June 11, 2001

Document Mail Center (HFZ-401)

Center for Devices & Radiological Health

Food and Drug Administration

9200 Corporate Blvd.

Rockville, MD 20850

Re: Supplement 14 to PMA P890057

Amendment 4

Model 3100B High Frequency Oscillatory Ventilator

Dear Sir or Madam:

Enclosed are 6 copies of Amendment 4 to Supplement 14 of PMA 890057.
This amendment is being submitted in response to information requested
by e-mail from Joanna Weitershausen to Alex Stenzler. The e-mail is
titled (FW: Panel Meeting) and is dated (6/5/01).

The first 28 pages provide additional information that was specifically
requested. The last 7 pages include additional information that
SensorMedics feels would benefit the panel members. The following page
includes a table of contents describing the contents of this amendment.

The information contained in this amendment is not considered to be
confidential and may be released under FOI.

If you have any questions regarding this submission, please contact me
at telephone number (714) 283-2228 x8461, or at fax number (714)
283-8426. Additional contacts are Paul Kittinger at x8351 and Alex
Stenzler at x8327.

Sincerely,

Earl W. Draper

Director of Quality Systems

#### Table of Contents

####### Item Page

Operators Manual (pages 20-24) (PMA pgs 516-520) 3 through 7

"Performance Graphs"

Operators Manual (pages 91-99) (PMA pgs 587-595) 4 through 16

"Clinical Guidelines"

Ventilator and Physiological Timed Variables 17 through 20

Poolability and Discontinuance of Treatment Analysis 21 through 22

MTBF / Diaphragm Rupture Analysis 23

Corrected Patient Enrollment Chart (PMA page 162) 24

Corrected Study Site Information (PMA page 153-154) 25 through 27

Corrected Outcome Chart (PMA page 164) 28

Additional Information 29 through 35

**Table 2. Daily Ventilator and Physiologic Variables for the HFOV and
Conventional Ventilation arms during the first three days taken at
approximately 8-hour intervals**

+----------+----+----------+-------+-------+---+-------+-------+-------+
| # FiO2   |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | n     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day1     |    | 60       | .51   | .15   |   | 57    | .60   | .19   |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # Day 2  |    | 55       | .52   | .17   |   | 54    | .54   | .18   |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    |    | 45       | .51   | .15   |   | 48    | .51   | .17   |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| **PIP**  |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | n     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day1     |    | 60       |       |       |   | 57    | 37    | 8     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # Day 2  |    | 55       |       |       |   | 54    | 38    | 9     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    |    | 45       |       |       |   | 48    | 37    | 9     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| **PEEP** |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | N     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day1     |    | 60       |       |       |   | 57    | 13    | 3     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # Day 2  |    | 55       |       |       |   | 54    | 13    | 4     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    |    | 45       |       |       |   | 48    | 13    | 4     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # TV/kg  |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | N     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day1     |    | 60       |       |       |   | 57    | 8     | 2     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # Day 2  |    | 55       |       |       |   | 54    | 8     | 3     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    |    | 45       |       |       |   | 48    | 8     | 2     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| #        |    | HFOV     |       |       |   | CV    |       |       |
| Mean Paw |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | N     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day1     |    | 60       | 29    | 6     |   | 57    | 23    | 7     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # Day 2  |    | 55       | 28    | 6     |   | 54    | 23    | 8     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    |    | 45       | 28    | 6     |   | 48    | 22    | 8     |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| #        |    | HFOV     |       |       |   | CV    |       |       |
|  Delta-P |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | N        | mean  | stdev |   | N     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day1     |    | 60       | 66    | 14    |   | 57    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| # Day 2  |    | 55       | 65    | 13    |   | 54    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    |    | 45       | 66    | 17    |   | 48    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| *        |    |          |       |       |   |       |       |       |
| *PaCO2** |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | n     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 1    | p  | 72       | 44.93 | 13.43 |   | 70    | 44.96 | 13.10 |
|          | re |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 1  | 72       | 49.68 | 16.63 |   | 65    | 43.83 | 10.33 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 66       | 48.06 | 13.33 |   | 65    | 41.57 | 9.79  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 62       | 47.73 | 14.20 |   | 56    | 42.46 | 10.51 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 2    | 1  | 62       | 46.85 | 12.83 |   | 56    | 42.91 | 10.11 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 60       | 48.18 | 12.66 |   | 54    | 42.50 | 12.03 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 56       | 47.27 | 12.91 |   | 50    | 43.58 | 14.91 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    | 1  | 54       | 48.33 | 12.50 |   | 54    | 43.02 | 13.53 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 47       | 49.23 | 14.30 |   | 49    | 42.78 | 10.63 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 42       | 52.14 | 14.29 |   | 44    | 44.59 | 11.94 |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| **pH**   |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | n     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 1    | p  | 73       | 7.37  | 0.10  |   | 71    | 7.34  | 0.11  |
|          | re |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 1  | 72       | 7.34  | 0.13  |   | 66    | 7.36  | 0.11  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 67       | 7.35  | 0.11  |   | 66    | 7.36  | 0.11  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 62       | 7.35  | 0.09  |   | 56    | 7.36  | 0.10  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 2    | 1  | 62       | 7.36  | 0.09  |   | 56    | 7.37  | 0.18  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 59       | 7.36  | 0.08  |   | 54    | 7.37  | 0.10  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 56       | 7.37  | 0.09  |   | 52    | 7.38  | 0.11  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    | 1  | 54       | 7.36  | 0.08  |   | 54    | 7.37  | 0.11  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 47       | 7.37  | 0.07  |   | 48    | 7.39  | 0.09  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 42       | 7.34  | 0.08  |   | 44    | 7.37  | 0.09  |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| **PO     |    |          |       |       |   |       |       |       |
| 2/FiO2** |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | HFOV     |       |       |   | CV    |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    | n        | mean  | stdev |   | n     | mean  | stdev |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 1    | p  | 73       | 1     | 36.98 |   | 71    | 1     | 41.66 |
|          | re |          | 10.88 |       |   |       | 09.92 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 1  | 72       | 1     | 61.14 |   | 64    | 1     | 58.54 |
|          |    |          | 41.63 |       |   |       | 27.34 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 65       | 1     | 1     |   | 64    | 1     | 51.55 |
|          |    |          | 77.87 | 26.69 |   |       | 31.20 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 61       | 2     | 1     |   | 56    | 1     | 57.05 |
|          |    |          | 05.68 | 65.16 |   |       | 43.14 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 2    | 1  | 59       | 1     | 88.12 |   | 54    | 1     | 65.68 |
|          |    |          | 72.20 |       |   |       | 49.80 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 58       | 1     | 1     |   | 54    | 1     | 69.17 |
|          |    |          | 81.59 | 07.53 |   |       | 62.80 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 55       | 1     | 73.97 |   | 50    | 1     | 63.80 |
|          |    |          | 69.45 |       |   |       | 53.98 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
| Day 3    | 1  | 53       | 1     | 73.34 |   | 54    | 1     | 93.75 |
|          |    |          | 66.00 |       |   |       | 66.94 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 2  | 46       | 1     | 65.61 |   | 48    | 1     | 73.94 |
|          |    |          | 77.31 |       |   |       | 63.96 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          | 3  | 41       | 1     | 75.45 |   | 44    | 1     | 79.74 |
|          |    |          | 73.72 |       |   |       | 62.77 |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+
|          |    |          |       |       |   |       |       |       |
+----------+----+----------+-------+-------+---+-------+-------+-------+

  ----------- ------ ----------- ------- ------- -- ------- ------- -------
                                                                    

  **OI**                                                            

                     HFOV                           CV              

                     n           mean    stdev      n       mean    stdev

  Day 1       pre    68          24.04   15.48      69      26.36   17.24

              1      72          26.19   13.19      61      25.06   20.13

              2      66          23.15   11.41      61      21.46   13.54

              3      59          19.33   10.32      55      19.18   11.65

  Day 2       1      58          19.98   9.79       54      19.28   12.98

              2      56          20.81   11.56      53      17.38   11.72

              3      55          21.19   13.57      48      21.20   23.67

  Day 3       1      52          19.57   11.22      52      19.58   20.13

              2      44          18.44   8.65       48      18.16   18.51

              3      41          19.21   9.71       44      18.90   18.76

                                                                    

  **Cardiac                                                         
  Output**                                                          

                     HFOV                           CV              

                     n           mean    stdev      n       mean    stdev

  Day 1       pre    33          7.41    2.33       34      7.94    3.46

              1      31          6.98    2.01       26      7.41    3.42

              2      34          6.83    2.75       27      7.71    3.26

              3      31          6.69    2.33       25      7.12    2.86

  Day 2       1      26          6.44    2.13       19      8.25    5.06

              2      28          6.32    2.45       24      7.22    3.19

              3      28          6.44    2.75       24      6.80    2.70

  Day 3       1      25          6.53    2.60       21      6.98    2.86

              2      24          6.74    2.81       20      7.95    2.98

              3      18          7.44    2.66       17      7.47    2.31

                                                                    

                                                                    

  **PCWP**                                                          

                     HFOV                           CV              

                     n           mean    stdev      n       mean    stdev

  Day 1       pre    34          16.18   3.72       30      17.20   4.46

              1      30          18.43   2.96       28      18.32   4.70

              2      29          20.07   3.99       22      18.59   4.53

              3      26          20.42   6.34       20      19.50   4.07

  Day 2       1      24          20.21   5.81       19      18.58   3.76

              2      24          20.17   5.17       25      18.88   4.56

              3      23          20.22   5.12       24      19.04   4.36

  Day 3       1      23          20.91   7.22       21      18.52   3.50

              2      21          19.14   5.42       17      19.12   3.69

              3      15          19.53   4.53       18      17.56   2.81

                                                                    

                                                                    

                                                                    

  Patients                                                          
  In-Study                                                          

                     HFOV                           CV              

                     n                              n               

  Day 1       pre    75                             73              

              1      74                             71              

              2      73                             68              

              3      68                             65              

  Day 2       1      66                             65              

              2      64                             60              

              3      60                             59              

  Day 3       1      58                             56              

              2      50                             52              

              3      46                             51              
  ----------- ------ ----------- ------- ------- -- ------- ------- -------

The In-Study Table identifies the number of patients who had not exited
the study at each measurement time. The difference between this number
and the n for the measurements represents data that was not available
for an enrolled patient at that measurement time.

As indicated elsewhere a repeated measures analysis of variance
identified statistically significant differences between ventilators for
only PaCO2, PaO2/FiO2 and pulmonary capillary wedge pressure (PCWP).

**Poolability and Discontinuance of Treatment Analysis**

The statistical review of the data submitted with the PMA reflected two
questions relative to the analyses performed for the data submitted.
These two comments questioned evidence to support the poolability of
data, and interest in a discussion and statistical review of the effects
of discontinuation of therapy on the interpretation of the data. The
following addresses both these questions.

### Poolability

Table 1 below is a tabulation of the enrollment and outcome by
ventilator from each of the 10 centers that recruited patients. The two
outcomes included are death within 30 days and the combined variable,
death or chronic lung disease (D.CLD) at 30 days. Some variation in
overall outcome between the centers would be expected due to chance and
patient population (e.g., medical vs. trauma). Statistical analysis
reveals that there is no significant difference in the overall rate of
death (chi-squared p= 0.432) or D.CLD. (chi-squared p= 0.097) among
centers.

  ---------- ----- ---------- ------- -- ----- -------- ------- -- ------- ------- -- -------- --------
                                                                   \% Risk \% Risk    RR (H/C) RR (H/C)

  **Site**         **HFOV**                    **CV**              Death   D.CLD      Death    D.CLD

             n     Death      D.CLD      n     Death    D.CLD                                  

  1          10    4          8          10    6        9          50%     85%        0.67     0.89

  2          11    5          11         10    3        6          38%     81%        1.52     1.67

  3          9     5          7          10    8        10         68%     89%        0.69     0.78

  4          8     3          6          7     4        6          47%     80%        0.66     0.88

  5          1     0          0          0     0        0          0       0                   

  6          6     1          5          5     3        3          36%     73%        0.28     1.39

  7          7     2          5          10    5        6          41%     65%        0.57     1.19

  8          4     0          2          3     1        2          14%     57%        0        0.75

  9          14    6          10         13    5        7          41%     63%        1.11     1.33

  10         5     2          5          5     3        5          50%     100%       0.67     1.0
  ---------- ----- ---------- ------- -- ----- -------- ------- -- ------- ------- -- -------- --------

Table 1. D.CLD is the combined variable, death or continued respiratory
support at 30 days.

Died is also the outcome at 30 days. RR is the relative risk of HFOV/CMV
(H/C)

The relative risk for the two outcomes (HFOV/CMV) is also included in
the table. Statistical analysis reveals that there is no significant
difference in the odds ratio of Death or D.CLD among centers.
(Mantel-Haentzel p= 0.142, and =0.513). The risk of death was greater
for HFOV treatment than for CMV treatment at only two of the 10 centers,
which is consistent with the trend toward a survival benefit for HFOV in
the pooled data. The risk of D.CLD among the centers is evenly balanced,
consistent with no statistical trend in the pooled data. The two centers
that enrolled the most patients (48 patients) had the worst HFOV
outcomes relative to CMV. However at the next 2 highest enrolling
centers (39 patients) the HFOV outcomes are quite favorable. The trend
toward reduced mortality with HFOV and comparable D.CLD is also
reflected in the results from the smaller centers.

One third of the patients were enrolled at three centers outside the US.
These three centers in Toronto are all University affiliated hospitals
with a standard of care similar to the US. The studies were conducted at
these sites consistent with the protocol and US Investigational Device
Regulations.

There being no statistically identified site inhomogeneity, no
subjectively observable site bias, or inconsistency of standard of care
in the foreign data we can see no reason not to pool the data for
analysis

# Patient Discontinuation

A small percent of the patients (14%) exited the study early, prior to
the primary anticipated exits (death, weaned from mechanical
ventilation, or 30 days on study). Only 3 of these 20 patients were
alive without respiratory support at 30 days (2/8 HFOV, 1/12 CMV). An
additional 8 still required respiratory support at 30 days (2/8 HFOV,
6/12 CMV). The 30 day mortality in these CMV patients was 42% (5/12)
slightly lower than the 52% seen in all CMV patients. In contrast, the
30 day mortality seen in these HFOV patients was 50% (4/8) slightly
higher than the 37% seen in all HFOV patients.

This study was designed with the outcomes to be analyzed based on an
intention to treat. The protocol did permit patients in the experimental
HFOV arm, who meet specific treatment failure criteria to be returned to
conventional ventilation if the attending physician thought it was in
the patient's interest. This occurred in 4 of the 8 cases (mortality
2/4). Interestingly, many of the early exits from the CMV arm (7/12)
went on to receive high frequency ventilation (mortality 3/7). One
conservative approach to dealing with early discontinuations is to treat
them as deaths (failures). In the intention to treat analysis the
mortality in the HFOV group was 37% (28/75) and 52% (38/73). If the
discontinued patients were pooled with the deaths the outcome would be
48% (36/75) for HFOV and 68% (50/73) for CMV. The later proportions are
significantly different (p = 0.012). An alternative approach would be to
discard all early discontinuations from the analysis. This approach also
results in a significant difference. (HFOV 24/67, CMV 33/61, p=0.047).
There was a strong trend toward reduced mortality in the HFOV treatment
that approached significance (p= 0.072).

The two approaches to making adjustments for patients that discontinued
the study early each reflect an improvement in the statistical
significance of improved mortality from HFOV treatment. This suggests
that there was some bias in the study as a result of early
discontinuation, and speculatively, that bias might have been a result
of successful HFOV rescue of CMV assigned patients. This observation
further supports the overall conclusion that HFOV is at least as
effective as CMV.

######## Diaphragm Rupture Analysis

*Statement:*

SensorMedics was requested to explain why failure of the driver
diaphragm does not affect the safety and effectiveness of this device,
and describe how the risk to the patient from an intra-procedure failure
of the device is mitigated. SensorMedics was also asked to comment
regarding the MTBF of the driver and the subsequent rebuilding
frequency.

*Response:*

Failure (rupture) of the driver diaphragm does not occur
catastrophically nor has our experience indicated that a diaphragm
rupture causes the 3100B to fail catastrophically or to instantaneously
cause a detriment in its ability to deliver the specified tidal volume.
Diaphragm ruptures occur directly from wear over long periods of
operation, not suddenly. In the 3100B clinical trials all of the
reported diaphragm ruptures were observed after patient treatment had
been concluded, when replacing patient circuit/bellows assemblies or in
setting up and verifying correct performance before placing another
patient on the 3100B. During these clinical trials, there were no
reports of actual intra-procedure failures of the 3100B caused by driver
diaphragm ruptures, nor, based on our experience and life testing, is it
likely that a driver diaphragm rupture would/cause an intra-procedure
device failure. SensorMedics, throughout supplement 14, has utilized
torn diaphragms as a measure of MTBF. It should be noted, however, that
the torn diaphragm did not cause a device failure. While the driver
should be replaced once a torn diaphragm is discovered, the ventilator
can continue to perform adequately for quite some time.

SensorMedics has conducted driver reliability tests and has found the
average mean time between diaphragm tears to be in excess of 2000 hours,
and has therefore included a recommended driver rebuild frequency of
2000 hours.

To ensure continued performance of the Ventilator in the event of a
diaphragm tear, SensorMedics has conducted tests on a driver having a
typical rupture; its performance (tidal volume versus frequency and
power setting) was no different than that of a new driver as tested in a
new 3100B. A driver with a diaphragm rupture can operate completely
normally for a lengthy period, many hours if not several days, allowing
operators more than adequate time to both discover the rupture and, as
necessary, switch to another 3100B or alternate method to continue
patient treatment.

Nevertheless, if a major intra-procedure driver failure from a diaphragm
rupture were to occur, it would be preceded by a period in which the
operating temperature of the driver would increase to higher levels,
thus activating over-temperature indicators to alert operators. Also,
other alarms would be activated as the driver's performance began to
slowly reduce. This reduced performance would result in decreases in
mean airway and/or oscillatory pressures.

  ------- -------------------------------- ------- ---- ------- ------------
  Site \#                                  HFOV    CV   Total   Rate/month

  1       Wilford Hall / BAMC              10      10   20      .53

  2       Toronto Hospital                 11      10   21      .62

  3       Wellselley / Mt Sinai            9       10   19      .79

  4       Maine Medical Center             8       7    15      .48

  5       Bronson Methodist                1            1       

  6       Loma Linda                       6       5    11      .44

  7       University Virginia              7       10   17      .85

  8       Alleghany General                4       3    7       .30

  9       Barnes Jewish-Washington Univ    14      13   27      1.50

  10      Sunnybrook                       5       5    10      .83

          Total                            75      73   148     
  ------- -------------------------------- ------- ---- ------- ------------

Table 1

In the original submission (page 162), the patients from Maine Medical
Center were switched in the above columns and the single patient from
Bronson Methodist was not included in the total column.

6\. Study Site Information

+-----------------------------------------------------------------------+
| **SITES:**                                                            |
|                                                                       |
| **1.**                                                                |
+-----------------------------------------------------------------------+
| Wilford Hall Medical Center                                           |
+-----------------------------------------------------------------------+
| Lackland AFB, TX                                                      |
+-----------------------------------------------------------------------+
| 78236-5300                                                            |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Stephen Derdak DO                                                     |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **2.**                                                                |
|                                                                       |
| The Toronto Hospital                                                  |
+-----------------------------------------------------------------------+
| 200 Elizabeth Street                                                  |
+-----------------------------------------------------------------------+
| Toronto, Ontario                                                      |
+-----------------------------------------------------------------------+
| M5G2C4/Canada                                                         |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| John Granton, MD                                                      |
+-----------------------------------------------------------------------+

+---+-----------------------------------------------------------------+---+
|   | **3a.**                                                         |   |
|   |                                                                 |   |
|   | The Wellesley Hospital                                          |   |
+---+-----------------------------------------------------------------+---+
|   | 160 Wellesley St. East                                          |   |
+---+-----------------------------------------------------------------+---+
|   | Toronto, Ontario                                                |   |
+---+-----------------------------------------------------------------+---+
|   | M4Y1J3, Canada                                                  |   |
+---+-----------------------------------------------------------------+---+
|   | **PI**                                                          |   |
|   |                                                                 |   |
|   | Thomas Stewart MD                                               |   |
+---+-----------------------------------------------------------------+---+
| * |                                                                 |   |
| * |                                                                 |   |
| 3 |                                                                 |   |
| b |                                                                 |   |
| . |                                                                 |   |
| * |                                                                 |   |
| * |                                                                 |   |
|   |                                                                 |   |
| M |                                                                 |   |
| o |                                                                 |   |
| u |                                                                 |   |
| n |                                                                 |   |
| t |                                                                 |   |
| S |                                                                 |   |
| i |                                                                 |   |
| n |                                                                 |   |
| a |                                                                 |   |
| i |                                                                 |   |
| H |                                                                 |   |
| o |                                                                 |   |
| s |                                                                 |   |
| p |                                                                 |   |
| i |                                                                 |   |
| t |                                                                 |   |
| a |                                                                 |   |
| l |                                                                 |   |
+---+-----------------------------------------------------------------+---+
| 6 |                                                                 |   |
| 0 |                                                                 |   |
| 0 |                                                                 |   |
| U |                                                                 |   |
| n |                                                                 |   |
| i |                                                                 |   |
| v |                                                                 |   |
| e |                                                                 |   |
| r |                                                                 |   |
| s |                                                                 |   |
| i |                                                                 |   |
| t |                                                                 |   |
| y |                                                                 |   |
| A |                                                                 |   |
| v |                                                                 |   |
| e |                                                                 |   |
| n |                                                                 |   |
| u |                                                                 |   |
| e |                                                                 |   |
+---+-----------------------------------------------------------------+---+
| T |                                                                 |   |
| o |                                                                 |   |
| r |                                                                 |   |
| o |                                                                 |   |
| n |                                                                 |   |
| t |                                                                 |   |
| o |                                                                 |   |
| , |                                                                 |   |
| O |                                                                 |   |
| n |                                                                 |   |
| t |                                                                 |   |
| a |                                                                 |   |
| r |                                                                 |   |
| i |                                                                 |   |
| o |                                                                 |   |
+---+-----------------------------------------------------------------+---+
| M |                                                                 |   |
| 5 |                                                                 |   |
| G |                                                                 |   |
| 1 |                                                                 |   |
| X |                                                                 |   |
| 6 |                                                                 |   |
| / |                                                                 |   |
| C |                                                                 |   |
| a |                                                                 |   |
| n |                                                                 |   |
| a |                                                                 |   |
| d |                                                                 |   |
| a |                                                                 |   |
+---+-----------------------------------------------------------------+---+
| * |                                                                 |   |
| * |                                                                 |   |
| P |                                                                 |   |
| I |                                                                 |   |
| * |                                                                 |   |
| * |                                                                 |   |
|   |                                                                 |   |
| T |                                                                 |   |
| h |                                                                 |   |
| o |                                                                 |   |
| m |                                                                 |   |
| a |                                                                 |   |
| s |                                                                 |   |
| S |                                                                 |   |
| t |                                                                 |   |
| e |                                                                 |   |
| w |                                                                 |   |
| a |                                                                 |   |
| r |                                                                 |   |
| t |                                                                 |   |
| , |                                                                 |   |
| M |                                                                 |   |
| D |                                                                 |   |
+---+-----------------------------------------------------------------+---+

+-----------------------------------------------------------------------+
| **4.**                                                                |
|                                                                       |
| Maine Medical Center                                                  |
+-----------------------------------------------------------------------+
| 22 Bramhall Drive                                                     |
+-----------------------------------------------------------------------+
| Portland, ME                                                          |
+-----------------------------------------------------------------------+
| O4102                                                                 |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Sandy Bagwell, MD                                                     |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **5.**                                                                |
|                                                                       |
| Bronson Medical Center                                                |
+-----------------------------------------------------------------------+
| 252 E. Lovell Street                                                  |
+-----------------------------------------------------------------------+
| Kalamazoo, MI                                                         |
+-----------------------------------------------------------------------+
| 49007-5345                                                            |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Bill Shillingwall DO                                                  |
+-----------------------------------------------------------------------+

**IRB's:**

+-----------------------------------------------------------------------+
| Darlene Castro                                                        |
|                                                                       |
| Clinical Research Div.                                                |
+-----------------------------------------------------------------------+
| AF Medical Operations                                                 |
+-----------------------------------------------------------------------+
| Office Surgeon General                                                |
+-----------------------------------------------------------------------+
| Bolling AFB,DC 20332                                                  |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| M Elvis                                                               |
+-----------------------------------------------------------------------+
| Medical Research Directorate                                          |
+-----------------------------------------------------------------------+
| CCRW 2-814                                                            |
+-----------------------------------------------------------------------+
| The Toronto Hospital                                                  |
+-----------------------------------------------------------------------+
| 200 Elizabeth Street                                                  |
|                                                                       |
| Toronto, Ontario                                                      |
|                                                                       |
| M5G2C4, Canada                                                        |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| E Keystone                                                            |
+-----------------------------------------------------------------------+
| Research Institute                                                    |
+-----------------------------------------------------------------------+
| The Wellesley Hospital                                                |
+-----------------------------------------------------------------------+
| 160 Wellesley St. East                                                |
+-----------------------------------------------------------------------+
| Toronto, Ontario                                                      |
|                                                                       |
| M4Y1J3, Canada                                                        |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| Bill Wilson                                                           |
+-----------------------------------------------------------------------+
| Mount Sinai Hospital                                                  |
+-----------------------------------------------------------------------+
| 600 University Avenue                                                 |
|                                                                       |
| Toronto, Ontario                                                      |
+-----------------------------------------------------------------------+
| M5G1X6/Canada                                                         |
+-----------------------------------------------------------------------+

  -----------------------------------------------------------------------
  D Hayes MD

  MMC-Research Institute

  125 John Roberts Road

  Suite 5

  S. Portland, ME 04106
  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  Robert Hume MD

  Bronson Medical Center

  252 E. Lovell Street

  Kalamazoo, MI

  49007-5345
  -----------------------------------------------------------------------

**Key Dates/Info:**

+-----------------------------------------------------------------------+
| IRB Approval: 8/5/97                                                  |
|                                                                       |
| First subject: 10/26/97                                               |
|                                                                       |
| Patients enrolled: 20                                                 |
+-----------------------------------------------------------------------+

IRB approval: 7/7/97

First subject: 12/11/97

Patients enrolled: 21

IRB approval: 8/28/97

First subject: 12/4/97

Patients enrolled: 5

ICU closed and study terminated: 6/1/98

+-----------------------------------------------------------------------+
| IRB approval: 10/13/98                                                |
|                                                                       |
| First subject: 8/25/98                                                |
|                                                                       |
| Patients enrolled: 14                                                 |
+-----------------------------------------------------------------------+

IRB approval: 6/25/97

First subject: 1/28/98

Patients enrolled: 15

IRB approval: 8/14/97

First subject: 3/14/98

Patients enrolled: 1

Study terminated: 10/30/98

**SITES:**

+-----------------------------------------------------------------------+
| **6.**                                                                |
|                                                                       |
| Loma Linda University MC                                              |
+-----------------------------------------------------------------------+
| 11234 Anderson Street                                                 |
|                                                                       |
| Loma Linda CA,                                                        |
+-----------------------------------------------------------------------+
| 92354                                                                 |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Ronald Perkins MD                                                     |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **7.**                                                                |
|                                                                       |
| University Virginia Hospital                                          |
+-----------------------------------------------------------------------+
| P.O. Box 10010                                                        |
+-----------------------------------------------------------------------+
| Charlottesville, VA                                                   |
+-----------------------------------------------------------------------+
| 22906                                                                 |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Stuart Lowson MB.B                                                    |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **8.**                                                                |
|                                                                       |
| Allegheny General Hospital                                            |
+-----------------------------------------------------------------------+
| 320 East Avenue                                                       |
+-----------------------------------------------------------------------+
| Pittsburgh, PA                                                        |
+-----------------------------------------------------------------------+
| 15212-4772                                                            |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Brian Carlin MD                                                       |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **9.**                                                                |
|                                                                       |
| Barnes Jewish-Washington Univ MC                                      |
+-----------------------------------------------------------------------+
| One Barnes Hospital Plaza                                             |
+-----------------------------------------------------------------------+
| St Louis MO                                                           |
+-----------------------------------------------------------------------+
| 63110-1093                                                            |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Timothy Buchman MD PhD                                                |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **10.**                                                               |
|                                                                       |
| SunnyBrooke Health Science                                            |
+-----------------------------------------------------------------------+
| 2075 Bayview Avenue                                                   |
+-----------------------------------------------------------------------+
| North York, Ontario                                                   |
+-----------------------------------------------------------------------+
| Canada M4N3M5                                                         |
+-----------------------------------------------------------------------+
| **PI**                                                                |
|                                                                       |
| Terry Smith MD                                                        |
+-----------------------------------------------------------------------+

IRB's:

+-----------------------------------------------------------------------+
| William Saukel MD.                                                    |
+-----------------------------------------------------------------------+
| LLUMC IRB                                                             |
+-----------------------------------------------------------------------+
| 11188 Anderson Street                                                 |
|                                                                       |
| Loma Linda CA,                                                        |
+-----------------------------------------------------------------------+
| 92354                                                                 |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| David A Peura MD                                                      |
+-----------------------------------------------------------------------+
| Human Investigations Comm.                                            |
+-----------------------------------------------------------------------+
| UVa Health System                                                     |
+-----------------------------------------------------------------------+
| P.O. Box 483                                                          |
+-----------------------------------------------------------------------+
| Charlottesville, VA                                                   |
|                                                                       |
| 22908                                                                 |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| Richard N Fogoros MD.                                                 |
+-----------------------------------------------------------------------+
| IRB Allegheny General Hospital                                        |
+-----------------------------------------------------------------------+
| 320 East Avenue                                                       |
|                                                                       |
| Pittsburgh, PA                                                        |
+-----------------------------------------------------------------------+
| 15212-4772                                                            |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| P Girgsley                                                            |
+-----------------------------------------------------------------------+
| WUMC-IRB                                                              |
+-----------------------------------------------------------------------+
| Washington University                                                 |
+-----------------------------------------------------------------------+
| P.O. Box 8089                                                         |
|                                                                       |
| St Louis, MO                                                          |
+-----------------------------------------------------------------------+
| 63110-1093                                                            |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| Philip Hebert MD PhD                                                  |
+-----------------------------------------------------------------------+
| Research Ethics Board                                                 |
+-----------------------------------------------------------------------+
| SunnyBrooke Health Science                                            |
+-----------------------------------------------------------------------+
| 2075 Bayview Avenue                                                   |
|                                                                       |
| North York, Ontario                                                   |
+-----------------------------------------------------------------------+
| Canada M4N3M5                                                         |
+-----------------------------------------------------------------------+

**Key Dates/Info:**

IRB Approval: 7/8/98

First subject: 10/8/98

Patients enrolled: 11

IRB approval: 10/13/98

First subject: 3/16/99

Patients enrolled: 17

IRB approval: 8/21/98

First subject: 3/30/99

Patients enrolled: 7

IRB approval: 84/7/99

First subject: 5/20/99

Patients enrolled: 27

IRB approval: 1/27/99

First subject: 11/1/99

Patients enrolled: 10

In the original submission (pages 153-154), The Wellesley Hospital and
Mount Sinai Hospital in Toronto were listed separately. The two ICU's
data were treated as a single center when The Wellesley Hospital closed
and the personnel and PI transferred to Mt. Sinai. The data for these
units was combined in the analysis. There were also two institutions
incorrectly labeled by their identified number.

Table 8: Status at 1 month and 6 months

+------------------------------+--------+--------+---+--------+--------+
|                              | HFO    | HFO    |   | CMV    | CMV    |
+------------------------------+--------+--------+---+--------+--------+
| End Points                   | 1 M    | 6 M    |   | 1 M    | 6 M    |
+------------------------------+--------+--------+---+--------+--------+
| Died                         | 37 %   | 47 %   |   | 53 %   | 59 %   |
+------------------------------+--------+--------+---+--------+--------+
| Survived (resp. support)     | 41 %   | 0 %    |   | 21 %   | 3 %    |
+------------------------------+--------+--------+---+--------+--------+
| Survived                     | 21%    | 53 %   |   | 26 %   | 38 %   |
+------------------------------+--------+--------+---+--------+--------+
| ##  1 month p= 0.038         |        |        |   |        |        |
+------------------------------+--------+--------+---+--------+--------+
| **6 months p= 0.086**        |        |        |   |        |        |
+------------------------------+--------+--------+---+--------+--------+

In the original submission (page 164) the percentage for survival in the
CMV group at 6 months was entered as 26%. The correct number is 38%.

Conclusions Drawn From Comparisons of ARDS Studies with MOAT2

MOAT2 was a prospective randomized multicenter comparison of the
SensorMedics 3100B HFOV and conventional mechanical ventilation for the
treatment of ARDS. Both ventilators used a strategy aimed at
normalization of lung volumes and minimization of peak ventilatory
pressures. Patients were exited from the study at 30 days, death or upon
successful weaning from mechanical ventilation. The primary endpoint was
status at 30 days, however secondary endpoints included status at 6
months and the incidence of specific adverse events while on study.

To determine the benefit of HFOV in the management of ARDS, the data
from the HFOV treated patients must be considered both in comparison
with the control subjects as well as compared with other published
ventilator trials in similar patient populations. Specific
characteristics associated with higher risk of mortality include patient
age^1,3,10^, specific ARDS triggering etiologies^3,8-11^, severity of
hypoxemia^3,10-13^, existing air leaks^14^, immune compromised^4^, and
ventilator strategies that use high volumes and pressures^5,6^.

The two populations for the treatment and control arms in this study
were very well balanced (tables 1a and 1 b) and contained no
statistically significant differences.

+------------------------------------+----------------+----------------+
| ##### Table 1a                     |                |                |
| . Baseline Patient Characteristics |                |                |
+------------------------------------+----------------+----------------+
|                                    | HFOV           | #### CMV       |
+------------------------------------+----------------+----------------+
| Number                             | 75             | 73             |
+------------------------------------+----------------+----------------+
| Age (years)                        | 48 (17)        | 51 (18)        |
+------------------------------------+----------------+----------------+
| Percent \> 70 years age            | 15%            | 16%            |
+------------------------------------+----------------+----------------+
| Weight (kg)                        | 78 (25)        | 81 (26)        |
+------------------------------------+----------------+----------------+
| Gender (% male)                    | 52%            | 64%            |
+------------------------------------+----------------+----------------+
| Apache II Score                    | 22 (6)         | 22 (9)         |
+------------------------------------+----------------+----------------+
| ARDS Trigger:                      |                |                |
+------------------------------------+----------------+----------------+
| Sepsis Syndrome                    | 47%            | 47%            |
+------------------------------------+----------------+----------------+
| Pulmonary Infection                | 19%            | 16%            |
+------------------------------------+----------------+----------------+
| Trauma                             | 21%            | 18%            |
+------------------------------------+----------------+----------------+
| other                              | 13%            | 19%            |
+------------------------------------+----------------+----------------+
| Confounding Dx                     |                |                |
+------------------------------------+----------------+----------------+
| Air leak                           | 16%            | 19%            |
+------------------------------------+----------------+----------------+
| Immune compromise                  | 12%            | 14%            |
+------------------------------------+----------------+----------------+
| 5 or more days preCMV              | 22%            | 36%            |
+------------------------------------+----------------+----------------+

> Continuous data presented as mean std dev). Discrete data presented as
> %. PaO2 denotes the partial pressure of arterial oxygen (mm Hg) and
> FiO2 the fraction of inspired oxygen. Oxygenation Index is the mean
> airway pressure x FiO2 x 100 divided by the PaO2. None of the
> differences between the groups was statistically significant. APACHE
> II score is a multivariate assessment of patient severity.

+------------------------------------+----------------+----------------+
| ##### Table 1b.                    |                |                |
|  Baseline Physiological Parameters |                |                |
+------------------------------------+----------------+----------------+
|                                    | HFOV           | #### CMV       |
+------------------------------------+----------------+----------------+
| number                             | 75             | 73             |
+------------------------------------+----------------+----------------+
| PIP (cm H2O)                       | 39 (7)         | 38 (8)         |
|                                    |                |                |
| Mean Paw (cm H2O)                  | 22 (5)         | 23 (6)         |
+------------------------------------+----------------+----------------+
| ###### PEEP (cm H2O)               | 13 (3)         | 14 (3)         |
+------------------------------------+----------------+----------------+
| Respiratory rate (/min.)           | 18 (5)         | 20 (6)         |
+------------------------------------+----------------+----------------+
| Tidal Volume (cc/kg)               | 8.2 (3)        | 7.8 (3)        |
+------------------------------------+----------------+----------------+
| FiO2                               | .71 (.19)      | .72 (.19)      |
+------------------------------------+----------------+----------------+
| PaO2                               | 76 (20)        | 73 (18)        |
+------------------------------------+----------------+----------------+
| PaCO2                              | 44 (12)        | 45 (12)        |
+------------------------------------+----------------+----------------+
| PH                                 | 7.37 (.09)     | 7.34 (.11)     |
+------------------------------------+----------------+----------------+
| PaO2/FiO2                          | 114 (37)       | 111 (42)       |
+------------------------------------+----------------+----------------+
| ##### Oxygenation Index            | 24 (15)        | 27 (19)        |
+------------------------------------+----------------+----------------+
| ##### Apache 2                     | 22 (6)         | 22 (9)         |
+------------------------------------+----------------+----------------+

> Continuous data presented as mean (stdev). PIP denotes the peak
> inspiratory pressure, PEEP the positive end expiratory pressure. PaO2
> denotes the partial pressure of arterial oxygen and FiO2 the fraction
> of inspired oxygen. PaCO2 the partial pressure of arterial carbon
> dioxide. Oxygenation Index is the mean airway pressure x FiO2 x 100
> divided by the PaO2. None of the differences between the groups was
> statistically significant.

At 30 days of study entry, the mortality in the conventionally
ventilated patients was 52 percent while in the HFOV group the mortality
was 37 percent, a 29 percent lower relative mortality. While there were
more patients on some form of respiratory support in the HFOV group at
30 days, fewer of them required mechanical ventilation versus only
supplemental oxygen than in the control group (61% vs. 73%). At six
months, although the mortality differences narrowed, there was still a
20 percent mortality benefit for patients in the HFOV group. There was
no residual need for respiratory support in the HFOV treated patients at
six months. None of these differences reached statistical significance.

The largest multicenter prospective randomized ventilator trial in ARDS
that has demonstrated a statistically significant benefit with use of a
specific management approach has been the NIH lower tidal volume.^5^
This study compared patients managed with 6 ml/kg tidal volume as
compared with patients managed with 12 ml/kg. They reported a mortality
of 31 percent in the patients treated with 6 ml/kg tidal volume as
compared with the 39.8 percent mortality in the control group (a
reduction of 22%). A comparison of the patients in the MOAT2 study with
the NIH patients may be important when considering the effectiveness of
HFOV.

The NIH trial enrolled patients with less severe respiratory failure as
the entrance criteria included patients who had acute lung injury as
define by a PaO2/FiO2 (P/F) ratio \<300 torr.^5^ There was also no
minimum level of end expiratory pressure (PEEP) required for entry.
Entrance in the MOAT2 trial required a P/F \<200 on a minimum PEEP of 10
cmH2O. As a result, the severity of the patients in the MOAT2 trial
overall was very different than in the NIH trial. The mean P/F in the
NIH trial was 136 and in the MOAT2 trial it was 112. In support of the
differences in severity of disease, the MOAT2 patients had P/F values
recorded on a minimum PEEP of 10 cmH2O. A prior

publication evaluating the influence of a P/F \<150 with a PEEP of 5
cmH2O on mortality in ARDS reported that if the P/F was \>150, the
mortality was 23%.^3^ However, if the P/F on 5 cmH2O was \<150, the
mortality rose to 68%. Similar increases in mortality have been reported
with P/F's less than 100.^7^ Additionally, the mean Oxygenation Index in
the NIH trial was 12 versus 25 in MOAT2.

Sepsis syndrome was the triggering mechanism for ARDS in 47% of both
groups in the MOAT2 trial, while it accounted for only 27% of the NIH
patients. Our own analysis of prior HFOV data and consistent with other
conventional ventilation data, presence of sepsis has a negative impact
on survival and/or morbidity.^4,8-11^ This alone could account for the
outcome differences seen between these trials.

When the MOAT2 trial was designed, there was no evidence that low tidal
volumes during mechanical ventilation would be beneficial. However, the
MOAT2 strategy for conventional ventilation was not as high a volume
target as was used in the control arm of the NIH trial. The targeted
tidal volume in MOAT2 was at 6-10 ml/kg of actual body weight. As a
result though of the NIH report, a post-hoc analysis of the mortality in
the control arm was performed with recalculation of delivered tidal
volume per kilogram of *ideal body weight*. Analysis of the mortality in
the conventionally ventilated patients, stratified by ideal body weight
follows in table 2.

  -------------- -------------- -------------- -------------- --------------
  TV/kg (IBW)    Mortality      N              Average VT     Std Dev

  \< 8 ml/kg     0.67           6              7.13           0.62

  8 to 10 ml/kg  0.44           25             9.15           0.58

  \> 10 ml/kg    0.46           28             11.54          0.66
  -------------- -------------- -------------- -------------- --------------

Table 2. MOAT2 Control Arm mortality by ideal body weight (IBW)

This analysis was limited by the small number of patients in the groups.
However, the trend tended to demonstrate that while the mortality in the
MOAT2 patients treated with conventional ventilation was higher than the
patients from the NIH trial, actual tidal volume appeared to have no
impact on outcome. It is evident that there may be other differences in
the patient population that resulted in the difference in outcome (e.g.
sepsis syndrome, derangement of oxygenation, duration of pre-entry
mechanical ventilation, etc.).

With the assistance of the ARDSnet data group, we further explored their
data to understand the differences between their outcomes and the MOAT2
control group. We were able to select patients from both the low and
high stretch groups who entered the NIH trial with PEEP's greater than
or equal to 10 cmH2O, with group average incidences of sepsis at 47% and
median P/F ratios in both groups at 112 so as to match the MOAT2 control
group for those parameters. The 28 day mortality from these two sicker
groups of patients rose slightly to 34.9 and 40.9 percent respectively.

To further explore the mortality in the control arm, we additionally
reviewed several other ARDS trials from the literature where there was
no difference in outcome. These included studies by Stewart^15^,
Brochard^16^, and Brower^17^. Table 3 reflects the data from these
trials.

+--------+------+------+------+-------+------+------+-----+--------+
|        | NIH  | Ste  | Br   | Bro   | M    | Ste  | Bro | Br     |
|        |      | wart | ower | chard | OAT2 | wart | wer | ochard |
|        | Con  |      |      |       |      |      |     |        |
|        | trol | Con  | Con  | Co    | Con  | S    | St  | Study  |
|        |      | trol | trol | ntrol | trol | tudy | udy |        |
+--------+------+------+------+-------+------+------+-----+--------+
| Vt/kg  | 11.8 | 10.7 | 10.2 | 10.3  | 10.2 | 7    | 7.3 | 7.1    |
| IBW    |      |      |      |       |      |      |     |        |
+--------+------+------+------+-------+------+------+-----+--------+
| PEEP   | 8.6  | 7.2  | 8.3  | 10.7  | 14   | 8.6  | 9.5 | 10.7   |
+--------+------+------+------+-------+------+------+-----+--------+
| Apache |      | 22   |      | 17    | 22   | 22   |     | 19     |
| 2      |      |      |      |       |      |      |     |        |
+--------+------+------+------+-------+------+------+-----+--------+
| Apache | 84   |      | 85   |       |      |      | 91  |        |
| 3      |      |      |      |       |      |      |     |        |
+--------+------+------+------+-------+------+------+-----+--------+
| PaO    | 134  | 145  | 150  | 155   | 111  | 123  | 129 | 144    |
| 2/FiO2 |      |      |      |       |      |      |     |        |
+--------+------+------+------+-------+------+------+-----+--------+
| Pr     | 36   | \<1  | 24   | 2.7   | 4.4  | \<1  | 24  | 2      |
| e-Vent | hrs  |      | hrs  |       |      |      | hrs |        |
| Days   | ARDS |      | ARDS |       |      |      | A   |        |
|        |      |      |      |       |      |      | RDS |        |
+--------+------+------+------+-------+------+------+-----+--------+
| Mor    | 40   | 47   | 46   | 38    | 52   | 50   | 50  | 47     |
| tality |      |      |      |       |      |      |     |        |
+--------+------+------+------+-------+------+------+-----+--------+

Table 3. Comparison of ARDS trials

In reviewing this data so as to understand possible causes of the
differences in outcomes between trials, it is evident that the patients
in the MOAT2 trial were on conventional ventilation for a longer period
prior to entry into the trial and had lower P/F's than any other trial.

The mortality in the MOAT2 conventional ventilation arm was not largely
different from the mortality in other ARDS trials. Of interest when
taken to an extreme of the trends from table 3, considering that the NIH
control arm had a mortality of only 40% at a tidal volume of 12 ml/kg,
and that all of the other trials also had the lowest mortalities in
their control (higher tidal volume) arms, one could hypothesize that
either large or small tidal volumes are protective and only moderate
tidal volumes are harmful. There is no evidence to support this argument
so that other mechanisms and/or patient populations selection most
likely explain these differences. This data is only one more reason why
comparisons of trials are extremely difficult and that the data for each
trial must stand on its own.

To further explore the possibility of differences in treatment effect of
HFOV in patients of varying initial severity of oxygenation, we
conducted a retrospective analysis of PaO2/FiO2, oxygenation index (OI),
and peak inspiratory pressure at entry, stratified at their median
levels. Interestingly, this post-hoc stratification of patients based on
initial peak airway pressure at enrollment, but not PaO2/FiO2 or OI,
showed a significant difference in mortality outcome between HFOV and
CV.

  ------------------------- ---------------------- ----------------------
                            HFOV                   CV

  N                         38                     42

  PIP                       33                     32

  PEEP                      13                     13

  Vt (ml/kg)                8.5                    7.9

  PaO2/FiO2                 115                    120

  Sepsis                    45%                    45%

  Median pre-CV days        1.5                    1.9

  Mortality 30 days         26%                    52% (p \< 0.018)

  Mortality 6 months        39%                    62% (p \< 0.045)
  ------------------------- ---------------------- ----------------------

Table 4. Patients stratified by median peak airway pressure (38 cm H2O)
at time of enrollment.

A post-hoc subgroup analysis of patients (table 4) stratified by median
enrollment peak airway pressure was then performed. There were no
differences between the groups

as related to entry data, however the analysis revealed a statistically
significant reduction in 30-day mortality in the HFOV treatment group
compared with the CV group (26% versus 52%; p=0.018), which persisted at
6 months (39% versus 62%; p=0.045). The mortality in this group of
patients was 16 percent relatively lower than the overall NIH low
stretch arm mortality (31%) and 26 percent relatively lower than the
matched population (34.9%). In contrast, there was no subsequent
mortality difference between treatment groups if baseline peak
inspiratory pressure was greater than the median. The groups in the
higher peak inspiratory pressure groups were not evenly matched and
therefore no interpretation of that data is meaningful.

Survival curves showing the proportion of survivors for all patients
enrolled (1a) and the patients with PIP 38 or lower prior to enrollment
(1b) are in the following graphs. Dark Black lines represent HFOV
patients and Light Grey lines CV patients. No enrolled patients died
after 89 days. The difference in survival rate in 1a did not reach
significance censored at 30 days or at 90 days (p= 0.057, 0.078
respectively). However both were significantly different in 1b (p=
0.019, and 0.026, 30 days and 90 days respectively)

Figure 1a

![](media/image1.wmf){width="2.875in" height="2.8305555555555557in"}

Figure 1b

![](media/image2.wmf){width="2.875in" height="2.83125in"}

Conclusions:

We believe that comparisons between trials are very difficult to
interpret; that each randomized controlled trial must be interpreted
within the patient populations from each trial; that multiple factors
can explain differences in outcomes between trials; and while the
differences in mortality at 30 days (29%) did not reach statistical
significance, considering the 6 month status, this may be interpreted as
supporting HFOV effectiveness. This is further supported by the post-hoc
analyses which do show significant differences (p \< 0.018). We submit
that use of the 3100B HFOV for treating patients with acute respiratory
failure is at least as effective as conventional ventilation and that
there are no increased risks that outweigh any potential benefit.

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