Figure S1 Box and whisker plots of bedside observations by fluid arm
Impaired perfusion at clinical review times over clinical review times
100
Bolus
Conscious level over clinical review times
No Bolus
95
100
% with any signs of impaired perfusion
90
Bolus
No Bolus
95
85
90
80
85
% Prostrate or in a Coma
75
70
65
60
55
50
45
40
35
30
25
80
75
70
65
60
55
50
45
40
35
30
25
20
20
15
15
10
10
5
5
0
0
0
No. at risk.
No. of
measurements
1
Bolus
2097
No
Bolus
1044
2097
1044
4
Bolus
2070
No
Bolus
1030
2041
1017
8
Bolus
2011
No
Bolus
1011
1987
997
24
Bolus
1972
No
Bolus
996
1946
984
0
48
Bolus
1899
No
Bolus
975
Bolus
1876
No
Bolus
968
1877
958
1823
945
No. at risk.
No. of
measurements
1
4
8
24
48
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
2097
1044
2070
1030
2011
1011
1972
996
1899
975
1876
968
2094
1044
2035
1014
1983
995
1942
981
1872
956
1814
943
Systolic Blood Pressure over clinical review times
Auxiliary Temperature over clinical review times
Bolus
42
No bolus
Bolus
No bolus
120
110
40
Temperature (°Celsius)
Systolic blood pressure (mmHg)
41
100
90
80
70
38
37
36
35
60
34
50
0
No. at risk.
No. of
measurements
39
1
4
8
24
0
48
Bolus
2097
No
Bolus
1044
Bolus
2070
No
Bolus
1030
Bolus
2011
No
Bolus
1011
Bolus
1972
No
Bolus
996
Bolus
1899
No
Bolus
975
Bolus
1876
No
Bolus
968
2066
1034
2010
1007
1966
989
1925
978
1857
954
1810
943
No. at risk.
No. of
measurements
1
Bolus
2097
No
Bolus
1044
2094
1041
4
Bolus
2070
No
Bolus
1030
2039
1015
8
Bolus
2011
No
Bolus
1011
1986
994
24
Bolus
1972
No
Bolus
996
1943
982
48
Bolus
1899
No
Bolus
975
Bolus
1876
No
Bolus
968
1874
958
1821
942
Respiratory rate over clinical review times
Bolus
Oxygen Saturation over clinical review times
No bolus
100
90
80
Oxygen saturation (%)
Respiratory rate (breaths per minute)
100
70
60
50
40
95
90
85
30
20
0
No. at risk.
No. of
measurements
1
Bolus
No
Bolus
2097
1044
2083
1041
4
Bolus
No
Bolus
2070
1030
2028
1008
8
Bolus
No
Bolus
2011
1011
1983
994
24
Bolus
No
Bolus
1972
996
1943
982
48
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
1899
975
1876
968
1871
955
1817
942
0
No. at risk.
No. of
measurements
1
4
8
No bolus
24
48
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
Bolus
No
Bolus
2097
1044
2070
1030
2011
1011
1972
996
1899
975
1876
968
2023
1015
2009
1003
1972
988
1934
977
1864
951
1814
940
Hypoglycaemia over clinical review times
Heart rate over clinical review times
230
Bolus
50
No bolus
Bolus
No Bolus
220
45
40
200
% with hypoglycaemia
Heart rate (beats per minute)
210
190
180
170
160
150
140
130
35
30
25
20
15
120
110
10
100
5
90
80
0
0
No. at risk.
No. of
measurements
1
Bolus
2097
No
Bolus
1044
2097
1044
4
Bolus
2070
No
Bolus
1030
2040
1017
8
Bolus
2011
No
Bolus
1011
1986
996
24
Bolus
1972
No
Bolus
996
1946
984
0
48
Bolus
1899
No
Bolus
975
Bolus
1876
No
Bolus
968
1876
958
1822
945
No. at risk.
No. of
measurements
1
4
8
24
48
Bolus
2097
No
Bolus
1044
Bolus
2070
No
Bolus
1030
Bolus
2011
No
Bolus
1011
Bolus
1972
No
Bolus
996
Bolus
1899
No
Bolus
975
Bolus
1876
No
Bolus
968
1981
989
1948
968
1885
942
1818
923
1778
903
1686
876
1
Table S1: Admission Presentation Syndromes by randomization arm.
Presentation Syndrome at
baseline
Fluid Arm
Combined
Albumin
Saline
bolus
No bolus
Total
N=1050
N=1047
N=2097
N=1044
N=3141
785 (75%)
804 (77%)
1589 (76%)
807 (77%)
2396 (76%)
34 (3%)
31 (3%)
69 (3%)
44 (4%)
109 (3%)
218 (21%)
245 (23%)
446 (21%)
230 (22%)
693 (22%)
Neurological only
71 (7%)
66 (6%)
146 (7%)
84 (8%)
221 (7%)
Respiratory and severe shock
86 (8%)
85 (8%)
166 (8%)
84 (8%)
255 (8%)
Respiratory and neurological
16 (2%)
23 (2%)
41 (2%)
17 (2%)
56 (2%)
171 (16%)
164 (16%)
321 (15%)
159 (15%)
494 (16%)
69 (7%)
70 (7%)
134 (6%)
66 (6%)
205 (7%)
120 (11%)
120 (11%)
257 (12%)
123 (12%)
363 (12%)
227 (22%)
202 (19%)
429 (20%)
204 (20%)
633 (20%)
- with respiratory
27 (3%)
24 (2%)
51 (2%)
30 (3%)
81 (3%)
- with neurological
75 (7%)
61 (6%)
136 (6%)
46 (4%)
182 (6%)
16 (2%)
10 (1%)
26 (1%)
19 (2%)
45 (1%)
109 (11%)
107 (10%)
216 (10%)
109 (11%)
325 (10%)
38 (4%)
41 (4%)
79 (4%)
33 (3%)
112 (4%)
Acid-base or Lactate
measurements available
(Classifiable severe shock)
Respiratory only
Severe shock/acidosis only
Severe shock and
neurological
All three presentations
None of the presentations
Non-ascertainable severe
shock/acidosis status*
- with respiratory and
neurological
- with neither respiratory
nor neurological
Missing information on two or
more presentations
NB Percentages are out of all those enrolled into that randomization arm
*see definition of severe shock; children with lactic acid or base deficit or systolic blood pressure
values missing were categorized as having ‘non-ascertainable severe shock status’.
2
Figure S2 : 48-hour mortality by baseline oxygen saturation level; hazard ratio for bolus
versus no bolus.
3
2.8
2.6
2.4
2.2
2
1.8
1.6
1.4
1.2
1
.8
.6
.4
Test for trend: p=0.02
.2
65
70
75
80
85
90
Oxygen saturation at baseline (%)
95% Confidence interval
95
100
Hazard Ratio
3
Figure S3: 48-hour mortality by baseline haemoglobin level; hazard ratio for bolus versus no
bolus.
3
2.8
2.6
2.4
2.2
2
1.8
1.6
1.4
1.2
1
.8
.6
.4
Test for trend: p=0.63
.2
1
2
3
4
5
6
7
8
9
Haemoglobin (g/mL)
95% Confidence interval
10
11
12
13
14
Hazard Ratio
4
Table S2: Terminal Clinical Events in children that died within 48 hours by baseline presentation.
Presentation at baseline
Terminal Clinical Event *
Respiratory
Respiratory
Cardiogenic
Respiratory
Cardiogenic
Neurological
+
+
+
only
only
only
Cardiogenic
Neurological
Neurological
Unknown
Total
Respiratory only
3 (100%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
3 (100%)
Severe shock/acidosis only
11 (20%)
34 (61%)
5 (2%)
0 (0%)
1 (2%)
1 (2%)
4 (7%)
56 (100%)
Neurological only
1 (20%)
0 (0%)
3 (60%)
0 (0%)
0 (0%)
1 (20%)
0 (0%)
5 (100%)
Respiratory + severe shock
21 (45%)
22 (47%)
1 (2%)
0 (0%)
1 (2%)
0 (0%)
2 (4%)
47 (100%)
Respiratory + neurological
1 (50%)
0 (0%)
0 (0%)
0 (0%)
1 (50%)
0 (0%)
0 (0%)
2 (100%)
Severe shock +neurological
5 (7%)
21 (29%)
33 (45%)
0 (0%)
7 (9%)
4 (5%)
4 (5%)
74 (100%)
All three presentations
7 (13%)
19 (36%)
15 (28%)
0 (0%)
7 (14%)
3 (6%)
2 (4%)
53 (100%)
None of the presentations
0 (0%)
2 (67%)
1 (33%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
3 (100%)
Unascertainable shock/acidosis
status with either respiratory or
neurological presentations
- respiratory only
8 (38%)
3 (14%)
2 (10%)
0 (0%)
2 (10%)
1 (5%)
5 (24%)
21 (100%)
3 (60%)
1 (20%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
1 (20%)
5 (100%)
- neurological only
1 (14%)
1 (14%)
2 (29%)
0 (0%)
0 (0%)
0 (0%)
3 (43%)
7 (100%)
- respiratory + neurological
1 (33%)
0 (0%)
0 (0%)
0 (0%)
1 (33%)
0 (0%)
1 (33%)
3 (100%)
3 (50%)
1 (17%)
0 (0%)
0 (0%)
1 (17%)
1 (17%)
0 (0%)
6 (100%)
more presentations
4 (12%)
22 (67%)
3 (9%)
0 (0%)
2 (6%)
1 (3%)
1 (3%)
33 (100%)
Total
61 (21%)
123 (41%)
63 (21%)
0 (0%)
21 (7%)
11 (4%)
18 (6%)
297 (100%)
- neither respiratory nor
neurological
Missing information on two or
* percentages are for each row and indicate how many of the deaths in each baseline presentation group go on to die of each terminal clinical event.
5
Figure S4a: Cumulative incidence of cardiogenic only, neurological only or respiratory only
TCE
6.5
6
Cardiogenic (Bolus)
Neurological (Bolus)
Respiratory (Bolus)
Cardiogenic (No Bolus)
Neurological (No Bolus)
Respiratory (No Bolus)
5.5
5
4.5
4
3.5
3
2.5
2
1.5
1
0
4
8
First hour
A
12
16
Second hour
S
N
A
S
20
24
28
Hours until death
Third hour
N
A
S
Fourth
N
A
S
32
36
A
S
44
Ninth to
twenty-fourth
Fifth to eighth
N
40
N
48
Twenty-fourth
to forty-eighth
A
S
N
A
S
N
992
980
996
954
945
975
38
34
20
16
13
9
At risk
Total
died
1050 1047 1044 1037 1033 1030 1024 1018 1021 1016 1010 1015 1010 1001 1011
%
1.2% 1.1% 1.3% 1.3% 1.5% 0.9% 0.8% 0.7% 0.6% 0.6% 0.9% 0.4% 1.7% 2.0% 1.4% 3.8% 3.5% 2.0% 1.7% 1.4% 0.9%
13
12
14
13
15
9
8
7
6
6
9
4
17
20
14
Figure S4b: Cumulative incidence for combined causes: respiratory and neurological,
cardiogenic and neurological, and unknown/other TCE
6.5
6
Unknown (Bolus)
Cardiogenic and Neurological (Bolus)
Respiratory and Neurological(Bolus)
Unknown (No Bolus)
Cardiogenic and Neurological (No Bolus)
Respiratory and Neurological (No Bolus)
5.5
5
4.5
4
3.5
3
2.5
2
1.5
1
.5
0
0
4
First hour
A
S
8
12
16
Second hour
N
A
S
N
20
24
28
Hours until death
Third hour
A
S
Fourth
N
A
S
32
36
Fifth to eighth
N
A
S
N
40
44
Ninth to
twenty-fourth
48
Twenty-fourth
to forty-eighth
A
S
N
A
S
N
992
980
996
954
945
975
38
34
20
16
13
9
At risk
Total
died
1050 1047 1044 1037 1033 1030 1024 1018 1021 1016 1010 1015 1010 1001 1011
%
1.2% 1.1% 1.3% 1.3% 1.5% 0.9% 0.8% 0.7% 0.6% 0.6% 0.9% 0.4% 1.7% 2.0% 1.4% 3.8% 3.5% 2.0% 1.7% 1.4% 0.9%
13
12
14
13
15
9
8
7
6
6
9
4
17
20
14
6
Table S3a: TCE by 48 hours by randomisation arm before or after the protocol amendment.
Before/after protocol amendment and randomisation arm (n=3141)
Terminal Clinical Event
Before amendment
Combined
Total enrolled
bolus
No bolus
Total
1691
844
2535
Cardiogenic (ongoing signs of
shock) only
After amendment
Subhazard
Combined
Subhazard
ratio
bolus
No Bolus
Total
406
200
606
1.59
73 (4.3%)
23 (2.7%)
96 (3.8%)
(1.00-2.55)
2.88
23 (5.7%)
4 (2%)
27 (4.5%)
1.10
Neurological only
33 (1.9%)
15 (1.8%)
48 (1.9%)
(0.60-2.02)
37 (2.2%)
11 (1.3%)
48 (1.9%)
(0.86-3.31)
(0.99-8.37)
1.36
11 (2.7%)
4 (2%)
15 (2.5%)
1.69
Respiratory only
ratio
(0.43-4.28)
1.66
10 (2.5%)
3 (1.5%)
13 (2.1%)
(0.46-6.03)
1.48
Cardiogenic and Neurological
7 (0.4%)
0 (0%)
7 (0.3%)
NA
3 (0.7%)
1 (0.5%)
4 (0.7%)
(0.15-14.3)
0 (0%)
2 (1%)
2 (0.3%)
NA
2 (0.5%)
0 (0.0%)
2 (0.3%)
NA
0.69
Respiratory and Neurological
11 (0.7%)
8 (0.9%)
19 (0.7%)
(0.28-1.70)
1.10
Unknown/Other
11 (0.7%)
5 (0.6%)
16 (0.6%)
(0.38-3.16)
NB: Percentages are out of all those enrolled in that arm either before or after the protocol amendment (totals are at the top of each column).
7
Table S3b: Terminal Clinical Event by 48 hours by randomisation arm by malaria status.
Malaria status and randomisation arm (n=3123*)
Terminal Clinical Event
Malaria
Non-malaria
Combined
Total enrolled
bolus
No bolus
Total
1202
591
1793
Cardiogenic (ongoing signs
of shock) only
Subhazard
Combined
Subhazard
ratio
bolus
No Bolus
Total
884
446
1330
ratio
2.06
58 (4.8%)
14 (2.4%)
72 (4.0%)
(1.15-3.70)
1.48
35 (3.9%)
12 (2.7%)
47 (3.5%)
(0.77-2.85)
1.31
Neurological only
24 (2.0%)
9 (1.5%)
33 (1.8%)
(0.61-2.83)
1.12
20 (2.3%)
9 (2.0%)
29 (2.2%)
(0.51-2.46)
1.28
Respiratory only
13 (1.1%)
5 (0.8%)
18 (1.0%)
(0.46-3.59)
1.94
34 (3.8%)
9 (2.0%)
43 (3.2%)
(0.93-4.02)
2.52
Cardiogenic and Neurological
5 (0.4%)
0 (0.0%)
5 (0.3%)
NA
5 (0.6%)
1 (0.2%)
6 (0.5%)
(0.29-21.67)
0.49
Respiratory and Neurological
6 (0.5%)
6 (1.0%)
12 (0.7%)
(0.16-1.52)
0.63
5 (0.6%)
4 (0.9%)
9 (0.7%)
(0.17-2.34)
1.51
Unknown/Other
4 (0.3%)
0 (0%)
4 (0.2%)
NA
9 (1.0%)
3 (0.7%)
12 (0.9%)
(0.41-5.60)
* There are 18 children that have a missing malaria result.
NB: Percentages are out of all those enrolled in that arm within the malaria group or non-malaria group (totals are at the top of each column)
8
Table S3c: Terminal Clinical Events in those with anemia and those without anemia at baseline.
Severe Anemia (<5g/dl haemoglobin) or no anemia (≥5g/dl haemoglobin) (n=3054*)
Terminal Clinical Event
/Syndrome
Combined
Total enrolled
bolus
No bolus
Total
655
332
987
Cardiogenic (ongoing signs of
shock) only
Haemoglobin ≥ 5g/dl
Severe Anemia
Subhazard
Combined
Subhazard
ratio°
bolus
No Bolus
Total
1384
683
2067
1.87
69 (11%)
19 (6%)
88 (9%)
(1.12-3.12)
1.63
23 (2%)
7 (1%)
30 (1%)
0.71
Neurological only
7 (1%)
5 (2%)
12 (1%)
(0.23-2.23)
12 (2%)
1 (0.3%)
13 (1%)
(0.79-47.3)
(0.70-3.79)
1.3
37 (3%)
14 (2%)
51 (2%)
6.12
Respiratory only
ratio°
(0.70-2.41)
1.3
34 (2%)
13 (2%)
47 (2%)
(0.69-2.46)
4 (0.3%)
0 (0%)
2 (0.2%)
NA
3.04
Cardiogenic and Neurological
6 (1%)
1 (0.3%)
7 (0.7%)
(0.36-25.4)
0.34
Respiratory and Neurological
2 (0.3%)
3 (1%)
5 (0.5%)
(0.05-2.01)
0.66
8 (0.6%)
6 (0.9%)
14 (0.7%)
2.54
Unknown/Other
5 (1%)
1 (0.3%)
6 (0.6%)
(0.30-21.7)
(0.23-1.89)
1.32
8 (0.6%)
3 (0.4%)
11 (0.5%)
(0.35-4.96)
*There are 87 children without a haemoglobin result at baseline.
°The sub-hazard ratio for bolus combined vs. no bolus takes into account the competing risks.
9
Table S4a: Mortality at 48 hours children with and without persisting features of shock
at one hour
Bolus
No
Albumin
Saline
combined
Bolus
Total¥
Relative risk*
21/445
22/430
43/876
8/323
51/1198
1.98
No shock at one hour
(5%)
(5%)
(5%)
(2%)
(4%)
(0.94-4.17)
Continued shock at
71/584
70/596
141/1180
50/701
191/1881
1.67
one hour
(12%)
(12%)
(12%)
(7%)
(10%)
(1.23-2.28)
*p-value for heterogeneity between the two relative risks. = 0.68
¥Measurements
available for 3079/3141 children as 39 had died and 23 had missing impaired
perfusion at one hour.
Table S4b: Mortality at 48 hours in those with or without hypoxia by their baseline
status.
Hypoxic at baseline
Albumin
No hypoxia at
one hour
Saline
Bolus
No Bolus
Total¥
Relative Risk
17/172
9/165 (5%)
(10%)
1.44
26/337 (8%)
11/205 (5%)
37/542 (7%)
(0.73-2.85)*
50/274
0.71
(18%)
(0.43-1.18)*
94/1969
2.64
(5%)
(1.53-4.54)†
26/175
1.96
(15%)
(0.71-5.39) †
Continued
hypoxia at one
17/101
hour
(17%)
31/191
14/90 (16%)
(16%)
19/83 (23%)
Without hypoxia at baseline
No hypoxia at
one hour
79/1312
44/661 (7%)
35/651 (5%)
(6%)
15/657 (2%)
Became
hypoxic at one
hour
22/129
10/62 (16%)
12/67 (18%)
(17%)
4/46 (9%)
*p-value for heterogeneity between risk ratios for those hypoxic at baseline p=0.10.
†p-value
or heterogeneity between risk ratios for those without hypoxia at baseline p=0.63
¥Measurements
available for 2960/3141 children as 39 had died and 142 had missing oxygen
saturation (103 at baseline, 39 at one hour.