1 Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology.
Anesth Analg 2007; 104: 575-81
2 Abad-Gurumeta A, Ripolles-Melchor J, Casans-Frances R, et al. A systematic review
of sugammadex vs neostigmine for reversal of neuromuscular blockade. Anaesthesia
2015; 70: 1441-52
Fo
3 Carron M, Zarantonello F, Tellaroli P, Ori C. Efficacy and safety of sugammadex
rP
compared to neostigmine for reversal of neuromuscular blockade: a meta-analysis of
ee
randomized controlled trials. J Clin Anesth 2016; 35: 1-12
rR
4 Hristovska AM, Duch P, Allingstrup M, Afshari A. The comparative efficacy and safety
of sugammadex and neostigmine in reversing neuromuscular blockade in adults. A
ev
Cochrane systematic review with meta-analysis and trial sequential analysis.
iew
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Anaesthesia 2018; 73: 631-41
Paton
F,
Paulden
M,
Chambers
D,
et
al.
Sugammadex
compared
with
neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic
review and economic evaluation. Br J Anaesth 2010; 105: 558-67
6 Mertes PM, Alla F, Trechot P, Auroy Y, Jougla E, Groupe d'Etudes des Reactions
Anaphylactoides P. Anaphylaxis during anesthesia in France: an 8-year national survey.
17
British Journal of Anaesthesia
J Allergy Clin Immunol 2011; 128: 366-73
7 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening
allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the
6th National Audit Project (NAP6). Br J Anaesth 2018; 121: 159-71
8 Tsur A, Kalansky A. Hypersensitivity associated with sugammadex administration: a
systematic review. Anaesthesia 2014; 69: 1251-7
Fo
9 Takazawa T, Tomita Y, Yoshida N, et al. Three suspected cases of sugammadex-
rP
induced anaphylactic shock. BMC Anesthesiol 2014; 14: 92
ee
10 NDA 22225: sugammadex injection. Anesthetic and analgesic drug products advisory
rR
committee (AC) meeting November 6, 2015 sugammadex AC briefing document.
ev
11 Miyazaki Y, Sunaga H, Kida K, et al. Incidence of Anaphylaxis Associated With
Sugammadex. Anesth Analg 2018; 126: 1505-8
iew
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 Seed MJ, Ewan PW. Anaphylaxis caused by neostigmine. Anaesthesia 2000; 55: 5745
13 Hermite L, Louvier N, Hilaire P, Orry D, Seltzer S, Collet E. Neostigmine induced
anaphylaxis in the wake of surgery. Anaesth Crit Care Pain Med 2015; 34: 109-11
14 Takazawa T Miyasaka K, Sawa T, Iida H. Current status of sugammadex usage and
the occurence of sugammadex-induced anaphylaxis in Japan. APSF Newsl 2018; 33:
18
Page 18 of 35
Page 19 of 35
11-2
15 Takazawa T, Sabato V, Ebo DG. In vitro diagnostic tests for perioperative
hypersensitivity, a narrative review: potential, limitations, and perspectives. Br J
Anaesth 2019; 123: e117-e25
16 Hopkins PM, Cooke PJ, Clarke RC, et al. Consensus clinical scoring for suspected
perioperative immediate hypersensitivity reactions. Br J Anaesth 2019; 123: e29-e37
Fo
17 Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically
rP
administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper.
rR
Allergy 2013; 68: 702-12
ee
18 Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General considerations
ev
for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002; 57: 45-
iew
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
British Journal of Anaesthesia
51
19 Mertes PM, Malinovsky JM, Jouffroy L, et al. Reducing the risk of anaphylaxis during
anesthesia: 2011 updated guidelines for clinical practice. J Investig Allergol Clin
Immunol 2011; 21: 442-53
20 Ue KL, Kasternow B, Wagner A, Rutkowski R, Rutkowski K. Sugammadex: An
emerging trigger of intraoperative anaphylaxis. Ann Allergy Asthma Immunol 2016;
117: 714-6
19
British Journal of Anaesthesia
21 Valent P, Akin C, Arock M, et al. Definitions, criteria and global classification of mast
cell disorders with special reference to mast cell activation syndromes: a consensus
proposal. Int Arch Allergy Immunol 2012; 157: 215-25
22 Baretto RL, Beck S, Heslegrave J, et al. Validation of international consensus equation
for acute serum total tryptase in mast cell activation: A perioperative perspective.
Allergy 2017; 72: 2031-4
Fo
23 Horiuchi T, Yokohama A, Orihara M, et al. Usefulness of Basophil Activation Tests for
rP
Diagnosis of Sugammadex-Induced Anaphylaxis. Anesth Analg 2018; 126: 1509-16
ee
24 Takazawa T, Horiuchi T, Yoshida N, Yokohama A, Saito S. Flow cytometric
rR
investigation of sugammadex-induced anaphylaxis. Br J Anaesth 2015; 114: 858-9
ev
25 Garcia-Ortega P, Marin A. Usefulness of the basophil activation test (BAT) in the
iew
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
diagnosis of life-threatening drug anaphylaxis. Allergy 2010; 65: 1204
26 Torres MJ, Romano A, Blanca-Lopez N, et al. Immunoglobulin E-mediated
hypersensitivity to amoxicillin: in vivo and in vitro comparative studies between an
injectable therapeutic compound and a new commercial compound. Clin Exp Allergy
2011; 41: 1595-601
27 Christiansen IS, Kroigaard M, Mosbech H, Skov PS, Poulsen LK, Garvey LH. Clinical
and diagnostic features of perioperative hypersensitivity to cefuroxime. Clin Exp Allergy
20
Page 20 of 35
Page 21 of 35
2015; 45: 807-14
28 Kroigaard M, Garvey LH, Menne T, Husum B. Allergic reactions in anaesthesia: are
suspected causes confirmed on subsequent testing? Br J Anaesth 2005; 95: 468-71
29 Marinho S, Kemp H, Cook TM, et al. Cross-sectional study of perioperative drug and
allergen exposure in UK practice in 2016: the 6th National Audit Project (NAP6) Allergen
Survey. Br J Anaesth 2018; 121: 146-58
Fo
30 O'Reilly-Shah VN, Wolf FA, Jabaley CS, Lynde GC. Using a worldwide in-app survey
rP
to explore sugammadex usage patterns: a prospective observational study. Br J Anaesth
rR
2017; 119: 333-5
ee
31 Savic L, Savic S, Hopkins PM. Sugammadex: the sting in the tail? Br J Anaesth 2018;
121: 694-7
iew
ev
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
British Journal of Anaesthesia
32 Hunter JM, Naguib M. Sugammadex-induced bradycardia and asystole: how great is
the risk? Br J Anaesth 2018; 121: 8-12
33 Greenaway S, Shah S, Dancey M. Sugammadex and laryngospasm. Anaesthesia
2017; 72: 412-3
34 Wu TS, Tseng WC, Lai HC, Huang YH, Wu ZF. Sugammadex and laryngospasm. J
Clin Anesth 2019; 56: 52
35 de Kam PJ, Nolte H, Good S, et al. Sugammadex hypersensitivity and underlying
21
British Journal of Anaesthesia
mechanisms: a randomised study of healthy non-anaesthetised volunteers. Br J Anaesth
2018; 121: 758-67
36 Min KC, Bondiskey P, Schulz V, et al. Hypersensitivity incidence after sugammadex
administration in healthy subjects: a randomised controlled trial. Br J Anaesth 2018;
121: 749-57
iew
ev
rR
ee
rP
Fo
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22
Page 22 of 35
Page 23 of 35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
British Journal of Anaesthesia
Table 1
Summary of the number of perioperative anaphylaxis events due to antagonists to NMBAs and other drugs
Number of cases
Hospital
Number of cases
each drug was
with GA
used
All cases of anaphylaxis
Caused by SUG
Caused by NEO
SUG
NEO
Anaphylaxis
Incidence (%)
95%CI (%)
Anaphylaxis
Incidence (%)
95%CI (%)
Anaphylaxis
0.026
0.009-0.056
0.008
0.000-0.046
0.000
0.000
0.042
0.014-0.099
0.043
0.009-0.127
0.000
0.000
0.037
0.008-0.108
0.017
0.000-0.093
0.000
0.000
0.017-0.163
0.020
0.001-0.113
0.000
0.000
0.022-0.057
0.020
0.007-0.044
0.000
0.000
Fo
23358
12149
1447
11773
6912
1374
8112
5983
116
6289
4918
220
All
49532
29962
3157
18
rP
0.064
0.036
ee
rR
ev
Abbreviations: GA, general anaesthesia; SUG, sugammadex; NEO, neostigmine; CI, confidence interval
23
iew
Incidence (%) 95%CI (%)
British Journal of Anaesthesia
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
Page 24 of 35
Table 2
A: Clinical background, anaphylactic symptoms and blood test results in patients with anaphylaxis due to sugammadex
Case
Age
(years)
75
34
Sex
Height Weight
(cm)
152
159
(kg)
71
62
ASA
PS
Previous
Previous
Onset of
surgical
exposure
reaction
history
to SUG
(min)
Fo
Yes
No
rP
No
No
Time to
Symptoms
achieve
score
haemodynamic
stability (min)
Tryptase
(ng mL-1)
(μg L-1)
Peak
Baseline
Peak
Baseline
ee
BP: 40/undetectable mmHg
Clinical
Histamine
HR: 120 bpm
25
15
19
30
20
27
20
124.0
0.9
13.9
1.9
17
11
49.3
1.1
22.0
2.8
13
19
7.0
0.3
104.0
5.8
Thoracic erythema
rR
BP: 70/40 mmHg
ev
Generalized erythema
BP: unmeasurable
13
159
40
No
No
iew
HR: 160 bpm
Facial swelling
Elevated AP
BP: 40/25 mmHg
65
168
65
Yes
Yes
<1
Generalized erythema
Elevated AP
BP: 75/35 mmHg
39
164
73
Yes
No
HR: 130 bpm
Thoracic erythema
62
159
57
UI
UI
BP 45/20 mmHg
Nausea
24
Page 25 of 35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
British Journal of Anaesthesia
All patients had a clinical score of 8 or above, suggesting possible anaphylaxis 16. Anaphylactic symptoms appeared after 80 mg of sugammadex administration
in case 3 and 200 mg of sugammadex in other cases. A past history of drug allergies was present in only case 4, as allergy to contrast media.
Abbreviations: ASA-PS, American Society of Anesthesiologists physical status classification; SUG, sugammadex; F, female; BP, blood pressure; HR, heart
rate; M, male; AP, airway pressure
B: Results of skin tests and basophil activation tests in patients with anaphylaxis following sugammadex administration
Skin tests
SPT
IDT
(mg mL-1)
(mg mL-1)
ND
Case
Delay in skin
Fo
rP
BAT
CD203c
CD63
ee
Delay in
tests
SUG concentration
(days)
(mg mL-1)
31
10
ND
0.1
57
rR
ND
49
10
56.4
negative
0.1
63
10
6.1
negative
0.1
59
4.3
ND
28
42.6
Result of BATs
BATs
Activated
SUG concentration
Activated
basophils (%)
(mg mL-1)
basophils (%)
26.3
positive
35
ND
10
40.5
positive
33
10
5.5
positive
11
0.1
3.7
positive
25.3
positive
49.3
ev
iew
(months)
Numerical values in the SPT and IDT columns indicate the concentration of sugammadex that resulted in positive skin reactions. A concentration of 100
mg/mL of sugammadex represents the undiluted / full-strength solution. The concentration of sugammadex and proportion of activated basophils when
basophils were most highly activated are shown in CD203c and CD63 columns. The percentage of activated basophils was obtained by subtracting 5%, which
is the value activated by the negative control. Assessment of the BAT was performed based on the threshold we determined in our previous study 23.
Abbreviations: BAT, basophil activation tests; SPT, skin prick tests; IDT, intradermal tests; SUG, sugammadex; ND, no data
25
British Journal of Anaesthesia
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
Page 26 of 35
Table 3
A: Clinical background, anaphylactic symptoms and blood test results in patients with anaphylaxis induced by drugs other than sugammadex
Case
Age
Sex
(years)
Height
Weight
ASA
Surgical
(cm)
(kg)
PS
History
Culprit drugs
61
54
147
171
44
79
Yes
Unknown
Symptoms
reaction
Clinical
Time to achieve
Histamine
Tryptase
score
haemodynamic
(ng mL-1)
(μg L-1)
(min)
Fo
Onset of
Peak
Baseline
Peak
Base
line
rP
Propofol
stability (min)
ee
Lidocaine
<1
Thoracic erythema
rR
1.0
0.9
1.0
1.1
12
10
1.5
1.2
7.9
7.0
35
30
34.9
0.9
35.3
3.9
Oral swelling
Elevated AP
ev
<1
17
BP: 44/37 mmHg
iew
Wheal and
erythema at
epidural catheter
insertion site
41
152
62
Yes
Rocuronium
<1
BP: 41/23 mmHg
HR: 170 bpm
Elevated AP
Decrease in SpO2 to
82%
26
Page 27 of 35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
British Journal of Anaesthesia
71
149
53
No
Cefazolin
10
BP: 40/18 mmHg
21
11.0
0.8
13.2
2.9
26
26
115.0
1.0
17.7
2.5
16
80
11.3
0.7
19.5
3.9
32
35
1.7
1.3
31.9
3.6
ev
21
30
9.6
0.9
2.4
1.2
BP: 65/37 mmHg
19
0.8
0.7
2.9
1.8
20
30
54.0
0.8
7.3
2.8
Generalized wheal
and erythema
26
168
56
No
Cefazolin
BP: 34/21 mmHg
HR: 133 bpm
Unmeasured SpO2
83
56
157
179
59
83
Fo
Yes
Yes
Unidentified
67
160
48
No
BP: 40/25 mmHg
HR: 125 bpm
rP
Elevated AP to 25
ee
Cefoperazone
-Sulbactam
Unknown
Cefazolin
cmH2O
rR
VF
Elevated AP
BP: 60/45 mmHg
HR: 120 bpm
iew
Generalized
erythema
78
155
50
Unknown
Rocuronium
10
Elevated AP
Generalized
erythema
10
21
180
67
Yes
Flurbiprofen
10
BP: 64/32 mmHg
HR: 120 bpm
Generalized
erythema and
itching
27
British Journal of Anaesthesia
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
11
132
28
No
Cefazolin
10
Page 28 of 35
BP: 40/22 mmHg
22
75
49.2
0.4
12.0
3.6
12
15
49.1
0.1
5.0
3.6
HR: 140 bpm
Decreased SpO2 to
80%
12
33
156
48
Unknown
Cefazolin
20
BP: 48/32 mmHg
HR: 140 bpm
Erythema at right
Fo
upper limb
rP
All patients had a clinical score of 8 or more, suggesting possible anaphylaxis 16. A past history of drug allergies to ciprofloxacin was seen in case 6 and to
tropicamide in case 8.
Abbreviations: ASA-PS, American Society of Anesthesiologists physical status classification; F, female; M, male; AP, airway pressure; BP, blood pressure;
HR, heart rate; VF, ventricular fibrillation
ee
rR
ev
iew
B: Results of skin tests and basophil activation tests in subjects with anaphylaxis to drugs other than NMBA antagonists
Skin tests
CD203c
Case
SPT
IDT
(mg mL-1)
BATs
CD63
Delay in skin
Delay in
tests
Drug concentration
Activated
Drug concentration
Activated
(days)
(mg mL-1)
basophils (%)
(mg mL-1)
basophils (%)
Results of BATs
BATs
(days)
ND
0.1
54
ND
ND
43
ND
negative
0.01
33
ND
28
Page 29 of 35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
British Journal of Anaesthesia
negative
0.02
61
25.4
positive
61
negative
0.2
55
49.4
positive
55
negative
negative
58
0.6
2.2
negative
58
negative
0.2
82
0.6
-1.6
2.4
negative
82
negative
0.02
48
0.6
5.2
0.06
positive
48
negative
0.1
35
ND
ND
ND
ND
non-responder
35
10
negative
0.1
66
10
0.9
negative
66
11
negative
0.02
46
10
7.1
10
5.1
positive
46
12
negative
0.2
28
10
57.2
10
49.2
positive
28
Fo
rP
ee
Intradermal tests showed positive reactions to the drug at the indicated dilution in all but one case. In case 6, the BAT was performed using the contrast agent,
iopamidol, but the result was negative. Numerical values in the drug concentration columns indicate the concentration of the culprit drug that most activated
basophils. The proportion of activated basophils when the basophils were most highly activated is shown in the activated basophils columns. The percentage of
activated basophils was obtained by subtracting 5%, which is the value activated by the negative control. Patients who showed no response to positive controls
are displayed as non-responders.
Abbreviations: BAT, basophil activation tests; SPT, skin prick tests; IDT, intradermal tests; ND, no data
rR
ev
29
iew
British Journal of Anaesthesia
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
Page 30 of 35
Table 4
Usage of neuromuscular blocking agents and their reversal agents
NMBAs
Reversal agents
Usage rate
Drug
Number of
Overall usage
patients
rate (%)
Rocuronium
44692
90.2
Vecuronium
246
0.5
Succinylcholine
1749
3.5
Total
46687
94.3
Share (%)
Fo
Drug
Number of
Overall usage
among cases
patients
rate (%)
with NMBAs
Share (%)
rP
(%)
95.7
Sugammadex
29962
60.5
64.2
90.5
0.5
Neostigmine
3157
6.4
6.8
9.5
Total
33119
66.9
70.9
100.0
3.7
100.0
ee
rR
ev
The usage rate of drugs was calculated by dividing the number of patients receiving each drug by the total number of patients receiving general anaesthesia.
The usage rate of drugs in cases with NMBAs was calculated by dividing the number of patients receiving each drug by the total number of patients receiving
NMBAs. The share was calculated from the usage rate of each drug among the categorized drugs.
30
iew
Page 31 of 35
Supplemental Table 1
Questions and answers in the survey questionnaire for anaesthetists
Question 1
Choices
Are you in an environment where you can freely use
Yes or No
sugammadex?
Question 2
What is your rate of use of sugammadex as an
Continuous variable from 0 to 100
antagonist to NMBAs?
Question 3
Select your reason(s) for choosing sugammadex, in
1. Certainty of antagonism of muscle relaxation, including
order of importance,
for deep muscular blockade
Fo
from among the following options.
2. Safety of antagonism of muscle relaxation with few
adverse effects
Question 4
3. Rapidity of antagonism of muscle relaxation
4. No particular reason
5. Others
ee
rP
Select your reason(s) for not choosing sugammadex, in
1. Existence of an alternative drug, neostigmine
order of importance,
2. Concerns about adverse events, including the occurrence
from the following options.
rR
of anaphylaxis
ev
3. Cost or cost benefit concerns
4. No particular reason
iew
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
British Journal of Anaesthesia
5. Others
31
British Journal of Anaesthesia
Supplemental Figure 1
Flow diagram of the study
The criteria fulfilled in each case are underlined.
Supplemental Figure 2
A: Chronological changes in the usage ratios of each NMBA antagonist. The average and standard
deviation of all the hospitals’ shares are shown. B and C: Chronological changes in the total number
of cases using antagonists to NMBAs at three of the hospitals and the number of their sales in Japan
as a whole. Since sugammadex was first released in Japan in 2010, the number of cases using
sugammadex (red open circles) and number of vials of sugammadex sold (red closed circles) were
calculated considering those of 2011 as 100% (B). The number of cases using neostigmine (blue open
circles) and number of vials of neostigmine sold (blue closed circles) were calculated considering those
of 2009 as 100% (C).
Fo
Supplemental Figure 3
Results of the online survey of anaesthetists. Reason(s) for choosing sugammadex (A) and reason(s)
for not choosing sugammadex (B) are shown. Each item was scored for ranking: The first item had a
score of five points, the second four points, the third three points, the fourth two points, and the fifth
one point. The total score of each item is displayed next to each bar. The number of reasons cited by
one respondent ranged from one to five, because the number of reasons was not specified. Therefore,
the total number of points for figure A and B does not match (922 vs. 637).
iew
ev
rR
ee
rP
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Page 32 of 35
32
Page 33 of 35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
British Journal of Anaesthesia
Suspected cases of anaphylaxis (n = 23)
Excluded (n = 5)
Fo
The clinical score was 11, blood tests and skin test
were not performed
The clinical score was 7, blood tests showed positive
results, skin tests were not performed
The clinical score was 7, blood tests showed negative
results, skin tests showed positive results
The clinical score was 14, blood tests showed
negative results, skin tests were not performed
The clinical score was 26, baseline data of blood tests
were missing, skin tests showed negative results
rP
ee
rR
ev
iew
Included in the study (n = 18)
Sugammadex-induced anaphylaxis (n = 6)
Anaphylaxis induced by drugs other than sugammadex ( n = 12)
British Journal of Anaesthesia
iew
ev
rR
ee
rP
Fo
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supplemental Figure 2
Page 34 of 35
Page 35 of 35
iew
ev
rR
ee
rP
Fo
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
British Journal of Anaesthesia
Supplemental Figure 3
...
論文の公開元へ
