more often demonstrated in
                                         (BAL) and protected                                            the trachea (16/24 and 13/25 cases) as compared with
                                         specimen brush (PSB).                                          the stomach (1/24 and 6/25 cases; p < 0.0001 and p =
                                         Sequences of colonization                                      0.02 respectively). In contrast, initial colonization
                                         were examined by                                               with Klebsiella species and Enterococcus faecalis was
                                         comparing isolates of the                                      more frequently demonstrated in the stomach (13/28
                                         same species, with                                             and 8/15 cases) as compared with the trachea (6/28
                                         concordance of minimum                                         and 0/15 cases; p = 0.02 and p < 0.0001,
                                         inhibitory concentration                                       respectively). The authors concluded that the stomach
                                         values to six antibiotics.                                     is unlikely to be an important source of pathogens
                                                                                                        leading to nosocomial pneumonia as diagnosed by
                                                                                                        BAL/PSB. Furthermore, the initial site and route of
                                                                                                        colonization might not be the same for all
                                                                                                        microorganisms




                                                                                                                                                                  21
Gravity-VAP trial - NCT01138540
Version 1.4.0
Palmer LB42                  Observational   Serial weekly oropharyngeal,     7 patients requiring chronic   Pseudomonas aeruginosa (PA) was present more
Am J Respir Crit Care 1994                   gastric, and tracheal cultures   ventilatory assistance         frequently and persistently in the trachea than the
                                             were taken over a 6-mo                                          oropharynx and stomach (p < 0.01) and members of
                                                                                                             the family Enterobacteriaceae (Ent. species) were also
                                                                                                             observed more commonly in the trachea than the
                                                                                                             oropharynx (p < 0.01). PA was seen in 6.7% of
                                                                                                             gastric specimens whereas Ent. species were found in
                                                                                                             40% of gastric specimens. Six identical strains from a
                                                                                                             total of 53 gastric isolates and 128 oropharyngeal
                                                                                                             isolates were cultured coincidentally from these two
                                                                                                             sites. Coincidental isolation of 11 strains was
                                                                                                             observed in 177 tracheal isolates and 53 gastric
                                                                                                             samples. Documented transfers from stomach to
                                                                                                             oropharynx ascertained by sequential isolation
                                                                                                             occurred in one of 118 cultures and transfer from
                                                                                                             stomach to trachea occurred in three of 134 cultures.
                                                                                                             Despite the use of H2blockers in 6 of 7 patients
                                                                                                             transfer of pathogens did not occur from the stomach
deLatorre FJ18               Observational   Simultaneous sample from         80 patients mechanically       90% of the patients had tracheal colonization at some
Am J Respir Crit Care 1995                   pharynx, stomach, and            ventilated                     time during MV. Only 19 patients presented tracheal
                                             trachea were obtained                                           colonization after pharyngeal or gastric colonization.
                                             throughout the MV period                                        Indigenous gram-negative and gram-positive
                                             and quantitative cultures                                       microorganisms colonized mainly the trachea from
                                             were performed.                                                 the start of or during MV without previous pharyngeal
                                                                                                             or gastric colonization (p < 0.05). Of the 12 patients
                                                                                                             who developed VAP, the microorganisms responsible
                                                                                                             had already colonized the trachea in 10 patients. Only
                                                                                                             10 of the 21 microorganisms isolated in VAP had
                                                                                                             previously colonized the pharynx or stomach.




                                                                                                                                                                      22
Gravity-VAP trial - NCT01138540
Version 1.4.0
Bonten MJ17                  Observational   Risk factors for the            141 ventilated patients   VAP was caused by EGB in 14 patients (10%) and by
Am J Respir Crit Care Med.                   development of ventilator-                                Pseudomonadaceae in 19 patients (13%). The
1995                                         associated pneumonia (VAP)                                duration of ventilation was a significant risk factor for
                                             and colonization of the                                   VAP caused by EGB and Pseudomonadaceae, and for
                                             respiratory tract and stomach                             acquired colonization in oropharynx, stomach, and
                                             with enteric gram-negative                                trachea with these species. Of 20 other variables,
                                             bacteria (EGB) and                                        oropharyngeal colonization with EGB on admission
                                             Pseudomonadaceae were                                     (hazard ratio [HR] = 4.5) and an infection on
                                             determined using univariate                               admission (HR = 2.7) were selected as risk factors for
                                             analysis and the Cox                                      VAP caused by EGB. Acquired colonization with
                                             proportional hazards model.                               Pseudomonadaceae in oropharynx (HR = 5.0) was the
                                                                                                       most important risk factor for VAP caused by these
                                                                                                       species. Gastric colonization with EGB or
                                                                                                       Pseudomonadaceae was no risk factors for VAP. For
                                                                                                       acquired oropharyngeal colonization with EGB only
                                                                                                       the duration of ventilation was a risk factor, whereas
                                                                                                       preceding colonization of the trachea with
                                                                                                       Pseudomonodaceae and duration of ventilation were
                                                                                                       risk factors for acquired oropharyngeal colonization
                                                                                                       with these species. In the Cox model, only the
                                                                                                       duration of ventilation was significantly related to
                                                                                                       acquire gastric colonization with EGB. Preceding
                                                                                                       colonization of the oropharynx and of the trachea with
                                                                                                       Pseudomonadaceae were risk factors for acquired
                                                                                                       colonization with these species in the stomach. In
                                                                                                       conclusion, duration of ventilation and colonization of
                                                                                                       the upper respiratory tract are the most important risk
                                                                                                       factors for VAP caused by EGB or
                                                                                                       Pseudomonadaceae




                                                                                                                                                                   23
Gravity-VAP trial - NCT01138540
Version 1.4.0
Garrouste-Orgeas M38         Observational   Oropharyngeal or gastric         86 ventilated, intensive care   A total of 31 cases (36%) of pneumonia were
Am J Respir Crit Care Med.                   colonizations were detected      unit (ICU) patients.            diagnosed. Oropharyngeal colonization, detected
1997                                         and quantified on admission                                      either on admission or from subsequent samples, was
                                             and twice weekly during                                          a predominant factor of nosocomial pneumonia as
                                             ICU stay. VAP diagnosis                                          compared with gastric colonization. For instance,
                                             was assessed on fiberoptic                                       oropharyngeal colonization with A. baumannii
                                             bronchoscopy with                                                yielded a 7.45-fold estimated increased risk of
                                             quantitative cultures of a                                       pneumonia as compared with patients not yet or not
                                             protected specimen brush                                         identically colonized (p = 0.0004). DNA genomic
                                             sampling and/or a plugged                                        analysis demonstrated that an identical strain was
                                             telescoping catheter                                             isolated from oropharyngeal or gastric samples and
                                             sampling. Bacterial strains                                      bronchial samples in all but three cases of pneumonia,
                                             responsible for colonization                                     due to S. aureus.
                                             and infection (Acinetobacter
                                             baumannii, Pseudomonas
                                             aeruginosa,
                                             Enterobacteriaceae, and
                                             Staphylococcus aureus) were
                                             compared using pulsed-field
                                             electrophoresis.
Inglis TJ40                  Observational   Samples were taken once          20 surgical intensive care      Gram-negative bacilli were isolated in a progressively
Br J Anaesth. 1998                           daily from gastric aspirates,    patients.                       increasing proportion of samples at successive
                                             tracheal tube lumen angle                                        sampling points, consistent with an endogenous-to-
                                             piece connector, Y piece,                                        external route of spread (patients, chi-square = 14.12,
                                             expiratory trap, and tracheal                                    P < 0.02; samples, chi-square = 106.15, P < 0.001).
                                             aspirates. Molecular typing                                      Identical strains of gram-negative bacilli, confirmed
                                             of isolates through repetitive                                   by REPS typing, were found at two or more sites in
                                             extragenic palindromic                                           seven patients. In all seven, gram-negative bacilli
                                             sequence analysis (REPS)                                         were first isolated from a site in the patient. In none of
                                                                                                              the 20 patients was there evidence of a sequence of
                                                                                                              colonization from the ventilator tubing or Y-piece
                                                                                                              connector towards the patient. Probable colonization
                                                                                                              sequences plotted from the time of first isolation
                                                                                                              supported the proposed sequence in six patients, and
                                                                                                              in five began with the stomach contents. Isolation
                                                                                                              sequences contrary to the proposed direction of
                                                                                                              colonization involved four bacterial species and two
                                                                                                              patients, and did not extend beyond two sample sites.


                                                                                                                                                                           24
Gravity-VAP trial - NCT01138540
Version 1.4.0
Cardeñosa Cendrero JA35   Observational   Tracheal, pharyngeal, and        123 surgical and medical        Tracheal colonization at some time during MV was
Chest. 1999                               gastric samples were             patients receiving mechanical   observed in 110 patients (89%). Eighty patients had
                                          obtained simultaneously          ventilation (MV).               initial colonization, 34 patients had primary
                                          every 24 h. In cases where                                       colonization, and 50 patients had secondary
                                          VAP was suspected                                                colonization. Nineteen patients had VAP, and 25
                                          clinically, bronchoscopy                                         organisms were isolated. For none of these organisms
                                          with protected specimen                                          was the stomach the initial site of colonization. Gram-
                                          brush and BAL were                                               positive organisms colonized mainly in the trachea
                                          performed. Semi quantitative                                     during the first 24 h of MV (p<0.001). On the
                                          cultures of pharyngeal                                           contrary, enteric Gram-negative bacilli (p<0.001) and
                                          samples and quantitative                                         yeasts (p<0.002) colonized the trachea secondarily.
                                          cultures for the remaining                                       Although the stomach can be a source of organisms
                                          samples were obtained.                                           that colonize the tracheobronchial tree, it is a much
                                                                                                           less common source of the bacteria that cause VAP.
                                                                                                           The pattern of colonization and risk factors may be
                                                                                                           different according to the type of organisms involved
Feldman C37               Observational   In the first part of this                                        The sequence of colonization in patients undergoing
Eur Respir J. 1999                        prospective study, the airway                                    mechanical ventilation was the oropharynx (36 h), the
                                          access tube was examined                                         stomach (3660 h), the lower respiratory tract (60-84
                                          for the presence of                                              h), and thereafter the endotracheal tube (60-96 h).
                                          secretions, airway                                               Nosocomial pneumonia occurred in 13 patients and in
                                          obstruction and bacterial                                        eight cases identical organisms were noted in lower
                                          colonization, in cases                                           respiratory tract secretions and in secretions lining the
                                          undergoing extubation or                                         interior of the endotracheal tube.
                                          tube change. In the second
                                          part of the study, the
                                          sequence of oropharyngeal,
                                          gastric, respiratory tract and
                                          endotracheal tube
                                          colonization was
                                          investigated by sequential
                                          swabbing at each site twice
                                          daily for 5 days in
                                          consecutive no infected
                                          patients.




                                                                                                                                                                       25
Gravity-VAP trial - NCT01138540
Version 1.4.0
Vallés J46                Observational   Samples from the tap water       Ninety-eight intubated         Overall 54.2% of patients presented colonization, and
Intensive Care Med 2004                   from each patient's room,        patients ventilated for more   tracheal colonization was present in 30.5%. Ten
                                          stomach, oropharynx,             than 72 hours                  patients had colonization at intubation, and four of
                                          subglottic secretions,                                          these developed ventilator-associated pneumonia
                                          trachea, and rectum were                                        (VAP) after a mean of 4+/-2 days. ICU-acquired
                                          collected when the patient                                      colonization occurred in 31 patients and 4 of these
                                          was intubated, and then three                                   developed VAP after a median of 10+/-5 days. P.
                                          times per week. Pulsed-field                                    aeruginosa was isolated from the room's tap water in
                                          gel electrophoresis was                                         62.4% of samples. More than 90% of tap water
                                          performed to type the strains.                                  samples had pulsotypes 1 and 2, which were
                                          Authors identified 1,607                                        frequently isolated in the stomach (59%) but were
                                          isolates pertaining to 35                                       only rarely associated with VAP.
                                          different pulsotypes.




                                                                                                                                                                  26
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4b Role of the oropharynx as a reservoir of pathogenic bacteria:

            Normal oropharyngeal flora in healthy no intubated patients comprises viridans streptococci,
Haemophilus spp. and anaerobes47. However, there is evidence that in critically ill patients the oral
flora shifts early to a predominance of aerobic gram negative pathogens, Pseudomonas aeruginosa and
MRSA48-51. Results shown in previous paragraphs challenge the hypothesis that oropharynx is
colonized by pathogens originating from the stomach. Oropharyngeal colonization is a major risk
factor in the VAP pathogenesis and several strategies such as oral rinse with antiseptics, oral care52,
subglottic aspiration and novel leak-proof cuffs are aimed to prevent colonization and pulmonary
aspiration of bacteria laden secretions, pooled above the tracheal tube cuff. Several studies have
reported, in patients after major heart surgery, reduction in incidence of VAP through regular oral rinse
                        53-55
with chlorhexidine              . However, results on efficacy of chlorhexidine as VAP preventive strategy
remain inconsistent in medical and surgical ICU patients56-59.
            Sub-glottic aspiration and leak-proof cuffs are specifically aimed at preventing aspiration of
oropharyngeal contents and do not directly alter oropharyngeal bacterial colonization; however the
decrease of VAP using such strategies emphasizes the role of the oropharynx in the pathogenesis of
VAP. A recent meta-analysis which included 6 randomized clinical trials has shown effectiveness of
subglottic secretions aspiration in preventing ventilator associated pneumonia12. Moreover Lorente et
      11
al.        have recently shown that the use of an endotracheal tube with polyurethane cuff and subglottic
secretion drainage efficiently prevents early- and late-onset VAP.




                                                                                                       27
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4c Efficacy of the semi recumbent position in VAP prevention:

       Only two prospective randomized clinical trials have assessed the efficacy of the
semirecumbent position on prevention of VAP (Table 2). Results are not consistent; however in the
trial conducted by Van Nieuwnehoven et al.60 the orientation of the head of the bed higher than 30
degrees was not achieved.




                                                                                               28
Gravity-VAP trial - NCT01138540
Version 1.4.0
Table 2 Studies assessing effects of the semirecumbent position on incidence of VAP


First Author/
                        Study type       Patients/Groups                       Outcome                          Notes
Journal/Year


                                                                                                                No differences in MV, ICU stay and mortality.
Van Nieuwnehoven60                       112/semirecumbent (28º)
                        Randomized                                             No difference in VAP             Semi-recumbent at 45º was not achieved.
Crit Care Med. 2006                      109/supine (10º)




                                                                               Semi-recumbent position          Conducted in a medical ICU, no surgical
Drakulovic MB14                          39/semirecumbent (45º)
                        Randomized                                             showed a statistical reduction   patients included. Stopped at interim analysis.
Lancet. 1999                             47 / supine (0º)
                                                                               in VAP, particularly in          No differences in duration of MV*, ICU stay,
                                                                               patients enterally fed.          mortality



                                                                               Supine head positioning
         13                              277 patients on MV for more than 24   during the first 24 hours of
Kollef MH
                        Observational    hours                                 mechanical ventilation
Jama 1998
                                                                               increased three folds risk for
                                                                               VAP



* MV – mechanical ventilation




                                                                                                                                                                  29
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4d Efficacy of the semi recumbent position in preventing gastric reflux and aspiration of gastric
content:

       All studies suggest that in patients intubated and mechanically ventilated with a naso-gastric
feeding tube in place, the semi-recumbent position significantly reduces aspiration of gastric contents
(Table 3). However, in the semi-recumbent position, pulmonary aspiration is not avoided even when an
esophageal balloon was used as preventive strategy61.




                                                                                                    30
Gravity-VAP trial - NCT01138540
Version 1.4.0
Table 3 Studies assessing efficacy of the semirecumbent position on prevention of gastric reflux


First Author/
                             Study type    Method                        Patients                                  Outcome
Journal Year
                                                                                                                   31 per cent of tracheal secretions were positive. Patients with
             62                            Pepsin in tracheal            360 intubated patients in the             pneumonia, as determined via the CPIS* had a greater number of
Metheny NA
                             Prospective   secretions as proxy for       semirecumbent with enteral feeding        secretions positive for pepsin compared to those without
Crit Care Med.2006
                                           gastric contents aspiration   studied for 4 days                        pneumonia (42 vs. 21%) on day 4. Low backrest elevation was a
                                                                                                                   risk factor for aspiration.


                                           Effect of an esophageal
                                                                         14 intubated patients in the
Orozco-Levi M61                            balloon on aspiration of                                                The inflated esophageal balloon decreased, but did not prevent,
                             Randomized                                  semirecumbent position with
Eur Respir J 2003                          gastric secretions.                                                     gastro-esophageal reflux and gastric aspiration.
                                                                         esophageal balloon inflated or deflated


                                                                                                                   Significant reduction in radioactivity of tracheal secretions in the
Orozco-Levi M8
                                           Radio-labeled gastric         15 intubated patients studied in both     semi-recumbent position. No difference in oropharyngeal
Am J Respir Crit Care Med.   Randomized
                                           contents                      supine and semi-recumbent position        radioactivity in both positions.
1995

                                           Radio-labeled gastric         19 patients                               Reduction of radioactive count in endobronchial secretions in
Torres A9                                  contents in supine vs.        (each patient was studied on two          semi-recumbent position associated with 77% reduction in
                             Randomized
Ann Intern Med. 19926                      semi-recumbent                separate days both in the semi-           radioactive counts detected in endobronchial secretions.
                                           positions                     recumbent and supine position)

                                           Radio-labeled gastric         70 patients studied in the
                                                                                                                   Authors did not find a statistically significant difference in
Ibanez J63                                 contents in supine vs.        semirecumbent and supine position, 50
                             Randomized                                                                            aspiration between supine and semirecumbent position, however
JPEN                                       semi-recumbent                of them with nasogastric tube and 20
                                                                                                                   the nasogastric tube significantly increased risk for aspiration
                                           positions                     without



*CPIS, Clinical Pulmonary Infection Score




                                                                                                                                                                                          31
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4e Efficacy of the semi recumbent position to prevent aspiration of oropharyngeal secretions:

       There are no studies evaluating the effects of the semi recumbent position on aspiration of
oropharyngeal secretions. The standard commercially available ETT cuff does not completely seal the
lower airways10. It is likely that the semirecumbent position increases the amount of oropharyngeal
secretions pooled above the tracheal tube cuff. The hydrostatic pressure of secretions exerted against
the cuff may facilitate the leakage across the ETT cuff into the lower airways, particularly when no
positive end expiratory pressure is applied11.

1.4f Feasibility of the semi recumbent position:

       The backrest elevation of 45° as reported in the first randomized clinical trial14 is not well
tolerated by patients, while 30° is more feasible and better tolerated.
       Drakulovich et al.14 did not report any data (i.e. mean elevation, time of elevations) on the bed
position, and how it was monitored. The authors only stated that: change in body position for more
than 45 minutes was a criterion to stop the study. This was the only study that reports success in
keeping the patients at 45º. Helman et al64 used a standardized order specifying head of the bed
position in 100 patients, followed by an education program. This significantly increased the number of
patients placed in the semirecumbent position (mean angle of the head of the bed: 35°; percent of time
at an angle >30°: 88%). Finally, van Nieuwenhoven et al.60 targeted a backrest elevation of 45° for the
semirecumbent position. Despite extensive experience and education of the healthcare personnel they
were not able to achieve these goals. The main elevations were 28.1° and 22.6°, respectively, on days 1
and 7 of mechanical ventilation




                                                                                                     32
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.4g Summary of the role of the semirecumbent position in prevention of VAP:

       Despite the worldwide use of the semirecumbent position, to date, clinical trials have not
provided persuasive evidence that the gastro-pulmonary route of colonization plays a center role in the
pathogenesis of VAP. The role of gastric reflux as risk factor for colonization of the trachea and
development of VAP remains controversial. Instead, oropharyngeal colonization and pulmonary
aspiration of oropharyngeal contents consistently have been acknowledged as the primary mechanism
for the onset of VAP. Only one randomized clinical trial has been conducted to prove the hypothesis
that the semirecumbent position (head of bed elevated 45°) prevents gastroesophageal reflux and
ultimately incidence of VAP. Moreover, clinical data show that the semirecumbent position can reduce,
but not prevent, gastric reflux and subsequent aspiration8;61. The clinical practice of caring for critically
ill mechanically ventilated patients at 45° elevation however is rarely achieved. In practice this is often
only successful using 20 to 30° elevation.




                                                                                                          33
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.5 Laboratory animal studies conducted at the National Institutes of
       Health to assess effects of gravity in the pathogenesis of ventilator
       associated pneumonia

       No animal studies were published before applying the semirecumbent position as clinical
standard of care. An animal model of long-term mechanically ventilation has been developed at the
National Institutes of Health, Pulmonary and Critical Care Medicine Branch, Division of Animal
Experimentation, in order to study physiopathology of VAP and assess efficacy and safety of
preventive strategies. Studies have been conducted in previously healthy sheep and pigs, free of
antibiotic therapy. In those studies VAP resulted by lung colonization of endogenous
oropharyngeal/gastric pathogens. Animals were deeply sedated and with optimal analgesia, moreover
muscle paralysis was often necessary for adequate positioning and ventilation. The model developed at
the National Institutes of Health closely resembles the intubated and deeply sedated patient with
several pulmonary defenses, such as cough and mucociliary clearance highly compromised.
       Several laboratory studies have been performed throughout the years, of those, 3 studies have
specifically assessed effects of gravity on the pathogenesis of VAP (Table 4). Remaining studies have
tested several devices/strategies aimed to reducing incidence of pneumonia.




                                                                                                  34
Gravity-VAP trial - NCT01138540
Version 1.4.0
Table 4 Studies conducted at the National Institutes of Health




First Author/Year      Animal model     Aim



Panigada/200365        Sheep            Role of the orientation of trachea/ETT in VAP



                                        Benefit of a ETT coated with silver-sulphadiazine to keep the ETT sterile and
Berra/200466           Sheep
                                        delay lung colonization



Berra/200467           Sheep            To test the efficacy and safety of continuous aspiration of subglottic secretions



Kolobow/200568         Sheep            Efficacy of a new device to remove mucus from the interior of the ETT



                                        Efficacy of a new device in preserving the bactericidal activity of a silver
Berra/200669           Sheep
                                        sulphadiazine coated tube up to 7 days



                                        Twenty-four hours test of a device aimed to aspirate mucus at the very tip of the
Kolobow/200670         Sheep
                                        ETT



                                        Seventy-two hours test of a device aimed to aspirate mucus at the very tip of the
Li Bassi/200771        Sheep
                                        ETT



Li Bassi/200872        Sheep            Effect of body positioning on mucus ciliary clearance



                                        Role of body position in development of VAP, in omnivore mechanically
Submitted Paper        Pig
                                        ventilated up to 168h

Studies specifically assessing effects of gravity on VAP are highlighted


All studies found lower incidence of pneumonia when trachea/ETT was oriented below horizontal
(Appendix A, Table 5) When data from all studies were pooled lower incidence of pneumonia
consistently benefit has been found with trachea/ETT oriented below horizontal (Appendix A, Table 6
and Figure 1)




                                                                                                                            35
Gravity-VAP trial - NCT01138540
Version 1.4.0
To briefly summarize data from all studies:
1. Sheep ventilated for 72 h with a tracheal orientation below horizontal retained excellent lung
functions with no evidence of VAP. In contrast, sheep ventilated with tracheal orientation above
horizontal had heavy lung bacterial colonization and pneumonia.
2. Tracheal mucosal clearance is highly impaired in the semirecumbent position, and bacteria, from the
oropharynx, easily translocate from the proximal trachea into the lungs. In sheep with the trachea
oriented below horizontal mucus clears toward the tip of the ETT, bacterial translocation and
development of pneumonia is totally prevented.
3. Previous results in sheep were reproduced in pigs to address previous limitation. Indeed, sheep are
ruminants, produce more oropharyngeal secretions and present different and higher bacterial
colonization of the gastrointestinal tract. Interestingly, pigs ventilated up to 168 hours with tracheal
oriented below horizontal had no lung colonization.
4. Continuous enteral feeding for up to 72 hours in either sheep or pigs, ventilated with trachea oriented
below horizontal was associated with 4/34 episodes of light colonization of the lungs and 0/34 cases of
pneumonia.


       Panigada et al65 firstly provided a comprehensive analysis of ETT and body position and the
development of VAP. Sheep were studied to assess effects of gravity on development of VAP. Animals
were ventilated for up to 72 hours. No antibiotics were administered at any time. Sheep were
randomized either to the “head up” position, or the “head down” position, with the orientation of the
trachea/ETT respectively above, or below the horizontal (0°). All sheep in the “head down” position
were placed in a rotational system that allowed routine body position change from one side to the other.
Half of the sheep with the head down received enteral feeding. All sheep in “head up” position had
significant decrease in PaO2/FiO2 and heavy bacterial colonization of the lungs. Conversely, sheep in
“head down” rotating position retained excellent lung function with normal PaO2/FiO2 and no
evidence of bacterial lung colonization and VAP.
       Berra L et al67 studied the effects of body position and continuous aspiration of subglottic
secretions via a dedicated tracheal tube (CASS TUBE) on development of VAP. Twenty-two sheep
were randomized into three groups. Eight sheep were kept prone, with the head elevated 30 degrees

                                                                                                       36
Gravity-VAP trial - NCT01138540
Version 1.4.0
above horizontal (Control group); 14 sheep were intubated with a ETT for continuous aspiration of
subglottic secretions; seven of these 14 sheep were kept prone with the head elevated 30 degrees above
horizontal, (CASS UP group); and 7 sheep with the trachea horizontal (CASS DOWN group).
Consistently, lungs were colonized in all sheep kept with a tracheal orientation 30 degrees above
horizontal. Lung colonization in the CASS UP group (median 6.1* 107 colony-forming units/g of
tissue) was lower in comparison to the control group (1.6*109 cfu/g). In the group CASS DOWN, the
lower respiratory tract was not colonized in six of seven sheep and one sheep showed low levels of
bacterial growth. Importantly, at autopsy, in all 14 sheep with CASS, authors found tracheal mucosal
injury of different degrees of severity, at the level of the suction port of the ETT. Therefore, tracheal
orientation rather than subglottic aspiration was the main factor to prevent the onset of VAP.
       In order to better understand underlying pathogenesis of VAP, Li Bassi G. et al.72 studied the
effect of body positioning on mucus clearance, a primary defense to prevent lung bacterial
colonization. They studied sixteen intubated sheep, randomized to be positioned with the orientation of
the trachea above (30º-45º – a model of the semirecumbent position in human), or below (5º) horizontal
(Trendelenburg position). Tracheal mucus velocity was measured via radiographic tracking of tantalum
disks. After 24 hours, sheep were electively euthanized, and samples from the airways, and lungs, were
taken for quantitative microbiological analysis. Tracheal mucus flow in sheep in the Trendelenburg
position was always towards the ETT cuff with an average speed of 2.1±1.1 mm/min. Mucus
constantly moved towards the glottis and pooled at the inflated ETT cuff and either cleared through the
ETT lumen or aspirated via tracheal suction. Instead, in sheep in the semirecumbent position, first cilia
moved mucus towards the glottis then, mucus accumulated at the inflated ETT cuff and gravitated to
the dependent (ventral) part of the trachea, and ultimately reversed direction and moved backward
towards and into the lungs. 6/8 sheep in the semi-recumbent position developed pneumonia, while no
pneumonia was found in any of the sheep positioned with the trachea oriented below horizontal. The
same microorganisms were consistently found at the proximal tracheal and into the lungs, suggesting
an intratracheal route of colonization.


       Additional experiments were performed to address limitation of previous studies. In particular,
concerned have been raised regarding the use of sheep in studies addressing pathogenesis of VAP.

                                                                                                      37
Gravity-VAP trial - NCT01138540
Version 1.4.0
Ruminants, in comparison to omnivores, produce more saliva and gastrointestinal apparatus is often
colonized with pathogens. Therefore pulmonary aspiration may be facilitated in the semirecumbent
position due to the higher hydrostatic pressure exerted by large amount of saliva above the tracheal
tube cuff and oropharynx may be colonized by pathogens already at the time of tracheal intubation.
       Zanella et al have recently concluded a study on 28 intubated pigs, randomized into five groups:
(group 1, HU) 8 pigs were placed with the tracheal axis 30° above horizontal (semirecumbent
position), and 18 pigs comprising group 2-4 were placed in the Trendelenburg position with the
tracheal axis 5°-10° below horizontal. Six pigs (group 2, HD 72) in the Trendelenburg position were
mechanically ventilated for 72 hours and did not receive enteral feeding. Group3 (HD 72 F), 6 pigs in
the Trendelenburg position were mechanically ventilated for 72 hours and received enteral feedings.
Group 4 (HD 168 F), 6 pigs in the Trendelenburg position were mechanically ventilated for 168 hours
and received enteral feeding. Group5 (HD 72 F DC), two pigs were mechanically ventilated for 72
hours, received enteral feeding, and had the ETT cuff completely deflated during the whole study. No
antibiotics were administered at any time during the study. At autopsy, we sampled the trachea and
lobar parenchyma for microbiologic analysis.
       In all the eight pigs in the semirecumbent position (group 1), lungs were heavily colonized with

pathogens (104-109 cfu/g) in all pigs. Conversely, none of the 18 pigs kept in the Trendelenburg
position (group 2-5) developed pneumonia (Appendix A, Table 7). The microbiological analysis
showed an absence of lung colonization in 16 pigs kept in the Trendelenburg position. In 1 pig

ventilated for 168h, 1 lobe had low level colonization (105 cfu/g) and in 1 pig ventilated for 168h, 2

lobes had low level colonization (104-105 cfu/g).




                                                                                                     38
Gravity-VAP trial - NCT01138540
Version 1.4.0
1.5a Summary of results from laboratory studies conducted at the National Institutes of Health

       Studies conducted at the National Institutes of Health have consistently shown in sheep and
pigs, mechanically ventilated for up to 7 days that orientation of the trachea and ETT slightly below
horizontal efficiently prevented bacterial colonization of the lungs. When sheep and pigs were
positioned with the trachea and ETT oriented above the horizontal (a model of the semi-recumbent
position in the human), lungs were heavily colonized with endogenous bacteria. These findings provide
experimental proof that the effectiveness of the semi recumbent position in comparison to the lateral
Trendelenburg position should be assessed in order to further decrease incidence of VAP.




                                                                                                  39
Gravity-VAP trial - NCT01138540
Version 1.4.0
2 Rationale of the study
       Gastro esophageal reflux is common in patients intubated and enterally fed73. The gastro
pulmonary theory of colonization has been developed to explain pathogenesis of ventilator associated
pneumonia. Indeed, in critically ill patients, following tracheal intubation, the stomach is often
colonized5;6 and authors suggested that the oropharynx of patients maintained supine is rapidly
colonized by gastric pathogens via gastro esophageal reflux9;24;45. The semirecumbent position has been
introduced in clinical practice to prevent/reduce gastroesophageal reflux and reduce translocation of
bacteria from the stomach into the oropharynx14. Currently, the semirecumbent position is strongly
recommended for all mechanically ventilated patients irrespective of colonization of the oropharynx
with pathogens. However, the primary mechanism for bacterial translocation from the oropharynx into
the lungs is through aspiration of bacteria-laden subglottic secretions across the ETT cuff2;74.
Interestingly, there is no experimental evidence or theoretical rationale why the semirecumbent
position will prevent this process, particularly in patients who present oropharyngeal colonization with
pathogens at the time of intubation or during the time on mechanical ventilation.
       The recovery position is a lateral position, widely used to prevent aspiration in the unconscious
patient, as it allows natural drainage of oropharyngeal secretions and gastric reflux through the mouth.
Laboratory studies conducted at the animal experimentation division of the National Institutes of
Health suggest that the a tracheal orientation below horizontal can totally prevent aspiration of
oropharyngeal contents across the ETT cuff and allow natural drainage of secretions away from the
airways. In the human such tracheal orientation can be reproduced positioning the patient in the lateral-
Trendelenburg position (Appendix B, Figure 1,2 and 3)
       Animal studies, reported in previous paragraphs, show no efficacy of the semirecumbent
position in preventing VAP, in comparison to the lateral Trendelenburg position65;67;72; Moreover,
those studies show that the inflated ETT cuff mechanically blocks outward mucociliary clearance.
These secretions become rapidly colonized via translocation of bacteria from the subglottic area into
the proximal trachea and ultimately those secretions flow backward into the lungs when the patient is
in the semirecumbent position72;74. Conversely, when trachea is oriented below horizontal all secretions
                                                                                                      40
Gravity-VAP trial - NCT01138540
Version 1.4.0
drain out from the lung.
       It is also important to emphasize that all studies conducted at the National Institutes of Health
were performed on deeply sedated animals and with several pulmonary defenses, such as cough and
mucociliary clearance highly impaired. Moreover, no antibiotics were administered before and during
those studies. In order to properly translate those results in clinical practice the lateral Trendelenburg
position should be applied particularly when patients are deeply sedated and with pulmonary defenses
compromised.




                                                                                                       41
Gravity-VAP trial - NCT01138540
Version 1.4.0
3 Objectives
       This study is planned to compare, in patients sedated, intubated/tracheostomized and
mechanically ventilated, the efficacy and safety of two body positions in reducing incidence of
ventilator-associated pneumonia. The semi-recumbent position prevents gastro-oropharyngeal
aspiration of bacteria laden gastric contents and the “gastro-pulmonary” route of colonization. The
lateral-Trendelenburg position aims to promote outward drainage of bacteria-laden oropharyngeal
secretion, while avoiding bacterial translocation from the oropharynx into the lungs.



4 Study Design
       This is a randomized, controlled, multi-center trial. Patients will be evaluated for eligibility by
one of the investigators of the Gravity-VAP Network. Following randomization patients will be
randomized to either the Semi-Recumbent or Lateral-Trendelenburg position group.


4.1 End points
Primary end point

       The primary endpoint will be incidence of ventilator-associated pneumonia within the first 14
days of tracheal intubation, confirmed by quantitative microbiology analysis of either bronchoalveolar
lavage (BAL) or mini-BAL fluids or secretions collected through protected specimen brush (PSB).


Secondary end points
   1. Duration of mechanical ventilation
   2. Duration of intensive care unit stay
   3. Duration of hospital stay
   4. Safety of the Semi-Recumbent and Lateral-Trendelenburg position
   5. Use of Sedatives
   6. Use of Antimicrobials

                                                                                                       42
Gravity-VAP trial - NCT01138540
Version 1.4.0
   7. ICU mortality
   8. Hospital mortality
   9. 28 Days mortality
   10. Assessment of nursing-related issues in the lateral-Trendelenburg position




                                                                                    43
Gravity-VAP trial - NCT01138540
Version 1.4.0
5 Subject Accrual

5.1 Screening and Research Centers
       The study will be initially conducted in 4 research centers that comprise the Gravity-VAP
Network. Following an initial interim analysis, mainly focused on feasibility of positioning the patient
in the semi-recumbent and lateral-Trendelenburg position, the protocol will be extended to various
European and North American Centers in order to efficiently enroll all patients according to the
planned sample size. Patients from each intensive care unit of the hospitals that comprises the Gravity-
VAP Network, expected to be ventilated for more than 48 hours will be screened. All patients admitted
in the critical care units will be daily screened by the research coordinator of each center. Once a study
candidate is identified, the enrollment criteria will be reviewed, and written informed consent will be
obtained from the patient, or their legally authorized representative. Each investigator involved in the
Gravity-VAP network will complete daily a screening log reporting whether the patients fulfill the
inclusion and exclusion criteria and reasons why patients that fulfill the inclusion criteria are not
enrolled. All patients must be enrolled, randomized and positioned within 6 hours from intubation.
All patients will be subject to standard measures for general critical care. In all intensive care units of
the Gravity-VAP trial any other change in practices to prevent VAP will be discouraged during the
study period. Feeding (enteral or parenteral) will be administered based on the decision of the
physician in charge.


5.2 Inclusion Criteria
   1. Age ≥ 18 years
   2. Patients expected to be oro-tracheally intubated for at least 48 hours or longer
   3. Enrollment time window within 6 hours following intubation


5.3 Exclusion Criteria
   1. Current and past participation in an other intervention trial conflicting with the present study

                                                                                                         44
Gravity-VAP trial - NCT01138540
Version 1.4.0
   2. Previous endotracheal intubation longer than 12 hours during the previous 30 days
   3. Patients with documented bronchiectasis
   4. Cystic fibrosis
   5. Witnessed pulmonary aspiration either prior or at intubation
   6. Patients with increased intracranial pressure, brain edema; or medical conditions that can
        worsen with increase in intracranial pressure
   7. Patients with significant heart failure and activity impairment (Class III-IV of the New York
        Heart Association (NYHA)
   8. Spinal cord injury
   9. BMI > 35, or weight above 300 pound
   10. Grade IV: Intra-abdominal pressure (IAP) > 25 mmHg or abdominal compartment syndrome
        (ACS), defined as a sustained IAP > 20 mmHg that is associated with new organ dysfunction /
        failure
   11. Pregnancy
   12. Orthopedic problems that will not allow the patient to be kept in one of the study positions


5.4 Informed Consent
Informed consent will be obtained from each patient or surrogate either before the study or
retrospectively in case the patient is unconscious at the time of enrollment.


5.5 Randomization
       Patients will be randomized to be positioned either in the semi-recumbent position with the
head of the bed elevated ≥ 30 degrees or in the lateral-Trendelenburg body position. A computer
generated random numbers using block randomization by site with a fixed block length of 10 patients
will be used.




                                                                                                      45
Gravity-VAP trial - NCT01138540
Version 1.4.0
6 Study procedures

6.1 Body Positions
6.1a Semi-recumbent position:
       Patients will be positioned supine with the head of the bed oriented ≥ 30 degrees (APPENDIX
B, figure 4). The orientation of the bed will be measured and recorded every six hours either via the
indicator of the bed itself or an air bubble contact angle measuring system applied on a flat rigid
surface of the bed (APPENDIX C, Orientation of the Bed Assessment).
6.1b Lateral Trendelenburg position:
       Patients will be positioned in a lateral position, similar to the recovery position; with the head of
the bed tilted 5-10 degrees in Trendelenburg position (Appendix B, Figure 1, 2 and 3). A vertical line
from the sternal notch to the ETT connector piece, passing through the middle of the trachea should be
used as a surface landmark. The patient should be always positioned in order to maintain this line
oriented slightly below horizontal. In order to position the patient the arm closest to the attending nurse
will be placed straight out from the body. The far arm will be positioned with the back of the hand
close to the near cheek. The patient's far knee will be grabbed and bended. Protecting the head with one
hand, the patient will be gently rolled toward the attending nurse by pulling the far knee over and to the
bed. Finally the head will be slightly tilted up. The hand should be close to and not under the cheek. A
pillow will be positioned behind the chest and close to the dependent forearm in order to prevent
compression of the axillary artery75. The head of the bed will be now tilted based on the tracheal
orientation to achieve an orientation of the area within the trachea where the ETT cuff is placed 2-5
degrees below horizontal and to ensure prevention of aspiration of oropharyngeal secretions across the
cuff. The orientation of the bed will be measured either via the indicator of the bed itself or an air
bubble angle measuring system, and recorded every six hours (APPENDIX C, Orientation of the Bed
Assessment). The ETT, exiting the mouth, will be oriented a few degrees below horizontal. The Y
piece will be oriented vertical, with the inspiratory line above the expiratory line. The head will be
positioned on a thin pillow with the eye closest to the pillow not touching the pillow. Patients will be

                                                                                                         46
Gravity-VAP trial - NCT01138540
Version 1.4.0
kept in the lateral position, with the body tilted of 90 degrees and rotated from one side to the other
side of their body every six hours. In order to rotate the patient from one side to the other, patient will
be firstly repositioned supine: protecting the head with one hand, the patient’s upper leg and arm will
be gently re-rolled externally, and then the aforementioned procedure to position the patient in the
recovery positioned will be re-applied. Pulse oxymeter will be preferentially positioned on the
dependent hand in order to assess arterial perfusion impairment during lateral body position. A pillow
will be positioned between the knees and behind the back as needed.


6.2 Preventive strategies
       Sites will be allowed to follow institutional practices for preventing VAP and will be
encouraged to avoid changing practices during the study


6.3 Respiratory gases humidification
       In all sites active humidification of respiratory gases, via heated humidifier, will be encouraged


6.4 Enteral Nutrition
       Patients who require enteral nutrition will be fed via a nasogastric tube. Gastric residuals will be
checked every 4-6 hr. Infusions will be held for 1 hour if gastric residual is >1.0 to 1.5 x hourly rate or
>150 ml before feeding. In patient with consistent high gastric residual either a nasoduodenal, or
nasojejunal tube will be placed


6.5 Weaning protocol

Patients need to be evaluated daily for eligibility to be extubated. Patients will be considered eligible to
initiate a spontaneous breathing trial (SBT) when the following criteria will be fulfilled]:
     1. Significant improvement or resolution of the underlying causes of acute respiratory failure
     2. No fever (≥38°C) or hypothermia (<35ºC)
     3.   Blood haemoglobin concentration ≥70 g.L-1
                                                                                                         47
Gravity-VAP trial - NCT01138540
Version 1.4.0
      4.   Hemodynamic stability
      5. Alertness and ability to communicate after discontinuing sedation (RASS≥0)
      6. Arterial O2 tension >60 mmHg with fraction of inspired oxygen (FIO2) ≤0.4 and positive
           end-expiratory pressure ≤5 cmH2O


Patients with previous tracheostomy will be not considered eligible for this protocol. During the
weaning protocol, if possible, patients will be cared for in the randomized position, however changing
from the lateral-Trendelenburg into the semirecumbent position will be allowed. Prior to the SBT,
assisted-control or pressure-support ventilation will be used depending on patients’ preferences or
tolerance. The T tube trial circuit is reported below:




No more than a SBT per day is strongly advice. The trial should be limited to two hours or less. The
patient should be monitored for increased effort (eg, nasal flaring, accessory muscle recruitment,
recession of the suprasternal and intercostal spaces, or paradoxic motion of the rib cage and abdomen).
In addition, the chest should be auscultated to detect new wheezing or crackles. Dyspnea and changes
of mental status, blood pressure, heart rate, or cardiac rhythm should be identified.


A SBT should be considered unsuccessful as the presence and persistence of one of the following
criteria occur:

                                                                                                    48
Gravity-VAP trial - NCT01138540
Version 1.4.0
   1) respiratory frequency >35 min-1
   2) arterial O2 saturation by pulse-oximetry <90% at FIO2 ≥ 0.40
   3) heart rate >140 or <50 min-1, or increases or decreases of more than 20% compared to MV
   4) systolic blood pressure >180 or <70 mmHg, or increases or decreases of more than 20%
       compared to MV
   5) decreased consciousness, agitation or diaphoresis
   6) thoracic-abdominal paradoxical movement


After a SBT trial failure, the patient should return to full ventilatory assistance. If no signs of SBT
failure appeared after 30-120 minutes the trial is considered successful. And the patient should be
extubated.




                                                                                                    49
Gravity-VAP trial - NCT01138540
Version 1.4.0
6.6 Ventilator-associated pneumonia diagnosis
        Pneumonia will be clinically suspected when a new, persistent, progressive radiographic lung
infiltrate will be present ≥ 48 hours following tracheal intubation with 2 or more of the following
clinical criteria:
    1. Fever (T≥38 ºC) or hypothermia (T<35ºC)
    2. Leukocitosis (WBC>10000/ml) or leucopenia (WBC<4000/ml)
    3. Purulent tracheal aspirates
    Diagnosis of VAP will be confirmed via bronchoalveolar lavage either blind or through fiberoptic
bronchoscopy. Importantly, based on previous laboratory studies, the lateral-Trendelenburg position
greatly enhances mucus clearance. However mucus still accumulates at the ETT cuff and eventually
become colonized. Consistently, in laboratory studies no differences were found in colonization of
proximal tracheal secretions65;67;72 between animals maintained in the semi-recumbent and
Trendelenburg position. Therefore, following clinical suspicion of VAP, distal sampling will be
performed to improve accuracy of VAP diagnosis and detect difference between groups. Clinical
suspicion of VAP will be microbiologically confirmed if quantitative cultures of BAL or mini-BAL
fluids will yield ≥ 104 colony-forming units (cfu)/ml and when samples obtained via PSB will yield ≥
103 cfu/ml.


6.7 Data Collection
6.7a Assessments during enrollment (Appendix C, Baseline Assessment):
As soon as the patient is enrolled demographic data will be retrieved:
    1. Personal Data
    2. Medical History
    3. Physical exam
    4. Hospital admitting diagnosis
    5. Reason for ICU admission
    6. Hospital stay before ICU admission
    7. Smoking habits
    8. Chronic alcohol abuse
                                                                                                 50
Gravity-VAP trial - NCT01138540
Version 1.4.0
   9. Intravenous drug abuse
   10. Immuno-competency status
   11. Acute physiology and chronic health evaluation (APACHE II) score
   12. Complete Blood Count
   13. Blood Chemistry (Sodium, Potassium, Blood Urea Nitrogen, Creatinine, Glucose, Aspartate
      Aminotransferase, Alanine Aminotransferase, Gamma glutamyltransferase, Total Bilirubin,
      Alkaline Phosphatase, Creatine Phosphokinase, Lactic Acid Dehydrogenase, Albumin)
   14. Hemodynamic parameters (heart rate, systolic, diastolic and mean arterial pressure, central
      venous pressure, and where a pulmonary artery catheter is in place, systolic, diastolic and mean
      pulmonary artery pressure, wedge pressure and cardiac output)
   15. Respiratory system parameters (inspiratory and expiratory tidal volume, respiratory rate,
      inspiratory fraction of oxygen, plateau pressure, and peak airways pressure)
   16. Current Therapy
   17. Preventive VAP strategies


6.7b Daily assessments during the study (Appendix C, Daily Assessment) up to 14 days:
   1. Body position will be continuously monitored and any change will be recorded (Appendix C:
      Change of Position Assessment)
   2. Type of artificial airway (tracheal tube or tracheostomy tube)
   3. Richmond agitation sedation scale (RASS) (Appendix D)
   4. Hemodynamic parameters ( heart rate, systolic, diastolic and mean arterial pressure, central
      venous pressure, and where a pulmonary artery catheter is in place, systolic, diastolic and mean
      pulmonary artery pressure, wedge pressure and cardiac output)
   5. Respiratory system parameters (inspiratory and expiratory tidal volume, respiratory rate,
      inspiratory fraction of oxygen, plateau pressure, and peak airways pressure)
   6. Blood gas parameters as indicated
   7. Complete blood count
   8. Blood Chemistry
   9. Chest X-ray

                                                                                                   51
Gravity-VAP trial - NCT01138540
Version 1.4.0
   10. Clinical signs of VAP: Fever, complete blood count, quality of tracheal secretions
   11. Sedative treatment
   12. Antimicrobial treatment
   13. Oral Care
   14. Stress ulcer prophylaxis
   15. Nutrition and methods of feeding
   16. Internal cuff pressure
   17. Aspiration of sub-glottic secretions
   18. Assessment of new pressure sores or worsening pressure sores (Appendix C, Pressure Sores
      Assessment)
   19. Adverse Events




                                                                                            52
Gravity-VAP trial - NCT01138540
Version 1.4.0
6.7c Assessments at extubation or after 14 days of tracheal intubation (Appendix C, Daily
Assessment):
   1. Physical exam
   2. Complete Blood Count
   3. Blood Chemistry (Sodium, Potassium, Blood Urea Nitrogen, Creatinine, Glucose, Aspartate
       Aminotransferase, Alanine Aminotransferase, Gamma glutamyltransferase, Total Bilirubin,
       Alkaline Phosphatase, Creatine Phosphokinase, Lactic Acis Dehydrogenase, Albumin)
   4. Hemodynamic parameters ( heart rate, systolic, diastolic and mean arterial pressure, central
       venous pressure, and where a pulmonary artery catheter is in place, systolic, diastolic and mean
       pulmonary artery pressure, wedge pressure and cardiac output)
   5. Respiratory system parameters (inspiratory and expiratory tidal volume, respiratory rate,
       inspiratory fraction of oxygen, plateau pressure, and peak airways pressure)
   6. Adverse Events


6.7d Assessments at 30 Days or after Hospital Discharge (Appendix C, Final Evaluation)
   1. Date of Mechanical Discontinuation
   2. ICU Discharge
   3. Hospital Discharge
   4. ICU survival
   5. Hospital survival
   6. 28 Days Survival
   7. ICU Adverse Events
   8. Nurse Survey


6.7e Alternatives to this clinical study
       Patients who choose not to participate in this study will receive standard care according to the
procedures of the ICU, without any repercussion.




                                                                                                    53
Gravity-VAP trial - NCT01138540
Version 1.4.0
6.8 Special Clinical and Laboratory Methods (include sample storage)
6.8a Bronchoalveolar Lavage

       Sampling area will be chosen based on the basis of the new pulmonary infiltrate seen on the
chest radiography. Patients will be prepared with 100% of inspiratory fraction of oxygen, adequate
sedation and paralysis as needed. The tip of the bronchoscope will be wedged into the chosen
subsegment of the lung and 20 ml sterile saline solution injected, aspirated and discarded. Additional 3
aliquots of 20-40 ml sterile saline will be injected and aspirated. Aspirated fluids will be sent to the
microbiology department for Gram stain and quantitative culture

6.8b Blind Bronchoalveolar lavage

       Patients will be prepared with 100% of inspiratory fraction of oxygen, adequate sedation and
paralysis as needed. The catheter will be advanced through the ETT approximately 5 cm beyond the tip
of the ETT; then the catheter tip will be flushed with 2 ml saline. Low flow of oxygen may be
administered by oxygen line connected to the catheter oxygen port. In order to reach the wedge
position the outer sheath will be hold in place and advanced the inner catheter until resistance is
encounter. Then the catheter will be locked in position. One aliquot of 25 ml sterile saline will be
injected and aspirated. Aspirated fluids will be sent to the microbiology department for Gram stain and
quantitative culture.


6.8c Nursing evaluation

       A questionnaire will be given to the nurses to highlight nursing feasibility and work load related
to position patients included in the control and study groups (APPENDIX C: Nurse Survey on Patient
Positioning).




                                                                                                      54
Gravity-VAP trial - NCT01138540
Version 1.4.0
7. Monitoring of Subjects and Criteria for Withdrawal of
Subjects

7.1 Stopping Rules
       Patients will be maintained in the randomized position and followed-up with daily assessments
for the entire duration of tracheal intubation or until the 14 day of tracheal intubation. As for the lateral-
Trendelenburg position, based on our previous animal studies, it is important to maintain such position
particularly when patients are deeply sedated and at higher risk for aspiration. Based on an intention to
treat analysis, data will be analyzed based on the initial treatment intent, irrespective of total duration
of the treatment. In particular, it should be acknowledged that patients randomized into the lateral-
Trendelenburg position group may be more at risk for non adherence to the recommended position,
particularly for scarce tolerance to the treatment; however the compliance to the recommended position
will be certainly high when patients are sedated and at the highest risk for aspiration. An extensive
educational program for the healthcare personnel will be undertaken in order to achieve this goal. In
conclusion, we will analyze data based on an intention to treat approach, with particular emphasis on
understanding feasibility of the novel position and adherence to the protocol when patients are deeply
sedated.

7.1a Exit Criteria:

Premature discontinuation of the trial will be allowed when one of the following conditions occurs:
   1. Death
   2. Transfer to another department
   3. Unexpected circumstances that do not allow a continuous monitoring and adjustment of the
       patient’s position and assessment of the daily clinical condition

7.1b Tracheostomy:

Percutaneous and surgical tracheostomies will not be considered as an exit criteria. Tracheostomies will be
                                                                                                         55
Gravity-VAP trial - NCT01138540
Version 1.4.0
carried out, according to local current standard practice. As soon as tracheostomy tube will be placed,
patients will be repositioned in the assigned position


7.1c Follow up:

       28-day survival and hospital mortality will be assessed within a month from initial enrollment
or at hospital discharge.




                                                                                                    56
Gravity-VAP trial - NCT01138540
Version 1.4.0
8. Analysis of the Study and Sample size Determination

8.1 Sample size
         Incidence of VAP from May 2008 to May 2009 for each center participating in the trial, divided
by type of intensive care unit were pooled together (Table 8). The analysis has shown an overall
incidence of VAP of 9.7/1000 ventilator days. We designed this study to detect a 50% reduction in
density of VAP from 9.70 to 4.85 per 1000 ventilator days. We calculated that approximately 800
patients (400 for each group) should be enrolled to detect a 50% reduction in density of VAP for a
statistical power of 90% with a 2 sided significance level of 0.05.


Table 8
                                                                               VAP Rate
                                                                               Per 1000 vent-days
Center                       Beds                    Critical Care Unit
                                                                               (May 2008 – May
                                                                               2009)
Hospital Clinic,
                             6                       Respiratory               9.5
Barcelona, Spain
Hospital Clinic,
                             8                       Medical                   9
Barcelona, Spain
Hospital Clinic,
                             8                       Surgical                  10
Barcelona, Spain
Massachusetts General
                             14                      Surgical                  10.06
Hospital, Boston, USA
Policlinico, Milano, Italy   8                       Medical                   11
Policlinico, Milano, Italy   8                       Surgical                  8.7
San Gerardo, Monza,
                             10                      Mixed Medical/Surgical    10.1
Italy
Average                                                                        9.77



8.2 Randomization


                                                                                                    57
Gravity-VAP trial - NCT01138540
Version 1.4.0
Randomization will be performed by a coordination centre located in the Epidemiology Unit, external
to the Clinic Department.


8.3 Interim analysis
In addition to periodic review of the safety data, 2 interim analyses will be performed. We foresee to
perform an interim analysis after inclusion of 40 patients, mainly to assess feasibility. In particular,
total time per day in which the patient is placed in the randomized position will be assessed. Following
400 patients, during the second interim analysis, we will be able to exclude a dramatic benefit (a
reduction of the frequency of primary end point to about 5% or less) or a dramatic harm (an increase of
the frequency of primary end point to about 30% or more).
The interim analyses will be performed by the Review Board.


8.4 Statistical analyses
Descriptive analyses will be performed, overall and for each participating Center.
Univariate analyses will compare distributions/means (continuous variable) and proportions
(categorical variables) across treatment groups, overall and for each Center.


For the analysis of primary end-point we will use multiple logistic regression, which will include the
covariates of interest a priori (based on literature findings) and those emerging from univariate
analyses.
The regression models will include the Center as a covariate. Effect modification of treatment by
Center will be assessed by including a Centre-Treatment interaction term in the model.
Time-course of VAP incidence will be examined using survival techniques (Nelson-Aalen, Kaplan-
Meier, Cox regression).


For the secondary end-points we will use multiple linear and logistic regression techniques for
continuous and dichotomous end-points, respectively. When analyzing durations (ventilation, ICU and
hospital stay), which usually are right-skewed, a transformation (e.g., logarithmic) will be applied to
obtain a Gaussian distribution.

                                                                                                     58
Gravity-VAP trial - NCT01138540
Version 1.4.0
9. Human Subjects Protection
        Protocol and any following amendment to the original protocol will be translated in Italian,
English and Spanish and submitted for the approval of each institutional review board (IRB). All
protocols of the study will require prior approval by each institutional review board, before enrollment
of patients. Study participants or a member of a patient’s family will sign and date an informed consent
prior enrollment into the study. Clinical information will not be released without the written consent of
the patient.


9.2 Evaluation of Benefits of the lateral-Trendelenburg position
The potential benefits associated with the lateral Trendelenburg position are the follows:
    1. Decrease/absence of bacterial colonization of the lower respiratory tract
    2. Decrease/absence of aspiration of gastric contents
    3. Decrease/absence of aspiration of oropharyngeal secretions
    4. Enhanced clearance of bronchial secretions and reduction of pulmonary atelectasis
    5. Increase in patient comfort
    6. Reduction in deep venous thrombosis, and pulmonary embolism
    7. Lower need of vasopressors, and fluids, due to the centralization of blood volume


9.3 Risk assessment of the lateral-Trendelenburg position
    •   Patients enrolled in the lateral-Trendelenburg positioning group will be at higher risk to be
        extubated and disconnection of vascular lines during routinely rotation Extubation will be
        prevented with a proper fixation of the ETT. Health care personnel will take particular care
        during the 6 hourly rotation of the patient. The procedure will be performed by 2 nurses, one
        dedicated to rotate the upper body and maintaining ETT in place and the second nurse in charge
        of lower body rotation. Vascular access lines disconnection will be also prevented during
        rotation.

                                                                                                      59
Gravity-VAP trial - NCT01138540
Version 1.4.0
   •   Moreover, patient in the treatment group may experience more often in comparison to patient
       position in the semirecumbent position edema of face, tongue, and eyes
   •   When patient are positioned on the side pressure ulcer may develop on the dependent surface of
       the arm and leg. A daily assessment of the patient will be performed particularly at the pressure
       points, such as the shoulder and the iliac region. All preventive measures to reduce incidence of
       pressure ulcers will be applied, such as proper skin cleaning, use of skin moisturizers, pillows
       or foam wedges to keep bony prominences from direct contact with each other and pad skin to
       device related pressure. Wound care with transparent film, hydrocolloids, alginates, gauzes,
       hydrogels and composites will be performed based on the wound characteristics.
   •   Ultimately in patients in the lateral-Trendelenburg position, the feeding via naso-gastric tube
       may be more difficult and result in higher gastro-esophageal reflux. In order to ensure proper
       enteral feeding and reduce reflux, unless contraindicated, post-pyloric feeding should be
       preferred in those patients.


9.4 Protocol Consent Processes and Documents

       Patient consent form, patient retrospective consent form, patient information sheet on protocol
and covering statement for patient’s relatives are reported in APPENDIX D.



10. Conflict of Interests


11. Adverse events reporting
       Each investigator of the Gravity-VAP network has responsibility for the safety of each subject
enrolled into the study. Each investigator will also review patient records for possible, unexpected,
adverse events during the study period.
       All unexpected serious events will be reported within few hours and a detailed written report
should be submitted.
                                                                                                     60
Gravity-VAP trial - NCT01138540
Version 1.4.0
           •   An adverse event is any undesirable experience associated with the use of a medical
               product in a patient. The event is serious and should be reported when the patient
               outcome is:
               Death
               Report if the patient's death is suspected as being a direct outcome of the adverse event.
               Life-Threatening
               Report if the patient was at substantial risk of dying at the time of the adverse event or it
               is suspected that the use or continued use of the product would result in the patient's
               death.
               Disability
               Report if the adverse event resulted in a significant, persistent, or permanent change,
               impairment, damage or disruption in the patient's body function/structure, physical
               activities or quality of life.
               Requires Intervention to Prevent Permanent Impairment or Damage
               Report if you suspect that the procedure may result in a condition which required
               medical or surgical intervention to preclude permanent impairment or damage to a
               patient.


           •   An unexpected adverse event is any experience not identified by type severity or
               frequency in the current study protocol, or an event unexpected during the course of
               mechanical ventilation




12. Data collection and Site Monitoring plan

12.1 Data Collection
       Data will be collected in dedicated forms (APPENDIX C). Each site will have a computer
dedicated to record all data in a custom designed website. Hard copy of the data will be kept for at least
                                                                                                       61
Gravity-VAP trial - NCT01138540
Version 1.4.0
5 years following the conclusion of the study. Each investigator of the gravity VAP network will be
responsible to collect all data. All adverse events will be reported to the IRB.
.


12.1 Site Monitoring
       All investigators of the Gravity-VAP trial will routinely meet every 3 months to monitor the
quality of the data collected and ensure safety of the lateral-Trendelenburg position



13. Compensations
No compensation will be offered to subjects participating in the study.




                                                                                                62
Gravity-VAP trial - NCT01138540
Version 1.4.0
14. References

                                            Reference List




   1. Vincent, J. L., D. J. Bihari, P. M. Suter, H. A. Bruining, J. White, M. H. Nicolas-Chanoin, M.

      Wolff, R. C. Spencer, and M. Hemmer. 1995. The prevalence of nosocomial infection in

      intensive care units in Europe. Results of the European Prevalence of Infection in Intensive

      Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274:639-644.



   2. Chastre, J. and J. Y. Fagon. 2002. Ventilator-associated pneumonia. Am.J.Respir.Crit Care

      Med. 165:867-903.



   3. Konrad, F., T. Schreiber, D. Brecht-Kraus, and M. Georgieff. 1994. Mucociliary transport in

      ICU patients. Chest 105:237-241.



   4. Sackner, M. A., J. Hirsch, and S. Epstein. 1975. Effect of cuffed endotracheal tubes on tracheal

      mucous velocity. Chest 68:774-777.



   5. Donowitz, L. G., M. C. Page, B. L. Mileur, and S. H. Guenthner. 1986. Alteration of normal

      gastric flora in critical care patients receiving antacid and cimetidine therapy. Infect.Control

                                                                                                         63
Gravity-VAP trial - NCT01138540
Version 1.4.0
      7:23-26.



   6. Hillman, K. M. 1983. Colonisation of the gastric contents in critically ill patients. Acta

      Anaesthesiol.Belg. 34:191-192.



   7. Daschner, F., I. Kappstein, I. Engels, K. Reuschenbach, J. Pfisterer, N. Krieg, and W. Vogel.

      1988. Stress ulcer prophylaxis and ventilation pneumonia: prevention by antibacterial

      cytoprotective agents? Infect.Control Hosp.Epidemiol. 9:59-65.



   8. Orozco-Levi, M., A. Torres, M. Ferrer, C. Piera, M. el-Ebiary, J. P. de la Bellacasa, and R.

      Rodriguez-Roisin. 1995. Semirecumbent position protects from pulmonary aspiration but not

      completely from gastroesophageal reflux in mechanically ventilated patients. Am.J.Respir.Crit

      Care Med. 152:1387-1390.



   9. Torres, A., J. Serra-Batlles, E. Ros, C. Piera, B. J. Puig de la, A. Cobos, F. Lomena, and R.

      Rodriguez-Roisin. 1992. Pulmonary aspiration of gastric contents in patients receiving

      mechanical ventilation: the effect of body position. Ann.Intern.Med. 116:540-543.



  10. Dullenkopf, A., A. Gerber, and M. Weiss. 2003. Fluid leakage past tracheal tube cuffs:

      evaluation of the new Microcuff endotracheal tube. Intensive Care Med. 29:1849-1853.




                                                                                                      64
Gravity-VAP trial - NCT01138540
Version 1.4.0
  11. Lorente, L., M. Lecuona, A. Jimenez, M. L. Mora, and A. Sierra. 2007. Influence of an

       endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia.

       Am.J.Respir.Crit Care Med. 176:1079-1083.



  12. Dezfulian, C., K. Shojania, H. R. Collard, H. M. Kim, M. A. Matthay, and S. Saint. 2005.

       Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis.

       Am.J.Med. 118:11-18.



  13. Kollef, M. H. 1993. Ventilator-associated pneumonia. A multivariate analysis. JAMA 270:1965-

       1970.



  14. Drakulovic, M. B., A. Torres, T. T. Bauer, J. M. Nicolas, S. Nogue, and M. Ferrer. 1999.

       Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated

       patients: a randomised trial. Lancet 354:1851-1858.



  15. Bonten, M. J., C. A. Gaillard, F. H. van Tiel, H. G. Smeets, G. S. van der, and E. E.

       Stobberingh. 1994. The stomach is not a source for colonization of the upper respiratory tract

       and pneumonia in ICU patients. Chest 105:878-884.



  16. Bonten, M. J., C. A. Gaillard, G. S. van der, F. H. van Tiel, A. J. Beysens, H. G. Smeets, and E.

       E. Stobberingh. 1995. The role of intragastric acidity and stress ulcus prophylaxis on

       colonization and infection in mechanically ventilated ICU patients. A stratified, randomized,
                                                                                                        65
Gravity-VAP trial - NCT01138540
Version 1.4.0
        double-blind study of sucralfate versus antacids. Am.J.Respir.Crit Care Med. 152:1825-1834.



  17. Bonten, M. J., D. C. Bergmans, A. W. Ambergen, P. W. de Leeuw, G. S. van der, E. E.

        Stobberingh, and C. A. Gaillard. 1996. Risk factors for pneumonia, and colonization of

        respiratory tract and stomach in mechanically ventilated ICU patients. Am.J.Respir.Crit Care

        Med. 154:1339-1346.



  18. de Latorre, F. J., T. Pont, A. Ferrer, J. Rossello, M. Palomar, and M. Planas. 1995. Pattern of

        tracheal colonization during mechanical ventilation. Am.J.Respir.Crit Care Med. 152:1028-

        1033.



  19.   2005. Guidelines for the management of adults with hospital-acquired, ventilator-associated,

        and healthcare-associated pneumonia. Am.J.Respir.Crit Care Med. 171:388-416.



  20. Tablan, O. C., L. J. Anderson, R. Besser, C. Bridges, and R. Hajjeh. 2004. Guidelines for

        preventing health-care--associated pneumonia, 2003: recommendations of CDC and the

        Healthcare Infection Control Practices Advisory Committee. MMWR Recomm.Rep. 53:1-36.



  21. Torres, A., S. Ewig, H. Lode, and J. Carlet. 2009. Defining, treating and preventing hospital

        acquired pneumonia: European perspective. Intensive Care Med. 35:9-29.




                                                                                                        66
Gravity-VAP trial - NCT01138540
Version 1.4.0
  22. Kollef, M. H., P. Silver, D. M. Murphy, and E. Trovillion. 1995. The effect of late-onset

       ventilator-associated pneumonia in determining patient mortality. Chest 108:1655-1662.



  23. Rello, J., D. A. Ollendorf, G. Oster, M. Vera-Llonch, L. Bellm, R. Redman, and M. H. Kollef.

       2002. Epidemiology and outcomes of ventilator-associated pneumonia in a large US database.

       Chest 122:2115-2121.



  24. Torres, A., M. el-Ebiary, N. Soler, C. Monton, N. Fabregas, and C. Hernandez. 1996. Stomach

       as a source of colonization of the respiratory tract during mechanical ventilation: association

       with ventilator-associated pneumonia. Eur.Respir.J. 9:1729-1735.



  25. Cook, D., G. Guyatt, J. Marshall, D. Leasa, H. Fuller, R. Hall, S. Peters, F. Rutledge, L.

       Griffith, A. McLellan, G. Wood, and A. Kirby. 1998. A comparison of sucralfate and ranitidine

       for the prevention of upper gastrointestinal bleeding in patients requiring mechanical

       ventilation. Canadian Critical Care Trials Group. N.Engl.J.Med. 338:791-797.



  26. Driks, M. R., D. E. Craven, B. R. Celli, M. Manning, R. A. Burke, G. M. Garvin, L. M.

       Kunches, H. W. Farber, S. A. Wedel, and W. R. McCabe. 1987. Nosocomial pneumonia in

       intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. The

       role of gastric colonization. N.Engl.J.Med. 317:1376-1382.



  27. Ephgrave, K. S., R. Kleiman-Wexler, M. Pfaller, B. M. Booth, D. Reed, L. Werkmeister, and S.
                                                                                                67
Gravity-VAP trial - NCT01138540
Version 1.4.0
      Young. 1998. Effects of sucralfate vs antacids on gastric pathogens: results of a double-blind

      clinical trial. Arch.Surg. 133:251-257.



  28. Kantorova, I., P. Svoboda, P. Scheer, J. Doubek, D. Rehorkova, H. Bosakova, and J. Ochmann.

      2004. Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial.

      Hepatogastroenterology 51:757-761.



  29. Mahul, P., C. Auboyer, R. Jospe, A. Ros, C. Guerin, K. Z. el, M. Galliez, A. Dumont, and O.

      Gaudin. 1992. Prevention of nosocomial pneumonia in intubated patients: respective role of

      mechanical subglottic secretions drainage and stress ulcer prophylaxis. Intensive Care Med.

      18:20-25.



  30. Prod'hom, G., P. Leuenberger, J. Koerfer, A. Blum, R. Chiolero, M. D. Schaller, C. Perret, O.

      Spinnler, J. Blondel, H. Siegrist, L. Saghafi, D. Blanc, and P. Francioli. 1994. Nosocomial

      pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as

      prophylaxis for stress ulcer. A randomized controlled trial. Ann.Intern.Med. 120:653-662.



  31. Thomason, M. H., E. S. Payseur, A. M. Hakenewerth, H. J. Norton, B. Mehta, T. R. Reeves, M.

      W. Moore-Swartz, and P. I. Robbins. 1996. Nosocomial pneumonia in ventilated trauma

      patients during stress ulcer prophylaxis with sucralfate, antacid, and ranitidine. J.Trauma

      41:503-508.


                                                                                                       68
Gravity-VAP trial - NCT01138540
Version 1.4.0
  32. Apte, N. M., D. R. Karnad, T. P. Medhekar, G. H. Tilve, S. Morye, and G. G. Bhave. 1992.

       Gastric colonization and pneumonia in intubated critically ill patients receiving stress ulcer

       prophylaxis: a randomized, controlled trial. Crit Care Med. 20:590-593.



  33. Eddleston, J. M., R. C. Pearson, J. Holland, J. A. Tooth, A. Vohra, and B. H. Doran. 1994.

       Prospective endoscopic study of stress erosions and ulcers in critically ill adult patients treated

       with either sucralfate or placebo. Crit Care Med. 22:1949-1954.



  34. Apte, N. M., D. R. Karnad, T. P. Medhekar, G. H. Tilve, S. Morye, and G. G. Bhave. 1992.

       Gastric colonization and pneumonia in intubated critically ill patients receiving stress ulcer

       prophylaxis: a randomized, controlled trial. Crit Care Med. 20:590-593.



  35. Cardenosa Cendrero, J. A., J. Sole-Violan, B. A. Bordes, C. J. Noguera, F. J. Arroyo, S. P.

       Saavedra, and C. F. Rodriguez de. 1999. Role of different routes of tracheal colonization in the

       development of pneumonia in patients receiving mechanical ventilation. Chest 116:462-470.



  36. Eddleston, J. M., A. Vohra, P. Scott, J. A. Tooth, R. C. Pearson, R. F. McCloy, A. K. Morton,

       and B. H. Doran. 1991. A comparison of the frequency of stress ulceration and secondary

       pneumonia in sucralfate- or ranitidine-treated intensive care unit patients. Crit Care Med.

       19:1491-1496.



  37. Feldman, C., M. Kassel, J. Cantrell, S. Kaka, R. Morar, M. A. Goolam, and J. I. Philips. 1999.
                                                                                                   69
Gravity-VAP trial - NCT01138540
Version 1.4.0
      The presence and sequence of endotracheal tube colonization in patients undergoing mechanical

      ventilation. Eur.Respir.J. 13:546-551.



  38. Garrouste-Org, S. Chevret, G. Arlet, O. Marie, M. Rouveau, N. Popoff, and B. Schlemmer.

      1997. Oropharyngeal or gastric colonization and nosocomial pneumonia in adult intensive care

      unit patients. A prospective study based on genomic DNA analysis. Am.J.Respir.Crit Care

      Med. 156:1647-1655.



  39. Garvey, B. M., J. A. McCambley, and D. V. Tuxen. 1989. Effects of gastric alkalization on

      bacterial colonization in critically ill patients. Crit Care Med. 17:211-216.



  40. Inglis, T. J., E. W. Lim, G. S. Lee, K. F. Cheong, and K. S. Ng. 1998. Endogenous source of

      bacteria in tracheal tube and proximal ventilator breathing system in intensive care patients.

      Br.J.Anaesth. 80:41-45.



  41. Kappstein, I., G. Schulgen, T. Friedrich, P. Hellinger, A. Benzing, K. Geiger, and F. D.

      Daschner. 1991. Incidence of pneumonia in mechanically ventilated patients treated with

      sucralfate or cimetidine as prophylaxis for stress bleeding: bacterial colonization of the

      stomach. Am.J.Med. 91:125S-131S.



  42. Palmer, L. B., S. V. Donelan, G. Fox, E. Bellemore, and W. H. Greene. 1995. Gastric flora in

      chronically mechanically ventilated patients. Relationship to upper and lower airway
                                                                                                       70
Gravity-VAP trial - NCT01138540
Version 1.4.0
       colonization. Am.J.Respir.Crit Care Med. 151:1063-1067.



  43. Reusser, P., W. Zimmerli, D. Scheidegger, G. A. Marbet, M. Buser, and K. Gyr. 1989. Role of

       gastric colonization in nosocomial infections and endotoxemia: a prospective study in

       neurosurgical patients on mechanical ventilation. J.Infect.Dis. 160:414-421.



  44. Simms, H. H., E. DeMaria, L. McDonald, D. Peterson, A. Robinson, and K. W. Burchard.

       1991. Role of gastric colonization in the development of pneumonia in critically ill trauma

       patients: results of a prospective randomized trial. J.Trauma 31:531-536.



  45. Torres, A., M. el-Ebiary, J. Gonzalez, M. Ferrer, B. J. Puig de la, A. Gene, A. Martos, and R.

       Rodriguez-Roisin. 1993. Gastric and pharyngeal flora in nosocomial pneumonia acquired

       during mechanical ventilation. Am.Rev.Respir.Dis. 148:352-357.



  46. Valles, J., D. Mariscal, P. Cortes, P. Coll, A. Villagra, E. Diaz, A. Artigas, and J. Rello. 2004.

       Patterns of colonization by Pseudomonas aeruginosa in intubated patients: a 3-year prospective

       study of 1,607 isolates using pulsed-field gel electrophoresis with implications for prevention of

       ventilator-associated pneumonia. Intensive Care Med. 30:1768-1775.



  47. Paster, B. J., S. K. Boches, J. L. Galvin, R. E. Ericson, C. N. Lau, V. A. Levanos, A.

       Sahasrabudhe, and F. E. Dewhirst. 2001. Bacterial diversity in human subgingival plaque.

       J.Bacteriol. 183:3770-3783.
                                                                                                       71
Gravity-VAP trial - NCT01138540
Version 1.4.0
  48. Johanson, W. G., A. K. Pierce, and J. P. Sanford. 1969. Changing pharyngeal bacterial flora of

       hospitalized patients. Emergence of gram-negative bacilli. N.Engl.J.Med. 281:1137-1140.



  49. Scannapieco, F. A., E. M. Stewart, and J. M. Mylotte. 1992. Colonization of dental plaque by

       respiratory pathogens in medical intensive care patients. Crit Care Med. 20:740-745.



  50. Valenti, W. M., R. G. Trudell, and D. W. Bentley. 1978. Factors predisposing to oropharyngeal

       colonization with gram-negative bacilli in the aged. N.Engl.J.Med. 298:1108-1111.



  51. Brennan, M. T., F. Bahrani-Mougeot, P. C. Fox, T. P. Kennedy, S. Hopkins, R. C. Boucher, and

       P. B. Lockhart. 2004. The role of oral microbial colonization in ventilator-associated

       pneumonia. Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod. 98:665-672.



  52. Mori, H., H. Hirasawa, S. Oda, H. Shiga, K. Matsuda, and M. Nakamura. 2006. Oral care

       reduces incidence of ventilator-associated pneumonia in ICU populations. Intensive Care Med.

       32:230-236.



  53. DeRiso, A. J., J. S. Ladowski, T. A. Dillon, J. W. Justice, and A. C. Peterson. 1996.

       Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory

       infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery.

       Chest 109:1556-1561.


                                                                                                     72
Gravity-VAP trial - NCT01138540
Version 1.4.0
  54. Houston, S., P. Hougland, J. J. Anderson, M. LaRocco, V. Kennedy, and L. O. Gentry. 2002.

      Effectiveness of 0.12% chlorhexidine gluconate oral rinse in reducing prevalence of nosocomial

      pneumonia in patients undergoing heart surgery. Am.J.Crit Care 11:567-570.



  55. Segers, P., R. G. Speekenbrink, D. T. Ubbink, M. L. van Ogtrop, and B. A. de Mol. 2006.

      Prevention of nosocomial infection in cardiac surgery by decontamination of the nasopharynx

      and oropharynx with chlorhexidine gluconate: a randomized controlled trial. JAMA 296:2460-

      2466.



  56. Grap, M. J., C. L. Munro, R. K. Elswick, Jr., C. N. Sessler, and K. R. Ward. 2004. Duration of

      action of a single, early oral application of chlorhexidine on oral microbial flora in

      mechanically ventilated patients: a pilot study. Heart Lung 33:83-91.



  57. Fourrier, F., D. Dubois, P. Pronnier, P. Herbecq, O. Leroy, T. Desmettre, E. Pottier-Cau, H.

      Boutigny, P. C. Di, A. Durocher, and M. Roussel-Delvallez. 2005. Effect of gingival and dental

      plaque antiseptic decontamination on nosocomial infections acquired in the intensive care unit:

      a double-blind placebo-controlled multicenter study. Crit Care Med. 33:1728-1735.



  58. Fourrier, F., E. Cau-Pottier, H. Boutigny, M. Roussel-Delvallez, M. Jourdain, and C. Chopin.

      2000. Effects of dental plaque antiseptic decontamination on bacterial colonization and

      nosocomial infections in critically ill patients. Intensive Care Med. 26:1239-1247.


                                                                                                     73
Gravity-VAP trial - NCT01138540
Version 1.4.0
  59. Panchabhai, T. S., N. S. Dangayach, A. Krishnan, V. M. Kothari, and D. R. Karnad. 2009.

      Oropharyngeal cleansing with 0.2% chlorhexidine for prevention of nosocomial pneumonia in

      critically ill patients: an open-label randomized trial with 0.01% potassium permanganate as

      control. Chest 135:1150-1156.



  60. van Nieuwenhoven, C. A., C. Vandenbroucke-Grauls, F. H. van Tiel, H. C. Joore, R. J. van

      Schijndel, d. T. van, I, G. Ramsay, and M. J. Bonten. 2006. Feasibility and effects of the

      semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit

      Care Med. 34:396-402.



  61. Orozco-Levi, M., M. Felez, E. Martinez-Miralles, J. F. Solsona, M. L. Blanco, J. M. Broquetas,

      and A. Torres. 2003. Gastro-oesophageal reflux in mechanically ventilated patients: effects of

      an oesophageal balloon. Eur.Respir.J. 22:348-353.



  62. Metheny, N. A., R. E. Clouse, Y. H. Chang, B. J. Stewart, D. A. Oliver, and M. H. Kollef.

      2006. Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients:

      frequency, outcomes, and risk factors. Crit Care Med. 34:1007-1015.



  63. Ibanez, J., A. Penafiel, J. M. Raurich, P. Marse, R. Jorda, and F. Mata. 1992. Gastroesophageal

      reflux in intubated patients receiving enteral nutrition: effect of supine and semirecumbent

      positions. JPEN J.Parenter.Enteral Nutr. 16:419-422.


                                                                                                     74
Gravity-VAP trial - NCT01138540
Version 1.4.0
  64. Helman, D. L., Jr., J. H. Sherner, III, T. M. Fitzpatrick, M. E. Callender, and A. F. Shorr. 2003.

       Effect of standardized orders and provider education on head-of-bed positioning in

       mechanically ventilated patients. Crit Care Med. 31:2285-2290.



  65. Panigada, M., L. Berra, G. Greco, M. Stylianou, and T. Kolobow. 2003. Bacterial colonization

       of the respiratory tract following tracheal intubation-effect of gravity: an experimental study.

       Crit Care Med. 31:729-737.



  66. Berra, L., M. L. De, Z. X. Yu, P. Laquerriere, A. Baccarelli, and T. Kolobow. 2004.

       Endotracheal tubes coated with antiseptics decrease bacterial colonization of the ventilator

       circuits, lungs, and endotracheal tube. Anesthesiology 100:1446-1456.



  67. Berra, L., M. L. De, M. Panigada, Z. X. Yu, A. Baccarelli, and T. Kolobow. 2004. Evaluation

       of continuous aspiration of subglottic secretion in an in vivo study. Crit Care Med. 32:2071-

       2078.



  68. Kolobow, T., L. Berra, B. G. Li, and F. Curto. 2005. Novel system for complete removal of

       secretions within the endotracheal tube: the Mucus Shaver. Anesthesiology 102:1063-1065.



  69. Berra, L., F. Curto, B. G. Li, P. Laquerriere, A. Baccarelli, and T. Kolobow. 2006.

       Antibacterial-coated tracheal tubes cleaned with the Mucus Shaver : a novel method to retain

       long-term bactericidal activity of coated tracheal tubes. Intensive Care Med. 32:888-893.
                                                                                                          75
Gravity-VAP trial - NCT01138540
Version 1.4.0
  70. Kolobow, T., B. G. Li, F. Curto, and A. Zanella. 2006. The Mucus Slurper: A novel tracheal

      tube that requires no tracheal tube suctioning. A preliminary report. Intensive Care Med.

      32:1414-1418.



  71. Li, B. G., F. Curto, A. Zanella, M. Stylianou, and T. Kolobow. 2007. A 72-hour study to test

      the efficacy and safety of the "Mucus Slurper" in mechanically ventilated sheep. Crit Care

      Med. 35:906-911.



  72. Li Bassi G., A. Zanella, M. Cressoni, M. Stylianou, and T. Kolobow. 2008. Following tracheal

      intubation, mucus flow is reversed in the semirecumbent position: possible role in the

      pathogenesis of ventilator-associated pneumonia. Crit Care Med. 36:518-525.



  73. Nind, G., W. H. Chen, R. Protheroe, K. Iwakiri, R. Fraser, R. Young, M. Chapman, N. Nguyen,

      D. Sifrim, R. Rigda, and R. H. Holloway. 2005. Mechanisms of gastroesophageal reflux in

      critically ill mechanically ventilated patients. Gastroenterology 128:600-606.



  74. Safdar, N., C. J. Crnich, and D. G. Maki. 2005. The pathogenesis of ventilator-associated

      pneumonia: its relevance to developing effective strategies for prevention. Respir.Care 50:725-

      739.



  75. Rathgeber, J., W. Panzer, U. Gunther, M. Scholz, A. Hoeft, J. Bahr, and D. Kettler. 1996.

      Influence of different types of recovery positions on perfusion indices of the forearm.
                                                                                                     76
Gravity-VAP trial - NCT01138540
Version 1.4.0
      Resuscitation 32:13-17.




                                  77
Gravity-VAP trial - NCT01138540
Version 1.4.0
  APPENDIX A: Laboratory animal studies conducted at
  the National Institutes of Health to assess effects of
  gravity in the pathogenesis of ventilator associated
  pneumonia

  Table 5 Incidence of Pneumonia and Colonization per study conducted at the National Institutes of
  Health


 Body                                                                                                            Rate of
                 MV (h)                 Study                 Group      Number of animals Rate of pneumonia
position                                                                                                       colonization
                                        Tantalum                                 8                0/8              0/8
                                     Mucus Shaver             Control            2                0/2              0/2
                                     Mucus Shaver            Treatment           6                0/6              0/6
                     24




                                   Mucus Slurper 24 h         Control            3                0/3              0/3
                                   Mucus Slurper 24 h        Treatment           3                0/3              0/3
                                       Total head down 24 hours                 22                0/22             0/22
                                        Panigada                                21                0/21             2/21
                                   Mucus Slurper 72h          Control            4                 ¼               1/4
     HEAD DOWN




                                   Mucus Slurper 72h         Treatment           6                0/6              0/6
                                         CASS                Treatment           7                0/7              0/7
                     72




                                Coated ETT+ Mucus Shaver     Treatment           6                0/6              0/6
                               Coated ETT + Mucus Shaver      Control            5                0/5              0/5
                                          Pig                                   12                0/12             0/12
                                      Deflated cuff                              2                0/2              0/2
                                       Total head down 72 hours                 63                1/63             3/63
                               Coated ETT + Mucus Shaver     Treatment           1                0/1              0/1
                     168




                                          Pig                                    6                0/6              2/6
                                       Total head down 168 hours                 7                0/7              2/7

                           Total Head down                                70                      1/70             5/70




                                                                                                                          78
  Gravity-VAP trial - NCT01138540
  Version 1.4.0
 Table 5 continued




 Body                                                  Number of
               MV (h)         Study          Group
                                                        animals
                                                                   Rate of pneumonia   Rate of colonization
position
                             Awake                        14             2/14                 8/14

                            Tantalum                      8              6/8                   6/8
                   24




                           Coated ETT      Treatment      8              0/8                   1/8

                           Coated ETT       Control       8              5/8                   6/8

                            Total head up 24 hours        38            16/38                 21/38
     HEAD UP




                              CASS          Control       8              5/8                   8/8

                            Panigada                      7              7/7                   7/7

                              CASS         Treatment      7              5/7                   7/7
                   72




                               Pig                        8              8/8                   8/8

                         Leak-proof cuff    Control       2              2/2                   2/2

                         Leak-proof cuff   Treatment      2              2/2                   2/2

                           Total head up 72 hours         34            30/34                 34/34

                        Total head up                     72            46/72                 55/72




                                                                                                              79
 Gravity-VAP trial - NCT01138540
 Version 1.4.0
Table 6 Data of incidence of pneumonia pooled from all studies conducted at the National Institutes of
Health

                     Time mechanical                                        Lung bacterial
                                        Total n     VAP Incidence (%)
                        ventilation                                        colonization (%)


  Below Horizontal         24 h         22 sheep          0 (0/22)              0 (0/22)



                                        51 sheep
  Below Horizontal         72 h                           1.5 (1/63)           4.8 (3/63)
                                         12 pigs



                                        1 sheep
  Below Horizontal        168 h                            0 (0/7)              28 (2/7)
                                         6 pigs



  Above Horizontal         24 h         38 sheep         42 (16/38)            55 (21/38)



                                        26 sheep
  Above Horizontal         72 h                          88 (30/34)            100 (34/34)
                                         8 pigs




                                                                                                   80
Gravity-VAP trial - NCT01138540
Version 1.4.0
Table 7 Lung bacterial colonization of studies in pig mechanically ventilated up to 168 hours (data are
reported as colony-forming units/g of lung tissue)


Head     Pig           Bacterium        RUL        RML        RLL       LUL        LML        LLL
Down     HD 72
Down     5615                           -          -          -         -          -          -
Down     5617                           -          -          -         -          -          -
Down     5623                           -          -          -         -          -          -
Down     5624                           -          -          -         -          -          -
Down     5653                           -          -          -         -          -          -
Down     5662                           -          -          -         -          -          -
Down     HD 72 F
Down     737                            -          -          -         -          -          -
Down     795                            -          -          -         -          -          -
Down     816                            -          -          -         -          -          -
Down     826                            -          -          -         -          -          -
Down     829                            -          -          -         -          -          -
Down     7900                           -          -          -         -          -          -
Down     HD 72 F DC
Down     865                            -          -          -         -          -          -
Down     888                            -          -          -         -          -          -
Down     HD 168 F
Down     72-3          C/Ms             -          7.6E+05    -         -          -          -
Down                   EnF              -          5.6E+03    -         -          -          -
Down                   StS              -          2.3E+04    -         -          -          -
Down     72-4                           -          -          -         -          -          -
Down     72-5          Lis              8.7E+05    -          -         -          -          4.0E+04
Down     72-7                           -          -          -         -          -          -
Down     827                            -          -          -         -          -          -
Down     8073                           -          -          -         -          -          -




                                                                                                        81
Gravity-VAP trial - NCT01138540
Version 1.4.0
Table 7 continued


Head     Pig          Bacterium        RUL        RML       RLL        LUL        LML       LLL
Up       HU
Up       5620         AeU              -          -         -          -          1.0E+05   5.0E+06
Up                    CbG              -          -         -          -          -         3.6E+03
Up                    CbS              -          1.4E+06   5.2E+07    -          3.5E+05   3.1E+07
Up       5621         CbG              8.3E+05    -         -          -          -         -
Up                    CbS              9.3E+07    2.7E+09   1.9E+09    1.5E+09    1.4E+09   2.8E+08
Up       5639         SmM              8.4E+04    4.4E+07   1.3E+07    5.0E+07    8.9E+07   2.2E+08
Up                    StS              3.7E+03    4.0E+06   1.2E+06    2.1E+07    3.1E+07   4.7E+07
Up       5644         OkS              1.8E+08    1.1E+09   2.5E+08    1.4E+07    1.1E+09   4.6E+06
Up                    StC/G            2.3E+06    2.8E+03   5.6E+06    1.1E+05    1.3E+07   3.0E+04
Up       5652         EsC              1.7E+03    3.2E+03   1.2E+03    -          -         -
Up                    ShE              -          -         -          2.3E+03    -         -
Up       5661         AcS              5.6E+07    -         8.0E+07    1.0E+06    -         4.7E+06
Up                    ArP              -          2.0E+07   -          -          4.2E+07   -
Up                    CbS              1.1E+09    5.3E+07   7.2E+08    7.1E+06    5.9E+07   7.7E+07
Up       8057         ArH              -          -         -          -          -         1.2E+04
Up                    BrV              5.9E+07    1.2E+06   8.7E+07    1.0E+03    3.2E+03   -
Up                    OkS              -          -         -          -          -         4.1E+04
Up                    StI              -          -         -          -          1.1E+03   -
Up                    StP              3.7E+07    -         5.6E+07    -          2.2E+03   4.9E+03
Up                    Stn              -          5.0E+06   -          -          -         -
Up                    ViV              3.0E+03    -         -          -          -         -
Up       8071         ArP              1.3E+06    4.0E+07   6.2E+07    6.4E+06    1.1E+07   8.8E+07
Up                    MiL              5.1E+04    5.3E+05   2.8E+06    2.7E+05    1.0E+06   1.1E+06
Up       8071         PsA              7.3E+03    2.9E+06   2.0E+06    3.3E+04    1.2E+06   4.2E+06
Up       8071         StA              1.5E+04    5.3E+05   1.7E+06    3.8E+06    2.9E+06   5.8E+06




HD 72, head down 72 hours; HD 72 F, head down 72 hours enteral feeding; HD 72 F DC, head down
72 hours enteral feeding deflated cuff; HD 168 F, head down 168 hours enteral feeding; HU, head up;
RUL, right upper lobe; RML, right middle lobe; RLL, right lover lobe; LUL, left upper lobe; LML, left
middle lobe; LLL, left lover lobe; AcS, Acinetobacter sp; AeU, Aerococcus urinae; ArH,
Arcanobacterium haemolyticum; ArP, Arcanobacterium pyogenes; BrV, Brevundimonas vesicularis;
C/Ms, Cellulomonas spp/Microbacterium spp; CbG, Corynebacterium genitalium; CbS,
Corynebacterium sp; EnF, Enteroccus faecalis; EsC, Escherichia Coli; Lis, Listeria sp; OkS, MiL,
Micrococcus luteus; Oerskovia sp; PsA, Pseudomonas aeruginosa; SmM, ShE, Staphyloccus
epidermidis; Stomatococcus mucilaginosus; StA, Streptococcus agalactiae; StC/G, Streptoccoccus
group C/G; StI, Streptococcus intermedius; StP, Streptococcus porcinus; Stn, Streptococcus sanguinis;
StS, Streptococcus suis; ViV, Vibrio vulnificus;




                                                                                                      82
Gravity-VAP trial - NCT01138540
Version 1.4.0
Figure 1 Incidence of pneumonia from data of studies conducted at the National Institutes of Health




                                                                                                      83
Gravity-VAP trial - NCT01138540
Version 1.4.0
APPENDIX B

Figure 1 Lateral-Trendelenburg position




                                          84
Gravity-VAP trial - NCT01138540
Version 1.4.0
Figure 2 Lateral-Trendelenburg position




Please note: Bed was oriented 20 degrees below horizontal in order to test feasibility of the position. However, lower orientation
of the bed is required to obtain a tracheal orientation few degrees below horizontal

                                                                                                                               85
Gravity-VAP trial - NCT01138540
Version 1.4.0
Figure 3 Lateral-Trendelenburg Position




A vertical line from the sternal notch to the ETT connector piece, passing through the middle of the trachea should be used as a
surface landmark. The patient should be always positioned in order to maintain this line oriented slightly below horizontal.
                                                                                                                               86
Gravity-VAP trial - NCT01138540
Version 1.4.0
Figure 4 Semi-Recumbent Position




                                   87
Gravity-VAP trial - NCT01138540
Version 1.4.0
               APPENDIX C: Data Collection Forms




                                                   88
Gravity-VAP trial - NCT01138540
Version 1.4.0
                        ASSESSMENT OF BED ORIENTATION


Patient Last and First Name________________________________________
Group of Randomization________________________________
Date Initial Visit_______________________________________


                     Bed                  Bed                  Bed                  Bed
    Day    Time   Orientation   Time   Orientation   Time   Orientation   Time   Orientation
                   (Degree)             (Degree)             (Degree)             (Degree)

     1

     2

     3

     4

     5

     6

     7

     8

     9

    10

    11

    12

    13

    14




                                                                                               89
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                  BASELINE

Data Collection
Patient Last and First Name

Group of Randomization

Date of Visit
Center
Date of Birth

Personal Data                                  Not
                                             Available
Address
City
State
ZIP CODE
Phone Number
Sex                  a) Male
                     b) Female

Height (cm)
Body Weight (kg)




                                                         90
Gravity-VAP trial - NCT01138540
Version 1.4.0
Coexisting disease
Neurological Disorder
1
2
3

Respiratory Disorder
1
2
3

Cardiovascular Disorder
1
2
3

Gastrointestinal and Pancreatic Disorder
1
2
3

Hepatic and Biliary Disorder
1
2
3

Hematologic and Spleen Disorder
1
2
3

Immunologic Disorder and Transplant
1
2
3

Endocrinologic Disorder
1
2
3

Genitourinary Disorder
1
2
3




                                           91
Gravity-VAP trial - NCT01138540
Version 1.4.0
Admission

Admission
Type of admission                Medical    Elective Surgery
                                 Emergency surgery       Not Available
Primary diagnosis on admission

                                                                         Not
Patient’s previous admission                            YES      NO
                                                                         Available
Out of hospital
Emergency room
Other ICU
Other department/division

Parameters

                                                                         Not
Habits                                                  YES      NO
                                                                         Available
Smoking habits
Chronic alcohol abuse
Intravenous drug abuse

Immuno-competency status:              Immuno-competent
                                       Immuno-compromised
Body Temperature                                                           Not
                                                                         Available
Body temperature (Cº)
                                                                         Not
Blood Chemistry                                                          Available
Hemoglobin (gr/dL)
Hematocrit (%)
Platelet count (/mL)
White Blood Cell (cells/µL/cu mm)
Sodium (mEq/L)
Potassium (mEq/L)
Glucose (mg/dL)
Blood Urea Nitrogen (mg/dL)
Creatinine (mg/dL)
Aspartate Aminotransferase (units/L)
Alanine Aminotransferase (units/L)
Total Bilirubin (mg/dL)
                                                                                     92
Gravity-VAP trial - NCT01138540
Version 1.4.0
Alkaline Phosphatase (units/L)
Creatine Phosphokinase (unit/L)
Lactic Acid Dehydrogenase (units/L)
Arterial Lactate (mg/dL)
Albumin (gr/dL)
                                                                       Not
Hemodynamic parameters                                                 Available
Heart rate (bpm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Central venous pressure (mmHg)
Systolic pulmonary pressure (mmHg)
Diastolic pulmonary pressure (mmHg)
Mean pulmonary pressure (mmHg)
Wedge pressure (mmHg)
Cardiac output (L/min)
                                                                       Not
Ventilator parameters                                                  Available
Inspiratory fraction of oxygen (%)
Tidal volume (ml)
Respiratory rate (breaths/min)
Plateau airways pressure (cmH2O)
Peak airways pressure (cmH2O)
PEEP (cmH2O)
Auto-PEEP (cmH2O)
                                                                       Not
Blood gases                                                            Available
pH arterial
PaO2 (mmHg)
PaCO2 (mmHg)
HCO3 (mEq/L)
Base excess (mEq/L)
SaO2 (%)
pH venous
PvO2 (mmHg)
PvCO2 (mmHg)
ScvO2 (%)

                                                                         Not
                                                                       Available
APACHE II

Antero-Posterior Chest X-Ray          None   Monolateral   Bilateral     Not
                                                                       Available
                                                                                   93
Gravity-VAP trial - NCT01138540
Version 1.4.0
Infiltrate

                                                           Not
Glasgow Coma Scale
                                                           Available
Eyes
Verbal
Motor

Parameters II

                                                            Not
Sedation Analgesia and Neuromuscular blockade               Available
RASS score
                                                            Not
                                                YES   NO
                                                            Available
Sedative 1
Sedative agent 1
Dose sedative agent 1 (mg/day)
Sedative 2
Sedative agent 2
Dose sedative agent 2 (mg/day)
Sedative 3
Sedative agent 2
Dose sedative agent 2 (mg/day)
Analgesic 1
Analgesic agent 1
Dose analgesic agent 1 (mg/day)
Analgesic 2
Analgesic agent 2
Dose analgesic agent 2 (mg/day)

Neuromuscular
Neuromuscular blocking agent
Dose neuromuscular blocking agent (mg/day)




                                                                        94
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                        Not
                                                            YES    NO
                                                                        Available
Antimicrobial treatment
Antibacterial agent 1
Route antibacterial agent 1
Dose antibacterial agent 1 (mg/day)
Antibacterial agent 2
Route antibacterial agent 2
Dose antibacterial agent 2 (mg/day)
Antibacterial agent 3
Route antibacterial agent 3
Dose antibacterial agent 3 (mg/day)
Antibacterial agent 4
Route antibacterial agent 4
Dose antibacterial agent 4 (mg/day)
Antibacterial agent 5
Route antibacterial agent 5
Dose antibacterial agent 5 (mg/day)
Antibacterial agent 6
Route antibacterial agent 6
Dose antibacterial agent 6 (mg/day)

Parameters III

                                                                        Not
Oral Decontamination                                         YES   NO
                                                                        Available
Oral decontamination: chlorhexidine
Frequency oral decontamination: chlorhexidine (times/day)




                                                                                    95
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                                     Not
Stress Ulcer Prophylaxis                                              YES       NO
                                                                                     Available
Stress ulcer prophylaxis: antiacids
Route stress ulcer prophylaxis: antiacids
Dose stress ulcer prophylaxis: antiacids (mg/day)
Stress ulcer prophylaxis: hystamine-2 blockers
Route stress ulcer prophylaxis: hystamine-2 blockers
Dose stress ulcer prophylaxis: hystamine-2 blockers (mg/day)
Stress ulcer prophylaxis: proton-pump inhibitors
Route stress ulcer prophylaxis: proton-pump inhibitors
Dose stress ulcer prophylaxis: proton-pump inhibitors (mg/day)
Stress ulcer prophylaxis: sucralfate
Route stress ulcer prophylaxis: sucralfate
Dose stress ulcer prophylaxis: sucralfate (mg/day)

                                                                                     Not
                                                                          YES   NO
                                                                                     Available
Selective Decontamination of the Digestive Tract
Selective decontamination of the digestive tract: antibacterial agent 1
Dose selective decontamination of the digestive tract: antibacterial
agent 1 (mg/day)
Selective decontamination of the digestive tract: antibacterial agent 2
Dose selective decontamination of the digestive tract: antibacterial
agent 2 (mg/day)
Selective decontamination of the digestive tract: antibacterial agent 3
Dose selective decontamination of the digestive tract: antibacterial
agent 3 (total/day).




                                                                                                 96
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                        Not
Nutrition                                                   YES    NO
                                                                        Available
Parental nutrition
Quantity parental nutrition (kcal/day)
Enteral nutrition
Quantity enteral nutrition (kcal/day)
Volume enteral nutrition (ml/day)
Volume gastric residual (ml/day)
Does the patient have post-pyloric feeding tube in place?


                                                                        Not
Cuff Pressure Measurement of the Morning Shift                          Available
Internal cuff pressure (cm H2O)


                                                                        Not
Aspiration of Sub-glottic Secretions                         YES   NO
                                                                        Available
Aspiration of sub-glottic secretions




                                                                                    97
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                   DAILY ASSESSMENT

DAY ______________

Data Collection
Patient Last and First Name
Group of Randomization
Date of Visit
Center
Date of Birth

                                       Endotracheal   Tracheostomy
                                          Tube            Tube
Artificial Airway

Body Temperature                                                       Not
                                                                     Available
Body temperature (Cº)
                                                                     Not
Blood Chemistry                                                      Available
Hemoglobin (gr/dL)
Hematocrit (%)
Platelet count (/mL)
White Blood Cell (cells/µL/cu mm)
Sodium (mEq/L)
Potassium (mEq/L)
Glucose (mg/dL)
Blood Urea Nitrogen (mg/dL)
Creatinine (mg/dL)
Aspartate Aminotransferase (units/L)
Alanine Aminotransferase (units/L)
Total Bilirubin (mg/dL)
Alkaline Phosphatase (units/L)
Creatine Phosphokinase (unit/L)
Lactic Acid Dehydrogenase (units/L)
Arterial Lactate (mg/dL)
Albumin (gr/dL)



                                                                                 98
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                       Not
Hemodynamic parameters                                                 Available
Heart rate (bpm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Central venous pressure (mmHg)
Systolic pulmonary pressure (mmHg)
Diastolic pulmonary pressure (mmHg)
Mean pulmonary pressure (mmHg)
Wedge pressure (mmHg)
Cardiac output (L/min)
                                                                       Not
Ventilator parameters                                                  Available
Inspiratory fraction of oxygen (%)
Tidal volume (ml)
Respiratory rate (breaths/min)
Plateau airways pressure (cmH2O)
Peak airways pressure (cmH2O)
PEEP (cmH2O)
Auto-PEEP (cmH2O)

                                                                       Not
Blood gases                                                            Available
pH arterial
PaO2 (mmHg)
PaCO2 (mmHg)
HCO3 (mEq/L)
Base excess (mEq/L)
SaO2 (%)
pH venous
PvO2 (mmHg)
PvCO2 (mmHg)
ScvO2 (%)

Antero-Posterior Chest X-Ray          None   Monolateral   Bilateral     Not
                                                                       Available
Infiltrate

Tracheal Aspirate                                   Yes      No          Not
                                                                       Available
Purulent Tracheal Secretions


                                                                                   99
Gravity-VAP trial - NCT01138540
Version 1.4.0
Parameters II

                                                           Not
Sedation Analgesia and Neuromuscular blockade              Available
RASS score

                                                           Not
                                                YES   NO
                                                           Available
Sedative 1
Sedative agent 1
Dose sedative agent 1 (mg/day)
Sedative 2
Sedative agent 2
Dose sedative agent 2 (mg/day)
Sedative 3
Sedative agent 2
Dose sedative agent 2 (mg/day)
Analgesic 1
Analgesic agent 1
Dose analgesic agent 1 (mg/day)
Analgesic 2
Analgesic agent 2
Dose analgesic agent 2 (mg/day)

                                                           Not
                                                YES   NO
                                                           Available
Neuromuscular
Neuromuscular blocking agent
Dose neuromuscular blocking agent (mg/day)




                                                                       100
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                           Not
                                                               YES    NO
                                                                           Available
Antimicrobial treatment
Antibacterial agent 1
Route antibacterial agent 1
Dose antibacterial agent 1 (mg/day)
Antibacterial agent 2
Route antibacterial agent 2
Dose antibacterial agent 2 (mg/day)
Antibacterial agent 3
Route antibacterial agent 3
Dose antibacterial agent 3 (mg/day)
Antibacterial agent 4
Route antibacterial agent 4
Dose antibacterial agent 4 (mg/day)
Antibacterial agent 5
Route antibacterial agent 5
Dose antibacterial agent 5 (mg/day)
Antibacterial agent 6
Route antibacterial agent 6
Dose antibacterial agent 6 (mg/day)

Parameters III

                                                                           Not
Oral Decontamination                                            YES   NO
                                                                           Available
Oral decontamination: chlorhexidine
Frequency oral decontamination: chlorhexidine (times/day)



                                                                           Not
Stress Ulcer Prophylaxis                                        YES   NO
                                                                           Available
Stress ulcer prophylaxis: antiacids
Route stress ulcer prophylaxis: antiacids
Dose stress ulcer prophylaxis: antiacids (mg/day)
Stress ulcer prophylaxis: hystamine-2 blockers
Route stress ulcer prophylaxis: hystamine-2 blockers
Dose stress ulcer prophylaxis: hystamine-2 blockers (mg/day)

                                                                                       101
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                                      Not
Stress Ulcer Prophylaxis                                              YES        NO
                                                                                      Available
Stress ulcer prophylaxis: proton-pump inhibitors
Route stress ulcer prophylaxis: proton-pump inhibitors
Dose stress ulcer prophylaxis: proton-pump inhibitors (mg/day)
Stress ulcer prophylaxis: sucralfate
Route stress ulcer prophylaxis: sucralfate
Dose stress ulcer prophylaxis: sucralfate (mg/day)

                                                                                      Not
                                                                           YES   NO
                                                                                      Available
Selective Decontamination of the Digestive Tract
Selective decontamination of the digestive tract: antibacterial agent 1
Dose selective decontamination of the digestive tract: antibacterial
agent 1 (mg/day)
Selective decontamination of the digestive tract: antibacterial agent 2
Dose selective decontamination of the digestive tract: antibacterial
agent 2 (mg/day)
Selective decontamination of the digestive tract: antibacterial agent 3
Dose selective decontamination of the digestive tract: antibacterial
agent 3 (total/day).
                                                                                      Not
Nutrition                                                             YES        NO
                                                                                      Available
Parental nutrition
Quantity parental nutrition (kcal/day)
Enteral nutrition
Quantity enteral nutrition (kcal/day)
Volume enteral nutrition (ml/day)
Volume gastric residual (ml/day)
Did the patient require Post-Pyloric Feeding?
                                                                                      Not
Cuff Pressure Measurement of the Morning Shift                                        Available
Internal cuff pressure (cm H2O)
                                                                                      Not
Aspiration of Sub-glottic Secretions                                      YES    NO
                                                                                      Available
Aspiration of sub-glottic secretions




                                                                                                  102
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                                          Not
Infection                                                YES     NO
                                                                          Available
Did the patient develop a new infection?
Site of new infection

                                                                          Not
Bacteremia                                               YES     NO
                                                                          Available
Bacteremia

                                                                          Not
VAP                                                      YES     NO
                                                                          Available
VAP suspected?
Microbiologically confirmed VAP?

                                               BAL        Mini-BAL    PSB
How did you obtain the LRT sample

VAP Etiology
Microorganism 1
Concentration Microorganism 1 (cfu/ml) (check the concentration factor)
103______ 104_______ 105______ 106_______ 107_______ 108_______
Microorganism 2
Concentration Microorganism 2 (cfu/ml) (check the concentration factor)
103______ 104_______ 105______ 106_______ 107_______ 108_______
Microorganism 3
Concentration Microorganism 3 (cfu/ml) (check the concentration factor)
103______ 104_______ 105______ 106_______ 107_______ 108_______

                                                                          Not
                                                                          Available
Mean Bed Orientation (degrees), while the patient is
placed in the randomized position (during previous 24
hours)




                                                                                      103
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                                         Not
Patient's position                            YES   NO
                                                         Available
Patient's position 1: Lateral-Trendelenburg
Total time x day (Hours and Minutes)
Patient's position 2: Semi-Recumbent
Total time x day (Hours and Minutes)
Patient's position 3: Supine Horizontal
Total time x day (Hours and Minutes)
Patient's position 4: Prone
Total time x day (Hours and Minutes)

Parameters IV

                                                         Not
Adverse Event during the previous 24 hours    YES   NO
                                                         Available


Displacement of tracheal tube

Loss of Intravascular access

Displacement of drain tube

Endotracheal tube obstruction

Vomiting




                                                                     104
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                   CHANGE OF POSITION ASSESSMENT
Patient Last and First Name________________________________________
Group of Randomization________________________________
Date Initial Visit_______________________________________
                                              DAY OF ASSESSMENT
      Day 1   Day 2   Day 3   Day 4   Day 5   Day 6   Day 7    Day 8   Day 9   Day 10    Day 11   Day 12   Day 13   Day 14




      TIME             Supine            Semi-                   Lateral-               Prone          Reason for
                      Horizontal       recumbent              Trendelenburg                         change of position




                                                                                                                             105
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                               PRESSURE SORES ASSESSMENT


  Patient Last and First Name________________________________________
  Group of Randomization________________________________
  Date Initial Visit_______________________________________
  Date Final Visit_______________________________________


  Does the patient present pressure sores at admission?    Yes          No


                   Day1 Day2 Day3 Day4 Day5 Day6 Day7 Day8 Day9 Day10 Day11 Day12 Day13 Day14
New
Pressure Sore?*

Is Pressure Sore
Worsening?^

  * Check the box only when a new pressure sore develops
  ^ Check only if one of the pressure sores is worsening




                                                                                           106
  Gravity-VAP trial - NCT01138540
  Version 1.4.0
                                     NURSE SURVEY ON PATIENT POSITIONING


Patient Last and First Name________________________________________
Group of Randomization________________________________
Date Initial Visit_______________________________________
Date Final Visit_______________________________________


How was in your opinion to initially place and maintain the patient in the randomized position?


                     Not Sure        Very Difficult         Difficult            Easy               Very Easy




How was in your opinion the workload to initially place and maintain the patient in the randomized position?


                     Not Sure       Extremely High           High                Low              Extremely Low




                                                                                                                  107
Gravity-VAP trial - NCT01138540
Version 1.4.0
                                     FINAL EVALUATION
Data Collection
Patient Last and First Name
Date of Visit
Center
Date of Birth

Enteral Nutrition during the 14-day study                             YES       NO
Did the patient require Post-Pyloric Feeding?

                                                                     YES        NO
Did the patient complete the study?


Cause of premature discontinuation                                    YES       NO
Death
Occurrence of a new condition originally indicated as exclusion
criteria
Non compliance to the protocol
Patient transferred to another department
Other
Other, please specify



Outcome                                                       Discontinued       No
                                                                             Discontinued
Mechanical Discontinuation
Date of Discontinuation of Mechanical Ventilation

Outcome                                                           Alive      Deceased
ICU
Date of outcome: ICU Discharge/Death
Hospital
Date of outcome: Hospital Discharge/Death
28 Days Survival
Date of 28 Days Death

                                                                                            108
Gravity-VAP trial - NCT01138540
Version 1.4.0
Adverse Events during the 14-day study   Yes   No
New pressure sores
Displacement of endotracheal tube
Loss of intravascular access
Displacement of drain tube
Endotracheal tube obstruction
Vomiting




                                                    109
Gravity-VAP trial - NCT01138540
Version 1.4.0
APPENDIX D

Richmond Agitation Sedation Scale (RASS) *

Score Term               Description

+4 Combative             Overtly combative, violent, immediate danger to staff

+3 Very agitated         Pulls or removes tube(s) or catheter(s); aggressive

+2 Agitated              Frequent non-purposeful movement, fights ventilator

+1 Restless              Anxious but movements not aggressive vigorous

0                        Alert and calm

-1 Drowsy                Not fully alert, but has sustained awakening

                         (eye-opening/eye contact) to voice (>10 seconds)

-2 Light sedation        Briefly awakens with eye contact to voice (<10 seconds)

-3 Moderate sedation     Movement or eye opening to voice (but no eye contact)

-4 Deep sedation         No response to voice, but movement or eye opening

                         to physical stimulation

-5 Unarousable           No response to voice or physical stimulation




                                                                                   110
Gravity-VAP trial - NCT01138540
Version 1.4.0
Procedure for RASS Assessment




1. Observe patient

a. Patient is alert, restless, or agitated.                                       (score 0 to +4)




2. If not alert, state patient’s name and say to open eyes and look at speaker.

b. Patient awakens with sustained eye opening and eye contact.                (score –1)

c. Patient awakens with eye opening and eye contact, but not sustained.       (score –2)

d. Patient has any movement in response to voice but no eye contact.          (score –3)




3. When no response to verbal stimulation, physically stimulate patient by shaking shoulder and/or
rubbing sternum.

e. Patient has any movement to physical stimulation.                          (score –4)

f. Patient has no response to any stimulation.                                (score –5)




* Sessler CN, Gosnell M, Grap MJ, Brophy GT, O'Neal PV, Keane KA et al. The Richmond Agitation-
Sedation Scale: validity and reliability in adult intensive care patients. Am J Respir Crit Care Med
2002; 166:1338-1344.

* Ely EW, Truman B, Shintani A, Thomason JWW, Wheeler AP, Gordon S et al. Monitoring sedation
status over time in ICU patients: the reliability and validity of the Richmond Agitation Sedation Scale
(RASS). JAMA 2003; 289:2983-2991.


                                                                                                    111
Gravity-VAP trial - NCT01138540
Version 1.4.0
APPENDIX E: CONSENT FORMS




                                  112
Gravity-VAP trial - NCT01138540
Version 1.4.0
Centre No.    ________________
City, Country ________________


                                          Gravity VAP-trial


                                   PATIENT CONSENT FORM


                              Version 1 – Tuesday, November 02, 2010


Title of project: Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg versus Semi-
Recumbent Body Position in Mechanically Ventilated Patients For The Prevention of Ventilator-
Associated Pneumonia


Local Investigator: [name and telephone number]:___________________________


                                                                       Patient Initials
1 I confirm that I have read and understand the information sheet
 dated __________________ for the above study and have had the
 opportunity to ask questions …………………………………

2 I understand that my participation is voluntary and that I am free
 to withdraw at any time, without giving any reason and without
 my medical care or legal rights being affected ……………..........

3 I understand that sections of any of my medical notes may be
 looked at by responsible individuals involved with the study. I
 give permission for these individuals to have access to my records
 ……………………………………………………………



                                                                                               113
Gravity-VAP trial - NCT01138540
Version 1.4.0
4 I give permission for my personal identifying information to be
  collected, stored and used by the study office to enable follow up
  of my health status. This is on the understanding that any
  information will be treated with the strictest security and
  confidentiality…………………………………………………….

5 I give permission for my local investigator to be contacted about
my health status ………………………………….............................

8 I agree to take part in the above study ……………………..……..




Name of patient                              Date                   Signature
____________________                    ____________________   ____________________


Name of person taking consent
(if not Principal Local Investigator)        Date                   Signature
____________________                    ____________________   ____________________


Name of Principal
Local Investigator                            Date                   Signature
____________________                    ____________________   ____________________




1 copy for patient, 1 for Principal Local Investigator, 1 to be kept with hospital notes




                                                                                           114
Gravity-VAP trial - NCT01138540
Version 1.4.0
Centre No.    ________________
City, Country ________________


                                           Gravity VAP-trial


                                PATIENT INFORMATION SHEET:
                         RETROSPECTIVE CONSENT FROM PATIENT
                               Version 1 – Tuesday, November 02, 2010


Title of project: Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg versus Semi-
Recumbent Body Position in Mechanically Ventilated Patients For The Prevention of Ventilator-
Associated Pneumonia


Local Investigator: [name and telephone number]:___________________________



During your stay in the intensive care unit you took part in a research study that is currently taking
place in many intensive care units around the world. It is important for you to understand why the
research is being done and what it involves. Please read the following information carefully and, if you
wish, discuss it with your relatives or friends. Ask if there is anything that is unclear or if you would
like any more information. Thank you for reading this.


1) What is the purpose of the study?
Patients who need help with their breathing (artificial ventilation) have a tube placed through their
mouths into their lungs. This tube is connected to the machine that assists their breathing.
Unfortunately, the tube inside your trachea increases the risk for developing respiratory infections, in
particular a disease called VENTILATOR-ASSOCIATED PNEUMONIA. At present, following
intubation of the trachea, patients are kept in bed laying on their back and with the head of the bed
angulated 30-45 degrees. This position is used to prevent that bacteria from your stomach reach your

                                                                                                     115
Gravity-VAP trial - NCT01138540
Version 1.4.0
mouth and then your respiratory system following intubation. However, we currently know that the
main mechanism to develop VENTILATOR-ASSOCIATED PNEUMONIA is through aspiration of
secretions within your mouth, which are often colonized with bacteria, irrespective of any position you
are place. Therefore, we are performing this trial to understand if maintaining tracheally intubated
patients on their side, as when they sleep in bed at night, we can avoid that bacteria from their mouth
enter into the respiratory system and ultimately prevent development of pneumonia in comparison to
the standard position in which all patients are maintained.
This trial has been designed by highly specialized doctors in the field of Intensive Care Medicine and
with great experience in clinical trials. This trial will involve hospitals in your country and many others
around the world, involving over 800 patients admitted into the intensive care units. This study has
been reviewed and approved by the Research Ethics Committee of your hospital.


2) Why have I been chosen?
Your doctors believe that you will you may be at risk for development of pneumonia following tracheal
intubation due to aspiration of bacteria into your trachea. Therefore, we will try if we can to prevent
this course of events.


3) Do I have to take part?
It is up to you to decide whether or not to take part to this trial. If you decide to take part, you are still
free to withdraw at any time and without giving a reason. A decision to withdraw at any time, or a
decision not to take part, will not affect the standard of care you receive.
If you do decide to take part you will be given this information sheet to keep and be asked to sign a
consent form, a copy of the consent form will be given to you.
4) What will happen to me if I take part?
Sometimes because we do not know which way of treating patients is best, we need to make
comparisons. People are put into groups and then compared. The groups are selected by a computer
that will decide on a chance basis (as if it were tossing a coin) whether you will be positioned either on
your back with the head of the bed elevated 30-45 degrees, or on your side, changing position from one
side to the other as often as you wish. All other care will continue in the usual manner. There are no

                                                                                                          116
Gravity-VAP trial - NCT01138540
Version 1.4.0
extra tests involved in taking part in this research. The chances of being selected for either group are
equal. As part of the study, routine information on your treatment will be collected. In addition,
appropriate personal identifying details will be collected to enable us to be kept informed about your
health once you have left the Intensive Care Unit. After you are being discharged by the intensive care
we will contact you to see how you are doing. If you decide not to allow us to follow up your health
status after the intensive care discharge, then we will abide by your wishes and not collect follow up
data on you. You do not have to give a reason, and the standard of care you receive will not be
affected.


5) What do I have to do?
You do not have to do anything yourself. The doctors and nurses on the Intensive Care Unit will keep
you informed at all times.


6) What are the possible risks and benefits of taking part?
This trial is evaluating the best patient’s position to prevent development of pneumonia. The risks
related to the new position lying on your side are currently unknown; however we expect very high
tolerance and limited adverse events, since often you lay on your side, during your sleep at home. The
potential benefit of taking part is that by lying on your side bacteria from the mouth do not enter your
trachea and therefore you do not develop pneumonia.
7) What if something goes wrong?
       If you are harmed by taking part in this research project, there are no special compensation
arrangements. If you are harmed due to someone’s negligence, then you may have grounds for a legal
action but you may have to pay for it. Regardless of this, if you wish to complain about any aspect of
the way you have been approached or treated during the course of this study, the Hospital will be
available to you.


8) Will my taking part be kept confidential?




                                                                                                    117
Gravity-VAP trial - NCT01138540
Version 1.4.0
All information that is collected about you during the course of the research study will be kept strictly
confidential. Your identifying details will be held in a secure environment and only accessed by the
research team for the purposes of follow up.


9) What will happen to the results of the research study?
The study is estimated to take around three years; it started in the September of 2010. It is hoped to be
finished by 2013. If you would like a copy of the published results, please contact the Principal Local
Investigator.


Contact for further information
If you would like further information, please feel free to contact
______________________________________________________________________,                    the   leading
investigator of the study on this unit.




                                                                                                     118
Gravity-VAP trial - NCT01138540
Version 1.4.0
Centre No.     ________________
City, Country ________________


                                           Gravity VAP-trial


                                PATIENT INFORMATION SHEET


                               Version 1 – Tuesday, November 02, 2010


Title of project: Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg versus Semi-
Recumbent Body Position in Mechanically Ventilated Patients For The Prevention of Ventilator-
Associated Pneumonia


Local Investigator: [name and telephone number]:___________________________


You are being asked to take part in a research study while you are here as a patient in the intensive care
unit. Before you decide, it is important for you to understand why the research is being done and what
it will involve. Please read the following information carefully and, if you wish, to discuss it with your
relatives or friends. Ask us if there is anything that is unclear or if you would like more information.
Thank you for reading this.


1) What is the purpose of the study?
Patients who need help with their breathing (artificial ventilation) have a tube placed through their
mouths into their lungs. This tube is connected to the machine that assists their breathing.
Unfortunately, the tube inside your trachea increases the risk for developing respiratory infections, in
particular a disease called VENTILATOR-ASSOCIATED PNEUMONIA. At present, following
intubation of the trachea, patients are kept in bed laying on their back and with the head of the bed
angulated 30-45 degrees. This position is used to prevent that bacteria from your stomach reach your
mouth and then your respiratory system following intubation. However, we currently know that the

                                                                                                      119
Gravity-VAP trial - NCT01138540
Version 1.4.0
main mechanism to develop VENTILATOR-ASSOCIATED PNEUMONIA is through aspiration of
secretions within your mouth, which are often colonized with bacteria, irrespective of any position you
are place. Therefore, we are performing this trial to understand if maintaining tracheally intubated
patients on their side, as when they sleep in bed at night, we can avoid that bacteria from their mouth
enter into the respiratory system and ultimately prevent development of pneumonia in comparison to
the standard position in which all patients are maintained.
This trial has been designed by highly specialized doctors in the field of Intensive Care Medicine and
with great experience in clinical trials. This trial will involve hospitals in your country and many others
around the world, involving over 800 patients admitted into the intensive care units. This study has
been reviewed and approved by the Research Ethics Committee of your hospital.


2) Why have I been chosen?
Your doctors believe that you will you may be at risk for development of pneumonia following tracheal
intubation due to aspiration of bacteria into your trachea. Therefore, we will try if we can to prevent
this course of events.


3) Do I have to take part?
It is up to you to decide whether or not to take part to this trial. If you decide to take part, you are still
free to withdraw at any time and without giving a reason. A decision to withdraw at any time, or a
decision not to take part, will not affect the standard of care you receive.
If you do decide to take part you will be given this information sheet to keep and be asked to sign a
consent form, a copy of the consent form will be given to you.
4) What will happen to me if I take part?
Sometimes because we do not know which way of treating patients is best, we need to make
comparisons. People are put into groups and then compared. The groups are selected by a computer
that will decide on a chance basis (as if it were tossing a coin) whether you will be positioned either on
your back with the head of the bed elevated 30-45 degrees, or on your side, changing position from one
side to the other as often as you wish. All other care will continue in the usual manner. There are no
extra tests involved in taking part in this research. The chances of being selected for either group are

                                                                                                          120
Gravity-VAP trial - NCT01138540
Version 1.4.0
equal. As part of the study, routine information on your treatment will be collected. In addition,
appropriate personal identifying details will be collected to enable us to be kept informed about your
health once you have left the Intensive Care Unit. After you are being discharged by the intensive care
we will contact you to see how you are doing. If you decide not to allow us to follow up your health
status after the intensive care discharge, then we will abide by your wishes and not collect follow up
data on you. You do not have to give a reason, and the standard of care you receive will not be
affected.


5) What do I have to do?
You do not have to do anything yourself. The doctors and nurses on the Intensive Care Unit will keep
you informed at all times.


6) What are the possible risks and benefits of taking part?
This trial is evaluating the best patient’s position to prevent development of pneumonia. The risks
related to the new position lying on your side are currently unknown; however we expect very high
tolerance and limited adverse events, since often you lay on your side, during your sleep at home. The
potential benefit of taking part is that by lying on your side bacteria from the mouth do not enter your
trachea and therefore you do not develop pneumonia.




7) What if something goes wrong?
       If you are harmed by taking part in this research project, there are no special compensation
arrangements. If you are harmed due to someone’s negligence, then you may have grounds for a legal
action but you may have to pay for it. Regardless of this, if you wish to complain about any aspect of
the way you have been approached or treated during the course of this study, the Hospital will be
available to you.


8) Will my taking part be kept confidential?



                                                                                                    121
Gravity-VAP trial - NCT01138540
Version 1.4.0
All information that is collected about you during the course of the research study will be kept strictly
confidential. Your identifying details will be held in a secure environment and only accessed by the
research team for the purposes of follow up.


9) What will happen to the results of the research study?
The study is estimated to take around three years; it started in the September of 2010. It is hoped to be
finished by 2013. If you would like a copy of the published results, please contact the Principal Local
Investigator.


Contact for further information
If you would like further information, please feel free to contact
______________________________________________________________________,                    the   leading
investigator of the study on this unit.




                                                                                                     122
Gravity-VAP trial - NCT01138540
Version 1.4.0
Centre No.     ________________
City, Country ________________


                                           Gravity VAP-trial


                     COVERING STATEMENT FOR PATIENT’S RELATIVE


                                Version 1 – Tuesday, November 02, 2010


Title of project: Prospective, Randomized, Multi-Center Trial of Lateral Trendelenburg versus Semi-
Recumbent Body Position in Mechanically Ventilated Patients For The Prevention of Ventilator-
Associated Pneumonia


Local Investigator: [name and telephone number]:___________________________



We would like your relative to take part in a research study while he/she is a patient in this intensive
care unit. Unfortunately, your relative is not well enough to be able to decide for him/herself whether
or not to participate. Legally, you cannot provide consent on his/her behalf. However, we ask you to
read the Patient Information Sheet carefully and give your opinion as to whether or not you think your
relative would have objected to taking part in this medical research.
When your relative has regained consciousness and has the ability to understand the purpose of this
study, we will explain the study to them and seek his/her permission to use the data we have collected
retrospectively.
If you have further questions either now or at any time subsequently, please feel free to contact leading
investigator of the study on this unit.


Thank you for your time in considering this request.



                                                                                                     123
Gravity-VAP trial - NCT01138540
Version 1.4.0
Contact for further information
If you would like further information, please feel free to contact
______________________________________________________________________,   the   leading
investigator of the study on this unit.


Attached: Patient Information Sheet




                                                                                   124
Gravity-VAP trial - NCT01138540
Version 1.4.0

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:79
posted:8/12/2011
language:English
pages:125