Hyperoxia and Hypertonic Saline in Septic Shock
NCT01722422
Funding: PHRC 2012; French Ministery of Health.
P. Asfar (Angers), F. Schortgen (Créteil), F. Meziani (Strasbourg), JF. Hamel (Angers), J.
Charpentier (Paris), JL. Diehl (Paris), B. Megarbane (Paris), JP. Bedos (Le Chesnay), F.
Grelon (Le Mans), C. Richard (Kremlin Bicêtre), S. Lasocki (Angers), J. Reignier (La Roche
Sur Yon), F. Legay (St Brieuc), Y. Cohen (Bobigny), M. Schenck (Strasbourg), D. Villers
(Nantes), D. Dreyfuss (Colombes), JM. Doise (Chalon Sur Saône), J. Devaquet (Suresnes),
D. Chatellier (Poitiers), T. Van Der Linden (Lomme), JP. Rigaud (Dieppe), J. Dellamonica
(Nice), F. Tamion (Rouen), D. Dreyfuss (Colombes), P. Radermacher (Ulm, Allemagne).
Hyperoxia :




Hemodynamic effects:
arterial vasoconsctriction
CO redistribution toward kidney and hepatosplanchnic beds.
Anti-bacterial effect
Anti-inflammatory effects
Short exposure  modest pulmonary toxicity during
sepsis
Hypertonic saline :
 Hemodynamic effects
Fast correction of hypovolemia for a small infused volume.
Positive inotropic effect
 Vasopressin vasoconstriction
 Anti-inflammatory and immuno-modulatory effects
↓ Cytokines
↓ Activation of PNN
↓ Lung histological injury
↓ Endothelial activation
 Oliveira et al. Clinical review: Hypertonic saline resuscitation in sepsis. Crit Care 2002.
 Oliveira et al. Acute haemodynamic effects of a hypertonic saline/dextran solution in stable patients
with severe sepsis. Intensive Care Med 2002.
 van Haren et al. Hypertonic fluid administration in patients with septic shock: a prospective
randomized controlled pilot study. Shock 2012
Methods: factorial design 2x2 without interaction
Main outcome: D28 mortality
Expected mortality 45 %
Decrease in mortality to 35 % (-22%)
with risk  = 0,05 and ß = 0,80 (bilateral test)
800 patients with stratification according to ARDS presence.
DSMB: interim analysis at 200, 400 and 600 recruited patients
Oxygen strategy (open 24h)
Fluid
strategy
(blind 72h)
Normoxia
3% Hypertonic saline
N=200
Hyperoxia (FiO2 = 1)
3% Hypertonic saline
N=200
Normoxia
Isotonic saline
N=200
Hyperoxia (FiO2 = 1)
Isotonic saline
N=200
Inclusion / exclusion criteria
• Inclusion:
– Septic shock (Bone’s criteria).
– Minimal dose of norepinephrine (NE) 0.1 µg/kg/min.
– Inclusion within the 6 first hours following NE start.
– Patient with invasive mechanical ventilation.
– Informed consent (relatives).
– Fluids ≥ 20ml/kg within the previous 24h.
• Exclusion:
–
–
–
–
Age < 18y.
Pregnancy.
Suspected or confirmed intracranial hypertension.
Limitation of care.
– Natremia < 130 mmol/L or > 145 mmol/L
– Patient with P/F ratio ≤ 100 with PEEP ≥ 5 cm H2O
– Patient admitted for cardiac arrest .
Enrollment
22 recruiting centres
Patient number
500
450
400
Actual inclusions
350
300
250
200
150
Expected inclusions
100
50
0
Nov 12
Nov 13
Jun 14
DSMB
• After enrolment of 441 patients, the trial
was prematurely stopped for excess
risk in both experimental (intervention)
groups.
Baseline characteristics : Oxygen strategy
NORMOXIA (n=217)
HYPEROXIA (n=217)
107 (49.3)
114 (52.5)
65%/35%
63.4% / 36.6%
66.3±14.6
67.8±12.7
73±16
72±17
Immunosuppression
172 (79%)
175 (81%)
Cancer/autoimmune disease
79 (38%)
76 (35%)
Heart failure
13 (6%)
11 (5%)
Kidney failure
23 (11%)
23 (11%)
Respiratory failure
14 (7%)
12 (6%)
Coronary disease
25 (12%)
26 (12%)
Cirrhosis
13 (6%)
8 (4%)
Lung
90 (42%)
101 (47 %)
Abdominal
55 (25%)
55 (25%)
Urinary
15 (7%)
19 (9%)
Skin and soft tissue
14 (6%)
9 (4%)
Neurological
3 (1%)
1 (0%)
Blood
2 (1%)
1 (0%)
Other or unknown
39 (18%)
31 (14%)
Community/nosocomial
133 (61%)
142 (65%)
PaO2/FiO2<200
Gender
Males/ females
Age
Weight
Comorbidities
Infection source
Infection origin
Baseline characteristics : Oxygen strategy
Fluid therapy before
inclusion (L)
NORMOXIA
HYPEROXIA
(n=217)
(n=217)
9% saline
2.9 ± 1.4
9% saline
2.8 ± 1.4
Colloids
0.22 ± 0.5
Colloids
0.26 ± 0.4
SAPS 2
56.2 ± 16.2
56.6 ± 15.3
SOFA score
10.3 ± 2.9
10.2 ± 2.7
PaO2/FiO2 ratio
228 ± 103
220 ± 103
0.40 (0.23-0.77)
0.40 (0.23-0.75)
Norepinephrine (µg/Kg/min)
Results
PaO2
NORMOXIA
HYPEROXIA
(n=217)
(n=217)
Inclusion
162±101
144±80
0.15
H12
103±40
272±129
0.000
H24
96±39
227±124
0.000
H72
88±24
95 ± 44
0.42
228 ± 103
220±103
0.42
H12
238±123
275±133
0.001
H24
245±120
260±170
0.95
H72
247±103
240±113
0,46
PaO2/FiO2 Inclusion
p value
Hyperoxia vs Normoxia
D28 mortality 77/217 (35.5%) versus 93/217 (42.9%) p=0.14
D90 mortality 90/217 (41.5%) versus 104/217 (47.9%) p = 0.21
Baseline characteristics : Fluid strategy
Isotonic saline (n=220)
Hypertonic saline (n=214)
114 (51.8)
107 (50.0)
62%
66%
66.7±13.7
67.4±13.7
73±18
72±15
Immunosuppression
45 (21%)
41 (19%)
Cancer/autoimmune disease
80 (37%)
75 (35%)
Heart failure
16 (7%)
8 (4%)
Kidney failure
23 (11%)
23 (11%)
Respiratory failure
14 (6%)
12 (6%)
Coronary disease
27 (12%)
24 (11%)
6 (3%)
15 (7%)
Lung
95 (43%)
96 (45%)
Abdominal
58 (27%)
52 (24%)
Urinary
19 (9%)
15 (7%)
Soft tissue and skin
8 (4%)
15 (7%)
Neurological
3 (1%)
1 (0%)
Blood
2 (1%)
1 (0%)
Other or unknown
35 (16%)
35 (16%)
Community
134 (61%)
142 (66%)
PaO2/FiO2<200
Gender
Males
Age
Weight
Comorbidities
Cirrhosis
Infection source
Infection origin
Baseline characteristics : Fluid strategy
Fluid therapy before
inclusion (L)
Isotonic saline
Hypertonic saline
(n=220)
(n=214)
9% saline
Colloids
2.9 ± 1.4
0.22 ± 0.5
9% saline
Colloids
2.8 ± 1.4
0.26 ± 0.5
SAPS 2
55.9 ± 15.2
57.2 ± 15.9
SOFA score
10.1 ± 2.8
10.4 ± 2.8
PaO2/FiO2 ratio
223 ± 106
225 ± 100
0.40 (0.23-0.73)
0.40 (0.22-0.83)
139 ± 4
139 ± 5
Norepinephrine (µg/Kg/min)
Plasma sodium (mmol/L)
Results
ISOTONIC
HYPERTONIC
(n = 220)
(n = 214)
2.5 ± 2.3
1.4 ± 1.0
0.000
9
84
0.000
Natremia at H72 (mmol/l)
140 ± 6
144 ± 6
0.000
Cumulative fluid intake from
inclusion to day 3 — liters
7.6±4.1
7.6±5.1
0.49
Fluid loading with experimental
treatment during first 72 hours
Study stop for hypernatremia
p value
Hypertonic vs Isotonic
D28 mortality 81/220 (36.8%) versus 89/214 (41.6%) p=0.33
D90 mortality 96/220 (43.6%) versus 98/214 (45.8%) p=0.5
Conclusions
• Compared to normoxia, hyperoxia may
be associated with a higher risk of
mortality at D28 in patients with septic
shock.
• Compared to isotonic saline, 3%
hypertonic saline did not reduce
mortality in patients with septic shock.