2727
2728
RESULTS
The main characteristics of the study
population are summarized in Table 1.
ARDS was diagnosed in 201 patients and
ALI in eight (11). At entry into the study,
survivors and nonsurvivors (at 28 days)
differed significantly in a number of vari-
ables (Table 1). These variables were introduced in a backward stepwise logistic
regression, and only three of them remained as independent risk factors of
death: the PaO2/FIO2 ratio as a marker of
the severity of oxygen exchange failure
(odds ratio [OR], 0.992; confidence interval [CI], 0.986 0.998), the VE/PaCO2 ratio, which is a rough surrogate for the
deadspace tidal volume ratio (VD/VT) (OR,
1.003; CI, 1.000 1.006), and the plasma
creatinine concentration (odds ratio,
1.385; CI, 1.116 1.720).
Time Course of the Pronation Response. Figure 1 summarizes for the entire group the time course of arterial oxygenation and PaCO2 response during the
10 days. The positive response to oxygenation was maintained over all 10 days,
although the trend was toward a slight
No.
Age, yrs
BMI, kgm2
SAPS II at enrollmenta
ALI/ARDSb
Days from intubation to first pronation
Cause of lung injury, %
Pneumonia
Aspiration
Other type of respiratory disease
Respiratory tract infection after surgery
Sepsis
Trauma
Other causes
Organ failure
Platelets, 109/L
Bilirubin, mol/L
Urea, mmol/L
Creatinine, mol/L
Ventilatory and gas exchange values
VT/kg ideal body weight, mL/kgc
Ve, L/min
PEEP, cm H2O
Mean Paw, cm H2O
PaO2/FIO2, mm Hg
PaCO2, mm Hg
pHa
Ve/PaCO2, mLmin1mm Hg1
VT, mL
Hemodynamics
Heart rate, beats/min
Mean arterial pressure, mm Hg
Systolic arterial pressure, mm Hg
Diastolic arterial pressure, mm Hg
Survivors
Nonsurvivors
116
56 17
24.8 3.9
39 13
5/111
3.8 6
93
59 18
24.6 16.1
42 12
3/90
4.5 5.6
.47
.25
.06
.73
.41
50.9
0.9
10.3
6.0
7.8
3.4
20.7
47.3
3.2
14.0
5.4
8.6
2.1
19.3
.71
.46
.55
.92
.97
.89
.95
205 122
27 50
27 24
123 106
167 140
60 120
35 28
177 150
.04
.01
.03
.002
10.4 2.7
10.0 2.4
9.9 2.7
16.9 4.0
135 44
45.2 11.3
7.39 0.09
237 90
667.8 174.8
10.4 2.7
11.3 3.4
9.9 2.9
17.7 4.8
115 47
45.3 12.6
7.38 0.09
269 110
639.8 148.2
.82
.001
.89
.18
.001
.97
.37
.02
.22
101 21
84 14
124.9 21.4
63.5 13.4
105 18
85 15
123 24.2
65.8 14
.29
.66
.56
.23
BMI, body mass index; SAPS, Simplified Acute Physiology Score; ALI, acute lung injury; ARDS,
acute respiratory distress syndrome; VT, tidal volume; Ve, total minute ventilation; PEEP, positive
end-expiratory pressure; Paw, airway pressure; pHa, arterial pH.
a
SAPS is used to assess the severity of illness and can range from 0 to 194, with higher scores
indicating a higher risk of death; bALI is characterized by a PaO2/FIO2 ratio of 300 mm Hg (39.9
kPa). ARDS is characterized by a PaO2/FIO2 ratio of 200 mm Hg (26.6 kPa); cthe predicted body
weight was calculated as 50 0.91 (height, 152.4 cm) for males and as 45.5 0.91 (height, 152.4 cm)
for females. Data are mean SD.
Figure 1. Mean values of PaO2/FIO2 ratio and PaCO2 immediately before prone positioning (open circles)
and at the end of the 6 hrs pronation (closed circles) during the 10-day study period. (Each calculation
includes only data for patients with all four measurements). The bars show the number of patients who
were in prone position each day for whom all four measurements were available.
Table 2. Ventilatory and gas exchanges changes after the first pronation
Survivors
Nonsurvivors
0.1 1.2
0.04 1.60
0.1 1.0
0.2 1.7
70. 72
0.9 7.9
1.2 0.8
4 67
4.1 5.8
0.1 1.6
0.35 1.78
0.0 0.7
0.3 1.8
71 73
2.1 8.4
1.0 0.8
20 70
6.2 9.8
.51
.20
.28
.71
.93
.008
.10
.01
.07
VT, tidal volume; Ve, total minute ventilation; PEEP, positive end-expiratory pressure; Paw, airway
pressure. Data are mean SD.
.0001), whereas PaCO2 remained constant or increased in 115 (PaCO2 nonresponders, mean PaCO2 increase 5.6 6.1
mm Hg [0.74 0.81 kPa]). The survival
rate at 28 days was significantly different
for PaCO2 responders and PaCO2 nonresponders (log rank, p .01, Fig. 3, lower
panel). Moreover, it appears that there is
a quantitative relationship between the
PaCO2 response and outcome: In fact,
considering the PaCO2 not as a dichotomous but as a continuous variable, its
relationship with outcome is shown in
DISCUSSION
Figure 2. Upper panel, PaO2/FIO2 responses at the first pronation (209 patients). The PaO2 responders
are patients whose PaO2/FIO2 ratio increased 20 mm Hg (2.66 kPa). Similar curves are obtained,
however, using other cutoff criteria (Table 3). Lower panel, Kaplan-Meier estimates of survival at 28
days in PaO2 responders and PaO2 nonresponders (p .65 by the log-rank test).
Table 3. PaO2 responders, classified according to the different cutoff of PaO2/FIO2 increase and mortality
rate
No. responders/nonresponders
Mortality rate, %
Log-rank
Chi-square
Relative risk of death
95% Confidence interval
Data are mean
2730
SD.
PaO2/FIO2
1 mm Hg
PaO2/FIO2
20 mm Hg
PaO2/FIO2 median
(58 mm Hg)
182/27
45/41
0.9486
0.67
0.90
0.561.46
150/59
44/46
0.6541
0.81
1.04
0.741.45
104/105
46/43
0.7906
0.63
0.93
0.691.26
Over the past two decades, 150 articles have discussed the prone position in
ALI/ARDS. The majority deal with acute
physiologic effects, and all focus on oxygenation. Only a few have reported PaCO2
changes, which were generally insignificant and considered of little or no importance (10, 12, 13). In this study, however,
we found a key role for changes in PaCO2
as an early prognostic index in the setting
of ALI/ARDS during prone positioning.
That increases in PaCO2 over time are
associated with a worse outcome in lasting ARDS has been known for many
years. In late ARDS, these increases reflect, more than a deterioration of oxygenation, major structural changes of the
lung, such as the development of pneumatoceles or pseudocysts (14). As expected, in this study we found a progressive increase of PaCO2 with time (Fig. 1).
The prognostic importance of CO2 exchange in early ARDS, as reflected by
increased pulmonary deadspace fraction,
was noted only recently (15). Our findings are consistent with that report. We
also found that the VE/PaCO2 ratio, which
is a crude surrogate of the deadspace to
tidal volume ratio, is an independent risk
factor of death in early ALI/ARDS.
However, the most important findings
were the differing prognostic values of
the PaCO2 and PaO2/FIO2 responses to the
first pronation. We found a strong association between the PaCO2 response and
outcome but no association with the
PaO2/FIO2 response to pronation whatever
criteria we used to define the PaO2/FIO2
responders.
The alveolar P CO 2 (P A CO 2 ) which
closely reflects PaCO2 if the shunt fraction
is not taken in account, is proportional to
the ratio of the rates of CO2 elimination
(VCO2) and alveolar ventilation (VA
VE[1 VD/VT]) according to the following equation:
PaCO2 (VCO2/VA)863
[1]
Figure 3. Upper panel, PaCO2 responses at the first pronation (209 patients). Lower panel, KaplanMeier estimates of survival at 28 days in PaCO2 responders and PaCO2 nonresponders (p .01 by the
log-rank test).
All patients
Responders
Nonresponders
Assisted ventilation
Responders
Nonresponders
Controlled ventilation
Responders
Nonresponders
Data are mean
No. of
Patients
No. of
Deaths
% of
Mortality
Relative
Risk
Confidence
Interval
94
115
33
60
35.1
52.2
1.48
1.072.05
.02
20
36
6
19
30.0
52.8
1.76
0.843.68
.10
74
79
27
41
36.5
51.9
1.42
0.952.05
.055
SD.
Group
1 PaCO2 responders
PaO2/FIO2 responders
2 PaCO2 responders
PaO2/FIO2 nonresponders
3 PaCO2 nonresponders
PaO2/FIO2 responders
4 PaCO2 nonresponders
PaO2/FIO2 nonresponders
Data are mean
28-Day
No. of No. of Mortality
Patients Deaths Rate, %
75
26
34.7
19
36.84
76
41
53.9
39
19
48.7
p
vs. 2 p .72
vs. 3 p .019
vs. 2 p .38
vs. 3 p .65
SD.
Table 6. Hemodynamic and metabolic variables in the PaCO2 responders and nonresponders at baseline, at 6 hrs of prone positioning, and at 24 hrs (in
supine)
Baseline
Patients
Systolic pressure, mm Hg
Diastolic pressure, mm Hg
Heart rate, beats/min
Minute ventilation, L/min
PaO2/FIO2, mm Hg
Creatinine, mg/100 mL
Platelets105, no./mm3
Bilirubin, mg/100 mL
SAPS
SOFAb,c
Ramsey scorec,d
6 Hrs Prone
24 Hrs Supine
Nonresponders
Responders
Nonresponders
Responders
Nonresponders
Responders
115
125 22
66 14
102 20
10.6 3.1
125.4 44.6
1.7 1.6
1.8 1.4
2.7 6.3
40.4 12.1
8.33 3.43
5.26 1.73
94
123 24
63 14
104 20
10.5 2.8
127.1 48.8
1.6 1.3
1.9 1.1
2.2 3.6
40.1 13.9
9.15 3.88
5.78 1.44
115
126 22
65 13
103 21
10.0 2.8a
183.2 80.2a
94
122 22
64 13
104 20
10.8 2.9
213.1 85.7
115
128 21
65 13
101 19
10.8 3.0
156.2 67.0
1.8 1.9
1.7 1.3
2.9 7.1
8.43 3.57
5.52 1.51
94
123 20
63 11
101 23
10.7 3.5
158.9 72.5
1.8 1.6
1.9 1.2
2.7 4.8
9.00 3.58
5.63 1.56
SAPS, Simplified Acute Physiology Score; SOFA, Sepsis-related Organ Failure Assessment. Data are mean SD.
p .05 vs. responders; bSOFA is used to describe organ dysfunction/failure and can range from 0 to 24, with higher scores indicating higher severity;
c
values reported refer to randomized trial patients only; dthe Ramsey scale is used to describe the sedation level; it can range from 1 to 6, where 1 indicates
anxious and agitated and 6 indicates nonresponsive.
a
2732
ndependently of the
ventilator
setting,
CONCLUSIONS
This study has several limitations. It is
retrospective, a number of physiologic
variables were not collected (because to
ensure that a multiple-center trial is feasible we have to keep variables to a minimum), and a control group at 6 hrs is
not available. However, a single fact remains true: Independently of the ventilator setting, which was maintained unmodified, the patients who reacted to
prone positioning with a decrease in
PaCO2 had a better outcome than the patients who did not. The PaCO2 change per
se does not seem to influence the outcome. However, the change during prone
positioning probably indicates some difference in the underlying pathology: a
lower potential for recruitment in PaCO2
nonresponders and a higher potential in
responders.
APPENDIX
Steering Committee: L. Gattinoni, G.
Tognoni. Scientific and Organizing Secretariat: L. Brazzi, R. Fumagalli, R.
Latini, R. Malacrida, D. Mascheroni, P.
Pelosi, A. Pesenti, G. Ronzoni. Nursing
Coordination: I. Adamini, D. Brambilla,
P. Di Giulio. Data Safety Monitoring
Board: B. Andreoni, P. Suter, M. G.
Valsecchi. Data Management and Analysis: L. Donati, V. Torri, V. Labarta. Participating Centers: Antella, S. M. Annunziata: U. Boncristiano, L. Manenti, A.
Orvieto; Arezzo, S. Donato: C. Boncompaghi, V. Capria, F. Magnanensi, C.
Recine; Asti: S. Cardellino, E. Costanzo,
M. Gavioso, A. Scotti; Como, SantAnna:
M. F. Magatti, P. Rossitto, A. Villa; Conegliano: U. Corbanese, M. De Zotti; Cuneo:
Crit Care Med 2003 Vol. 31, No. 12
7.
8.
9.
10.
11.
12.
13.
14.
15.
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