Conservative oxygen therapy in mechanically ventilated patients: a pilot before-and-after trial
Satoshi Suzuki; Glenn M. Eastwood; Neil J. Glassford; Leah Peck; Helen Young; Mercedes Garcia-Alvarez; Antoine G. Schneider; Rinaldo Bellomo
SUPPLEMENTAL DIGITAL CONTENT
RESULTS
Key findings after analysis of the first 50 patients in each group.
After extraction of the first 50 patients in each group, there were 3002 datasets on 758 MV days. There were no significant differences in baseline characteristics, oxygenation-related variables and blood gas results including FIO2, SpO2, PaO2, PaO2/FIO2 ratio, lactate and creatinine level.
In the conservative oxygen therapy group, patients had a significantly lower median TWAMV-SpO2
(95.5% [interquartile range 94.0-97.3] vs. 98.5% [97.2-99.1], p <.001) and TWAMV-PaO2 (83 mmHg [71-94] vs. 108 mmHg [94-131], p <.001) in the use of a lower TWAMV-FIO2 (0.27 [0.24-0.30] vs. 0.40 [0.35-0.44], p <.001) compared with the conventional group. Conservative oxygen therapy decreased the total amount of oxygen delivered during MV by approximately two-thirds (16259 L [8117-30005]
vs. 4964 L [1714-10499], p <.001) and delivered much less excess oxygen (3616 L [1634-7698] vs. 143 L [0-1164], p <.001).
Relative percentage changes in PaO2/FIO2 ratio between baseline and follow-up in the first 10 days were not significantly different between the groups (p = .79). The conservative oxygen therapy group had a trend of greater relative decrease in lactate levels from baseline and follow-up over the first 10 days (p = .09). We found no differences in changes in creatinine levels between the groups (p = .72).
There were no significant differences in any other clinical outcomes between the groups.
After adjusting for APACHE III score, primary diagnosis, reason for MV and use of RRT in the ICU, conservative oxygen therapy remained a trend of a greater relative decrease in lactate from baseline to the worst level and to day2, although they were not statistically significant (standardized coefficients of -0.14, p = 0.18 and standardized coefficients of -0.17, p = 0.096, respectively). Conservative therapy
group had a significant decreased risk for new non-respiratory organ failure in multivariable analysis (Adjusted odds ratio, 0.25; 95%CI, 0.092-0.70; p <.01). Adjusted odds ratiofor any other key outcomes with conservative oxygen therapy were not statistically significant.
Supplemental Table 1 Comparison of Oxygenation-related variables and blood gas results
Variable Conventional
(N = 51)
Conservative (N = 54)
p
TWAMV minute ventilation, L/min 8.6[6.7-10.4] 8.5[7.1-10.7] .85
TWAMV FIO2 0.40[0.35-0.44] 0.27[0.24-0.30] <.001
TWAMV PEEP, cmH2O 6.1[5-7.5] 5.2[5-7.4] .09
TWAMV SpO2, % 98.4[97.3-99.1] 95.5[94.0-97.3] <.001
TWAMV PaO2, mmHg 107[94-131] 83[71-94] <.001
TWAMV pH 7.44[7.41-7.45] 7.44[7.40-7.46] .13
TWAMV PaCO2, mmHg 40.3[36.9-44.7] 39.0[35.8-42.2] .12
TWAMV Hb, g/dL 8.9[8.1-10.3] 9.0[8.2-10.5] .45
%time with hyperoxemia, % 59[29-83] 13[2-36] <.001
%time with FIO2 of 0.21, % 0[0-0] 33[9-73] <.001
Total amount of oxygen usage, L 15580[8263-29351] 5122[1837-10499] <.001 Total amount of excess oxygen delivery, L 3472[1532-7178] 192[0-1184] <.001 TWAMV = time-weighted average during mechanical ventilation, FIO2 = fraction of inspired oxygen, PEEP = positive end-expiratory pressure, SpO2 = pulse oximetry derived oxygen saturation, PaO2 = arterial partial pressure of oxygen, PaCO2 = blood partial pressure of carbon dioxide, Hb = hemoglobin concentration, %time = percentage of time spent.
Supplemental Table 2 Comparison of PaO2/FIO2 ratio-, lactate- and creatinine-related variables
Variable Conventional
(N = 51)
Conservative (N = 54)
p
PaO2/FIO2 ratio
Lowest in the first 10 days, mmHg 158[120-237] 177[135-258] .20
%∆worsta, % -29[-47 to -1] -23[-50 to 0] .67
%∆24hb, % -1[-20 to 43] 3[-19 to 66] .75
%∆48hc, % 0[-20 to 50] 0[-24 to 75] .90 Lactate
Highest in the first 10 days, mmol/L 3.3[2.3-4.4] 3.2[2.1-6] .72
%∆worsta, % 78[21-171] 49[0-110] .09
%∆24hb, % 10[-18 to 56] 1[-27 to 23] .07
%∆48hc, % 6[-37 to 55] -23[-55 to 42] .09 Creatinine
Highest in the first 10 days, µmol/L 119[86-216] 130[86-267] .60
%∆worsta, % 21[6-43] 16[3-33] .45
%∆24hb, % 4[-3 to 12] 1[-6 to 9] .39
%∆48hc, % 1[-11 to 17] -1[-12 to14] .95 PaO2 = arterial partial pressure of oxygen, FIO2 = fraction of inspired oxygen.
a%∆worst = (worst value - baseline) / baseline x 100.
b%∆24h = (time-weighted average of day1 - baseline) / baseline x 100.
c%∆48h = (time-weighted average of day2 - baseline) / baseline x 100.
Supplemental Table 3 Comparison of secondary and tertiary outcomes
Variable Conventional
(N = 51)
Conservative (N = 54)
p
Laboratory results
Bilirubin total, µmol/L 9.3[5.9-24.1] 8.3[5.1-39.3] .95
ALP, U/L 81[58-132] 94[73-140] .14
ALT, U/L 46[25-86] 69[31-126] .09
GGT, U/L 74[38-156] 112[63-183] .08
CRP, mg/L 94.4[32.5-170.6] 68.6[22.3-118.8] .16
White cell count, x 109/L 11.2[7.8-14.7] 11.7[7.9-16.1] .70 Platelet count, x 109/L 182[101-264] 200[86-274] .77 New non-respiratory organ failure 25/51(49%) 16/51(31%) .11
Cardiovascular 12/18(67%) 7/16(44%) .30
Coagulation 10/50(20%) 10/50(20%) 1.00
Hepatic 3/47(6%) 5/47(11%) .71
Renal 7/46(15%) 6/41(15%) 1.00
Arrhythmia 24(47%) 16(30%) .11
Acquired RRT 2(4%) 5(9%) .43
Packed red blood cell 26(51%) 27(51%) 1.00
Use of anti-delirium drug 25(49%) 27(51%) 1.00
Haloperidol 6(12%) 8(15%) .78
Olanzapine 3(6%) 1(2%) .36
Quetiapine 19(37%) 22(42%) .69
Dexmedetomidine 9(18%) 7(13%) .59
Total amount of anti-delirium drug
Haloperidol, mg 0[0-35.5]a 0[0-28]a .62
Olanzapine, mg 0[0-390]a 0[0-15]a .29
Quetiapine, mg 0[0-2350]a 0[0-2325]a .78
Dexmedetomidine, µg/kg 0[0-132.3]a 0[0-172.4]a .61
Infection 28(55%) 31(58%) .71
Sputum 25(49%) 25(47%) 1.00
Urine 4(8%) 8(15%) .36
Blood 10(20%) 6(11%) .29
Incidence of severe hypoxemia 5(10%) 7(13%) .76
MV free days at 28 days 17.9[1.3-24.5] 17.5[10.5-23.6] .85 ICU free days at 28days 15.1[0-22.0] 13.1[3.4-21.3] .85
Hospital free days at 28days 0[0-15.6] 0[0-3.6] .08
28-day mortality 16(31%) 9(17%) .08
ALP = alkaline phosphatase, ALT = alanine aminotransfase, GGT = gamma-glutamyltransferase, CRP = C reactive protein, RRT = renal replacement therapy, MV = mechanical ventilation.
aValues are median [range].
Supplemental Table 4 Multivariable linear regression analyses with conservative oxygen therapy as the independent variable in the use of all blood gas results
Outcome Estimates Standard Error β p
P/F %∆worst in the first 10 daysa -2.11 4.97 -0.043 .67
P/F %∆24hb 16.51 14.84 0.12 .27
P/F %∆48hc 24.09 18.24 0.14 .19
Lac %∆worst in the first 10 daysa -54.28 37.85 -0.15 .16
Lac %∆24hb -16.41 12.57 -0.14 .20
Lac %∆48hc -30.08 16.94 -0.18 .079
Cr %∆worst in the first 10 daysa -7.23 17.97 -0.040 .69
Cr %∆24hb -1.82 4.79 -0.039 .71
Cr %∆48hc 3.49 8.54 0.041 .68
P/F = arterial partial pressure of oxygen/ fraction of inspired oxygen ratio, Lac = lactate, Cr = creatinine, β = standardized coefficients.
a%∆worst = (worst value - baseline) / baseline x 100.
b%∆24h = (time-weighted average of day1 - baseline) / baseline x 100.
c%∆48h = (time-weighted average of day2 - baseline) / baseline x 100.
The models for P/F-related variables were adjusted for APACHE III score, primary diagnosis and reason for mechanical ventilation; the models for Lac- and Cr-related variables were adjusted for APACHE III score, primary diagnosis, reason for mechanical ventilation and use of renal replacement therapy.
Supplemental Table 5 Adjusted odds ratio for key outcomes with conservative oxygen therapy
Outcome Number of events
(conventional : conservative)
Adjusted odds ratio (95% CI)a
p
Acquired RRT 2: 5 2.90(0.42-20.03) .28
Incidence of severe hypoxemia 5 : 7 1.78(0.46-6.84) .40
RRT = renal replacement therapy, CI = confidence interval.
aAdjusted for APACHE III score, primary diagnosis and reason for mechanical ventilation.
Only results from outcomes which occurred less than 25 times are reported here.
Supplemental Table 6 Secular trends in the study ICU for patient outcome and use of renal replacement therapy
Conventional Conservative p
Admissions 678 498
Patients 625 451
ICU mortality 61(10%) 38(8%) .52
RRT, episodes 26(4%) 31(6%) .07
RRT = renal replacement therapy.
Supplemental Figure 1
Frequency distribution of SpO2 in conservative therapy group after removal of the first dataset from each patient and datasets with FIO2 of 0.21. In a total of 920 data, 21% were observed at target SpO2
levels (90% to 92%).
Supplemental Figure 2
Changes in PaO2/FIO2 ratio (A), lactate (B), and creatinine (C) over time in the first 10 days in the use of all blood gas results of each patient during the whole mechanical ventilation period (N = 5735).
Similar trend was seen in all variables when compared with the main results. Error bars indicate the 95% confidence intervals. P value for comparison between groups with mixed linear model. B = baseline.