Background
Methods
Randomisation/group assignment
-
Group helium: 8-min cardiac arrest, treatment 24 h with a mixture of 50 % helium in oxygen.
-
Group argon: 8-min cardiac arrest, treatment 24 h with a mixture of 50 % argon in oxygen.
-
Group air: 8-min cardiac arrest, standard treatment 24 h with oxygen titrated to reach a 50 % oxygen in nitrogen gas mix.
Cardiac arrest and resuscitation protocol
Assessments
Statistics
Results
Helium/oxygen | Argon/oxygen | Air/oxygen |
Kruskall - Wallis
|
Non-ischemic sham
| ||
---|---|---|---|---|---|---|
Mean Arterial Pressure (MAP)a [mmHg] | Baseline (Before) | 100 [86–114] | 99 [90–108] | 100 [82–118] |
p = 1.00 |
90 [79–92]
|
5 min | 125 [115–137] | 121 [109–138] | 123 [109–129] |
88 [78–102]
| ||
15 min | 76 [62–94] | 79 [77–92] | 85 [69–100] |
98 [87–105]
| ||
30 min | 85 [65–98] | 73 [68–86] | 85 [66–93] |
NA
| ||
60 min | 95 [82–97] | 85 [67–101] | 99 [83–111] |
NA
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
0.004
a
|
0.964
| ||
Linear regression with clustered robust SE p = 0.621 | ||||||
(Coef. helium: −1.93 CI −11.49 to 7.63; Coef. argon: −4.71 CI −14.70 to 5.28) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Heart ratea [1 min−1] | Baseline (Before) | 300 [268–345] | 340 [298–383] | 360 [325–395] |
p = 0.10 |
300 [285–380]
|
5 min | 300 [288–325] | 290 [270–330] | 320 [265–355] |
320 [320–380]
| ||
15 min | 300 [285–325] | 310 [290–340] | 290 [280–340] |
360 [340–380]
| ||
30 min | 360 [320–400] | 320 [308–410] | 395 [345–420] |
NA
| ||
60 min | 340 [300–400] | 340 [323–435] | 420 [375–450] |
NA
| ||
Friedman-Test p
|
0.058
|
0.005
a
|
<0.001
a
|
0.369
| ||
Linear regression with clustered robust SE p = 0.056 | ||||||
(Coef. helium: −30.3 CI −56.0 to −4.7; Coef. argon: −17.3 CI −50.1 to 15.5) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Glucosea [mmol/l] | Baseline (Before) | 10.5 [8.9–11.6] | 9.9 [8.8–10.9] | 10.4 [8.4–11.1] |
p = 0.87 |
9.8 [8.7–11.2]
|
5 min | 13.7 [13.4–14.5] | 13.3 [11.1–16.0] | 13.5 [13.1–15.6] |
8.2 [7.5–10.2]
| ||
15 min | 12.5 [11.5–13.5] | 13.5 [11.2–14.3] | 13.7 [10.6–14.8] |
9.0 [7.0–10.6]
| ||
60 min | 5.7 [4.3–6.6] | 5.8 [5.1–6.4] | 5.7 [5.3–6.1] |
NA
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
<0.001
a
|
0.12
| ||
Linear regression with clustered robust SE p = 1.000 | ||||||
(Coef. helium: 0.06 CI −1.55 to 1.67; Coef. argon: 0.04 CI −1.63 to 1.70) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Lactatea [mmol/l] | Baseline (Before) | 1.2 [0.9–1.3] | 1.2 [1.0–1.7] | 1.1 [1.0–1.5] |
p = 0.72 |
1.0 [0.9–1.4]
|
5 min | 7.0 [6.4–7.5] | 7.2 [6.1–8.2] | 6.8 [6.3–8.0] |
1.0 [0.6–1.2]
| ||
15 min | 3.5 [3.2–3.8] | 3.2 [3.0–3.9] | 3.6 [3.0–4.4] |
0.9 [0.6–1.8]
| ||
60 min | 0.8 [0.6–1.2] | 0.7 [0.6–0.8] | 0.7 [0.6–0.8] |
NA
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
<0.001
a
|
0.531
| ||
Linear regression with clustered robust SE p = 0.771 | ||||||
(Coef. helium: 0.38 CI −0.81 to 1.57; Coef. argon: −0.04 CI −0.56 to 0.48) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
pHa
| Baseline (Before) | 7.50 [7.45–7.53] | 7.50 [7.45–7.54] | 7.42 [7.40–7.49] |
p = 0.17 |
7.41 [7.37–7.51]
|
5 min | 7.09 [7.01–7.15] | 7.02 [6.96–7.10] | 7.09 [6.98–7.16] |
7.44 [7.36–7.47]
| ||
15 min | 7.24 [7.16–7.28] | 7.16 [7.08–7.26] | 7.30 [7.10–7.31] |
7.45 [7.347–7.49]
| ||
60 min | 7.38 [7.32–7.44] | 7.35 [7.30–7.39] | 7.39 [7.33–7.41] |
NA
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
<0.001
a
|
0.967
| ||
Linear regression with clustered robust SE p = 0.631 | ||||||
(Coef. helium: 0.11 CI −0.37 to 0.15; Coef. argon: −0.02 CI −0.08 to 0.05) | ||||||
Time effect: fractional polynomial regression p = 0.037 | ||||||
pO2 [mmHg] | Baseline (Before) | 114 [106–124] | 114 [101–132] | 106 [83–139] |
p = 0.83 |
83 [74–97]
|
5 min | 203 [146–246] | 155 [127–250] | 195 [265–355] |
332 [270–342]
| ||
15 min | 125 [101–159] | 109 [105–143] | 129 [118–165] |
240 [90–324]
| ||
60 min | 159 [136–185] | 140 [128–181] | 195 [182–212] |
NA
| ||
Friedman-Test p
|
0.007
a
|
<0.001
a
|
<0.001
a
|
0.236
| ||
Linear regression with clustered robust SE p = 0.373 | ||||||
(Coef. helium: −45.5 CI −114.2 to 23.2; Coef. argon: −48.8 CI −118.9 to 21.3) | ||||||
Time effect: fractional polynomial regression p = 0.670 | ||||||
pCO2
a [mmHg] | Baseline (Before) | 32 [29–37] | 31 [27–35] | 37 [27–39] |
p = 0.69 |
34 [32–42]
|
5 min | 46 [38–66] | 53 [40–66] | 46 [37–52] |
35 [32–43]
| ||
15 min | 39 [36–53] | 44 [35–62] | 36 [32–46] |
36 [30–43]
| ||
60 min | 39 [34–47] | 41 [35–49] | 35 [31–39] |
NA
| ||
Friedman-Test p
|
0.002
a
|
0.003
a
|
0.013
a
|
0.335
| ||
Linear regression with clustered robust SE p = 0.741 | ||||||
(Coef. helium: 2.07 CI −6.03 to 10.17; Coef. argon: 3.40 CI −5.80 to 12.59) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Temp. [°C] | Baseline (Before) | 36.0 [35.7–36.2] | 36.4 [36.1–36.5] | 36.0 [35.8–36.2] |
p = 0.07 |
36.0 [35.8–37.1]
|
5 min | 35.3 [35.0–35.4] | 35.0 [34.8–35.6] | 35.3 [34.7–35.6] |
36.5 [36.0–36.9]
| ||
15 min | 36.2 [36.0–36.3] | 36.2 [35.8–36.2] | 36.2 [36.0–36.6] |
36.4 [36.1–36.6]
| ||
60 min | 36.8 [36.3–37.4] | 36.6 [36.4–37.2] | 37.0 [36.7–37.3] |
NA
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
0.002
a
|
0.967
| ||
Linear regression with clustered robust SE p = 0.378 | ||||||
(Coef. helium: 0.42 CI −0.54 to 1.37; Coef. argon: −0.84 CI −2.46 to 0.77) | ||||||
Time effect: fractional polynomial regression p = 0.487 |
Helium/oxygen | Argon/oxygen | Air/oxygen |
Kruskall - Wallis
|
Non-ischemic sham
| ||
---|---|---|---|---|---|---|
Weighta [g] | Baseline (Before) | 358 [343–383] | 343 [334–367] | 345 [326–372] |
p = 0.375
|
400 [375–413]
|
Day 1 | 342 [328–367] | 335 [314–361] | 339 [322–360] |
384 [360–409]
| ||
Wilcoxon Test p
|
0.01
|
<0.01
|
0.02
|
0.04
| ||
Day 2 | 338 [322–354] | 323 [306–351] | 323 [304–345] |
389 [365–404]
| ||
Day 3 | 342 [327–362] | 327 [306–355] | 330 [308–343] |
391 [361–408]
| ||
Day 4 | 339 [327–372] | 329 [309–365] | 328 [313–345] |
400 [369–410]
| ||
Day 5 | 348 [324–380] | 341 [319–370] | 332 [318–355] |
401 [374–415]
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
<0.001
a
|
<0.001
a
| ||
Linear regression with clustered robust SE p = 0.302 | ||||||
(Coef. helium: −11.9 CI −33.0 to 9.2; Coef. argon: −15.2 CI −36.1 to 5.6) | ||||||
Time effect: fractional polynomial regression p = 0.001 | ||||||
Tape Removal Testa [seconds] | Baseline (Before) | 18 [11–29] | 9 [5–12] | 13 [8–23] |
p = 0.06
|
17 [14–39]
|
Day 1 | 74 [21–120] | 120 [35–120] | 85 [23–120] |
10 [8–21]
| ||
Wilcoxon Test p
| 0.01 | <0.01 | <0.01 |
0.38
| ||
Day 2 | 21 [12–76] | 18 [11–111] | 17 [9–120] |
14 [7–18]
| ||
Day 3 | 20 [8–113] | 16 [11–120] | 31 [9–88] |
18 [15–95]
| ||
Day 4 | 14 [10–113] | 11 [7–59] | 17 [9–120] |
19 [7–96]
| ||
Day 5 | 12 [7–45] | 9 [5–44] | 11 [7–93] |
12 [7–17]
| ||
Friedman-Test p
|
0.018
a
|
0.002
a
|
0.023
a
|
0.086
| ||
Linear regression with clustered robust SE p = 0.980 | ||||||
(Coef. helium: −2.01 CI −35.88 to 31.86; Coef. argon: −3.24 CI −36.49 to 30.01) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Neuro Deficit Scorea [range: 0–100] | Baseline (Before) | 0 [0–0] | 0 [0–0] | 0 [0–0] |
p = 0.37 | 0 [0–0] |
Day 1 | 2.5 [0–3.0] | 3.0 [0.5–3.0] | 2.5 [0.5–3.0] | 0 [0–0] | ||
Wilcoxon Test p
| 0.02 | 0.02 | 0.03 | 1.0 | ||
Day 2 | 0 [0–2.3] | 0 [0–2.0] | 0 [0–1.5] | 0 [0–0] | ||
Day 3 | 0 [0–0.3] | 0 [0–1.3] | 0 [0–0.5] | 0 [0–0] | ||
Day 4 | 0 [0–0.3] | 0 [0–0.5] | 0 [0–0] | 0 [0–0] | ||
Day 5 | 0 [0–0.3] | 0 [0–0.3] | 0 [0–0] | 0 [0–0] | ||
Friedman-Test p | <0.001a
| <0.001a
| <0.001a
| 1.0 | ||
Linear regression with clustered robust SE p = 0.612 | ||||||
(Coef. helium: 0.50 CI −0.68 to 1.69; Coef. argon: 0.35 CI −0.63 to 1.32) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Vertical Pole Testa [range: 0–3] | Baseline (Before) | 0 [0–0] | 0 [0–0] | 0 [0–0] |
p = 0.60 | 0 [0–0] |
Day 1 | 2.5 [0.25–3.0] | 3.0 [1.0–3.0] | 2.5 [1.5–3.0] | 0 [0–0] | ||
Wilcoxon Test p
| 0.03 | 0.02 | 0.03 | 1.0 | ||
Day 2 | 0 [0–2.0] | 0 [0–1.5] | 0 [0–1.0] | 0 [0–0] | ||
Day 3 | 0 [0–0] | 0 [0–1.0] | 0 [0–0] | 0 [0–0] | ||
Day 4 | 0 [0–0] | 0 [0–0] | 0 [0–0] | 0 [0–0] | ||
Day 5 | 0 [0–0] | 0 [0–0] | 0 [0–0] | 0 [0–0] | ||
Friedman-Test p | <0.001a
| <0.001a
| <0.001a
| 1.0 | ||
Linear regression with clustered robust SE p = 0.663 | ||||||
(Coef. helium: 0.15 CI −0.34 to 0.64; Coef. argon: 0.21 CI −0.32 to 0.75) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Open Field Test: distancea [cm] | Baseline (Before) | 1691 [1327–1900] | 1769 [1620–2101] | 1580 [1520–1951] |
p = 0.23 | 1693 [1378–1938] |
Day 4 | 1673 [1161–1919] | 1320 [1144–1712] | 2058 [1698–2403] | 1034 [799–1698] | ||
Day 5 | 851 [758–1343] | 1240 [658–1606] | 962 [711–1629] | 774 [698–1196] | ||
Friedman-Test p | 0.06 | 0.07 | 0.24 | 0.02a
| ||
Linear regression with clustered robust SE p = 0.156 | ||||||
(Coef. helium: −244 CI −528 to 39; Coef. argon: −5 CI −465 to 455) | ||||||
Time effect: fractional polynomial regression p = 0.002 | ||||||
Open Field Test: mobility/immobility ratioa [%] | Baseline (Before) | 82 [77–88] | 88 [81–92] | 84 [82–87] |
p = 0.24
|
83 [80–85]
|
Day 4 | 81 [71–84] | 81 [75–88] | 85 [82–87] |
65 [54–84]
| ||
Day 5 | 59 [51–72] | 77 [50–86] | 67 [46–82] |
56 [41–65]
| ||
Friedman-Test p
|
0.15
|
0.20
|
0.06
|
<0.01
a
| ||
Linear regression with clustered robust SE p = 0.112 | ||||||
(Coef. helium: −4.63 CI −11.87 to 2.62; Coef. argon: 2.51 CI −6.22 to 11.24) | ||||||
Time effect: fractional polynomial regression p < 0.001 | ||||||
Open Field Test: extern/intern ratioa [%] | Baseline (Before) | 94 [93–96] | 94 [93–96] | 96 [94–97] |
p = 0.84
|
96 [93–98]
|
Day 4 | 99 [97–100] | 98 [96–99] | 95 [95–97] |
100 [97–100]
| ||
Day 5 | 100 [99–100] | 99 [99–100] | 99 [95–100] |
100 [98–100]
| ||
Friedman-Test p
|
0.02
a
|
0.03
a
|
0.03
a
|
0.03
a
| ||
Linear regression with clustered robust SE p = 0.501 | ||||||
(Coef. helium: 0.68 CI −1074 to 2.10; Coef. argon: 0.33 CI −1.55 to 2.22) | ||||||
Time effect: fractional polynomial regression p = 0.003 | ||||||
Open Field Test: rears/verticala [count] | Baseline (Before) | 15 [12–23] | 20 [19–23] | 19 [16–22] |
p = 0.21
|
17 [14–22]
|
Day 4 | 6 [5–8] | 5 [3–10] | 8 [5–9] |
9 [7–13]
| ||
Day 5 | 3 [1–4] | 6 [2–9] | 4 [2–7] |
7 [4–9]
| ||
Friedman-Test p
|
<0.001
a
|
<0.001
a
|
<0.001
a
|
<0.001
a
| ||
Linear regression with clustered robust SE p = 0.107 | ||||||
(Coef. helium: −2.73 CI −5.58 to 0.11; Coef. argon: −0.40 CI −4.13 to 3.33) | ||||||
Time effect: fractional polynomial regression p < 0.001 |
Helium/oxygen | Argon/oxygen | Air/oxygen | Kruskall - Wallis |
Non-ischemic sham
| |
---|---|---|---|---|---|
Fluoro-Jade [numbers of stained cells per mm] | 148 [140–166] | 154 [124–199] | 145 [138–182] |
p = 0.83 |
0 [0–0]
|
pyknotic cells in CA1 [%] | 53 [24–76] | 59 [44–86] | 80 [61–93] |
p = 0.09 |
0 [0–1]
|
CA1 cell layer atrophy (normalized: surface/length) [mm2/mm] | 0.065 [0.058–0.083] | 0.074 [0.061–0.080] | 0.061 [0.043–0.069] |
p = 0.11 |
0.082 [0.077–0.088]
|