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Non-adrenergic vasopressors for vasodilatory shock or perioperative

vasoplegia: a meta-analysis of randomized controlled trials

Article in Critical Care · December 2024

DOI: 10.1186/s13054-024-05212-7

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Kotani et al. Critical Care (2024) 28:439 Critical Care
https://doi.org/10.1186/s13054-024-05212-7

RESEARCH Open Access

Non‑adrenergic vasopressors
for vasodilatory shock or perioperative
vasoplegia: a meta‑analysis of randomized
controlled trials
Yuki Kotani1* , Alessandro Belletti2 , Filippo D’Amico2, Alessandra Bonaccorso2, Patrick M. Wieruszewski3,4,
Tomoko Fujii5, Ashish K. Khanna6,7, Giovanni Landoni2,8 and Rinaldo Bellomo9,10,11,12,13,14

Abstract
Background Excessive exposure to adrenergic vasopressors may be harmful. Non-adrenergic vasopressors may
spare adrenergic agents and potentially improve outcomes. We aimed to conduct a systematic review and meta-anal-
ysis of randomized controlled trials (RCTs) to evaluate the efficacy of non-adrenergic vasopressors in adult patients
receiving vasopressor therapy for vasodilatory shock or perioperative vasoplegia.
Methods We searched PubMed, Embase, and Cochrane Library for RCTs comparing non-adrenergic vasopressors
with adrenergic vasopressors alone or placebo in critically ill or perioperative patients. Each eligible study was catego-
rized into septic shock, cardiac surgery, or non-cardiac surgery. Non-adrenergic vasopressors included vasopressin,
terlipressin, selepressin, angiotensin II, methylene blue, and hydroxocobalamin. The primary outcome was mortality
at longest follow-up. We conducted a random-effects meta-analysis. We registered the protocol in PROSPERO Interna-
tional Prospective Register of Systematic Reviews (CRD42024505039).
Results Among 51 eligible RCTs totaling 5715 patients, the predominant population was septic shock in 30 studies, cardiac
surgery in 11 studies, and non-cardiac surgery in 10 studies. Cochrane risk-of-bias tool for randomized trials version 2 identi-
fied 17 studies as low risk of bias. In septic shock, mortality was significantly lower in the non-adrenergic group (960/2232
[43%] vs. 898/1890 [48%]; risk ratio [RR], 0.92; 95% confidence interval [95% CI], 0.86–0.97; P = 0.03; ­I2 = 0%), with none
of the individual non-adrenergic vasopressors showing significant survival benefits. No significant mortality difference
was observed in patients undergoing cardiac surgery (34/410 [8.3%] vs. 47/412 [11%]; RR, 0.82; 95% CI, 0.55–1.22; P = 0.32;
­I2 = 12%) or those undergoing non-cardiac surgery (9/388 [2.3%] vs. 18/383 [4.7%]; RR, 0.66; 95% CI, 0.31–1.41; P = 0.28; ­I2 = 0%).
Conclusions Administration of non-adrenergic vasopressors was significantly associated with reduced mortality
in patients with septic shock. However, no single agent achieved statistical significance in separate analyses. Although
the pooled effects of non-adrenergic vasopressors on survival did not reach statistical significance in patients under-
going cardiac or non-cardiac surgery, the confidence intervals included the possibility of both no effect and a clini-
cally important benefit from non-adrenergic agents. These findings justify the conduct of further RCTs comparing
non-adrenergic vasopressors to usual care based on noradrenaline alone.
Keywords Meta-analysis, Catecholamines, Arginine vasopressin, Angiotensin II, Methylene blue, Mortality

*Correspondence:
Yuki Kotani
[email protected]
Full list of author information is available at the end of the article

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
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Kotani et al. Critical Care (2024) 28:439 Page 2 of 14

Background Methods
Vasodilatory shock remains a clinical challenge in criti- This systematic review and meta-analysis followed the
cally ill and perioperative patients [1–3]. When fluid Preferred Reporting Items for Systematic Reviews and
resuscitation alone fails to restore blood pressure, vaso- Meta-Analyses (PRISMA) guidelines (see Supplementary
pressors represent the key intervention to correct hypo- material for completed checklist) [15]. We registered this
tension. There are three major mechanisms to maintain study in the PROSPERO International prospective regis-
blood pressure, i.e., the sympathetic nervous system, ter of systematic reviews (CRD42024505039). Our review
vasopressin system, and renin-angiotensin system (RAS). question was built using the following PICOS (Popula-
Each of them has the corresponding vasopressors (i.e., tion, Intervention, Comparison, Outcome, Study design)
catecholamines, vasopressin and its derivatives, and criteria: adult patients receiving vasopressor therapy for
angiotensin II) [4]. In addition, several vasoactive agents vasodilatory shock or perioperative vasoplegia (P); non-
with distinct mechanisms of action (e.g., methylene blue adrenergic vasopressors (I); adrenergic vasopressors or
and hydroxocobalamin) can also be used to restore blood placebo (C); mortality at the longest follow-up available
pressure [5, 6]. (O); RCTs (S).
Noradrenaline is recommended as the first-line vaso-
pressor [2]; however, excessive exposure to catechola- Search strategy and selection criteria
mines is associated with poor prognosis [7]. Thus, the Four researchers independently searched PubMed,
hypothesis has emerged that administration of non- Embase, and Cochrane Central Register of Controlled
adrenergic vasopressors may reduce the catecholamine Trials to identify relevant studies from inception to Jan-
burden and improve clinical outcomes. Consistent with uary 29, 2024. The complete search strategies are pre-
this, a previous meta-analysis of randomized controlled sented in the Supplementary material. We included RCTs
trials (RCTs) in 2015 showed potential survival benefits comparing non-adrenergic vasopressors with adrenergic
of non-adrenergic agents [8]. Other meta-analyses have vasopressors or placebo in adult patients receiving vaso-
suggested that vasopressin and its derivatives may reduce pressor therapy for vasodilatory shock or perioperative
arrhythmias in septic shock [9, 10] and that methylene vasoplegia. Non-adrenergic vasopressors included vaso-
blue might offer survival benefits in patients with sep- pressin, terlipressin, selepressin, angiotensin II, meth-
tic shock and in those undergoing cardiac surgery [11]. ylene blue, and hydroxocobalamin. Exclusion criteria
Moreover, angiotensin II, which became available for were non-randomized trials, quasi-randomized trials,
clinical use in 2017, has been tested in a clinical trial pri- observational studies, systematic reviews, commentaries,
marily involving septic shock patients [12] and in two editorials, narrative reviews, animal studies, or confer-
RCTs in cardiac surgical settings with promising findings ence abstracts. We also excluded studies without mortal-
[13, 14]. Finally, hydroxocobalamin was also tested in a ity data or enrolling pediatric patients (≤ 15 years old).
recent RCT for septic shock [6]. Given the heterogene- No restriction was applied to language. After removing
ity of these studies in terms of patient population, com- duplicates, four investigators assessed eligibility at the
parator, type of non-adrenergic agent, and shock severity, title/abstract level. Then, four investigators evaluated the
a dedicated analysis appears desirable to account for full text of all potentially relevant articles. In case of disa-
these between-trial differences and provide an updated greement, the final assessment was discussed with a sen-
assessment of the outcome impact of non-adrenergic ior investigator.
vasopressors.
Accordingly, we performed an updated systematic Data collection
review and meta-analysis. We aimed to test the hypoth- From eligible studies, two investigators independently
esis that non-adrenergic vasopressors reduce mortality in extracted the following variables using a standardized
adult patients receiving vasopressor therapy for vasodi- data collection form: first author name, publication year,
latory shock or perioperative vasoplegia. To address the number of participating centers, patient population,
heterogeneity of treatment effects across different popu- number of patients in the non-adrenergic and control
lations and different comparators, we separately analyzed group, the non-adrenergic vasopressor, the comparator,
studies according to patient group (septic shock, cardiac baseline vasopressor dose, type of comparator drug, and
surgery, and non-cardiac surgery) and performed sub- outcome data.
group analyses according to the comparator (adrenergic
agents or placebo). Risk of bias assessment
The risk of bias of each included RCT was assessed
independently by two investigators using the Cochrane
risk-of-bias tool for randomized trials version 2 (RoB 2)
Kotani et al. Critical Care (2024) 28:439 Page 3 of 14

[16]. The overall certainty of the evidence was evaluated To assess the possible effect modification for mortal-
according to the Grading of Recommendations Assess- ity by baseline vasopressor dose, we performed a meta-
ment, Development, and Evaluation (GRADE) methodol- regression analysis using a mixed-effects model. A
ogy [17]. The GRADEpro software was used to create the noradrenaline equivalent score was used to calculate the
GRADE evidence profile table [18]. total vasopressor dose [22]. The analysis was performed
using R 4.0.1.
Trial sequential analysis (TSA) was performed to inves-
Outcomes tigate the robustness of the pooled primary outcome data
The primary outcome was mortality at the longest availa- [23]. We used the weighted mortality data in the control
ble follow-up, given that mortality is the most frequently group and anticipated a 10% relative risk reduction when
reported patient-important primary outcome in criti- non-adrenergic vasopressors are applied, with a diver-
cal care RCTs [19]. Secondary outcomes included renal sity-adjusted information size calculated using a two-
replacement therapy (RRT), days of mechanical ventila- sided alpha of 0.05 and a power of 80%. The TSA Viewer
tion, days of intensive care unit (ICU) stay, days of hospi- software was used (Version 0.9.5.10 Beta. Copenhagen
tal stay, atrial fibrillation, vasopressor-free days at day 28, Trial Unit, Centre for Clinical Intervention Research,
and dose of noradrenaline. Dose of noradrenaline refers Rigshospitalet, Copenhagen, Denmark).
to the noradrenaline equivalent dose observed at the
longest follow-up available.
Results
From 6159 records identified through literature search,
Statistical analysis we included 51 RCTs with a total of 5715 patients
Initially, we categorized all the included RCTs into one of (Table 1 and Fig. 1) [5, 6, 12–14, 24–69]. The major exclu-
three distinct groups—septic shock, cardiac surgery, or sions and reasons for exclusion are shown in Table S2.
non-cardiac surgery—based on the majority population The predominant population investigated was septic
in each study. Meta-analysis was performed separately shock in 30 studies [5, 6, 12, 24–50], cardiac surgery in
for these three groups. Subgroup analysis was conducted 11 studies [13, 14, 51–59], and non-cardiac surgery in 10
according to type of non-adrenergic agents (vasopressin, studies [60–69]. The non-adrenergic agent assessed was
terlipressin, selepressin, angiotensin II, methylene blue, vasopressin in 16 studies [26, 29–32, 34, 37, 39, 45, 52, 54,
and hydroxocobalamin), comparator (placebo and adren- 56, 57, 59, 61, 68], terlipressin in 15 studies [24, 25, 28, 33,
ergic agents), baseline vasopressor dose (above or below 38, 42, 46, 48–50, 62, 65–67, 69], selepressin in two stud-
the median value in septic shock), exclusion of studies ies [36, 44], angiotensin II in five studies [12–14, 27, 51],
assessing nitric oxide scavengers (methylene blue and methylene blue in 11 studies [5, 35, 40, 41, 47, 53, 55, 58,
hydroxocobalamin), and studies with overall low risk of 60, 63, 64], and hydroxocobalamin in one study [5, 6, 12,
bias. We also performed the following sensitivity analy- 13, 25, 33, 34, 37, 39, 42, 45, 51, 53–58, 60–65, 67]. The
ses for the primary outcome: timing of assessment (< 28 remaining study randomized patients into three groups
days, 28 or 30 days, and > 30 days), exclusion of a study (vasopressin, terlipressin, or noradrenaline) and was
using dopamine as control treatment, exclusion of stud- categorized as a vasopressin study in subgroup analyses
ies using selepressin as the intervention, timing of admin- based on drug type [43].
istration (first-line versus second- or third-line therapy), Placebo was used as a comparator in 25 studies [5, 6,
studies published in high-impact journals [20, 21] (the 12, 13, 27, 35, 36, 39, 41, 44, 47, 53, 55–60, 62–67, 69],
complete journal selection is detailed in the Table S1), while adrenergic agents were administered and served as
and studies published before versus after 2014. comparator in 26 studies [14, 24–26, 28–34, 37, 38, 40,
Throughout this study, we calculated individual and 42, 43, 45, 46, 48–52, 54, 61, 68]. The baseline noradrena-
pooled effects estimate (risk ratio [RR] for binary vari- line equivalent dose was 0.28 µg/kg/min in septic shock
ables and mean difference [MD] or standardized mean [5, 6, 12, 24, 25, 29, 31, 33, 37–39, 41, 43–46, 49] and 0.20
difference [SMD] for continuous variables) with 95% µg/kg/min in cardiac surgery [14, 53–56, 58, 59], while no
confidence interval (CI) using a Mantel–Haenszel patient received vasopressors at baseline in non-cardiac
random-effects model for all the outcomes assuming surgery settings [60, 61, 63, 65, 68, 69]. The characteris-
heterogeneity of treatment effects due to clinical het- tics of the included studies and noradrenaline products
erogeneity among studies. Statistical heterogeneity was used are summarized in Table 1 and Table S3.
assessed using the ­I2 statistics, and publication bias was The risk of bias assessment using RoB 2 deemed 17
evaluated by visual inspection of funnel plots. We used studies as being at low risk of bias [5, 12–14, 27, 31, 32,
Review Manager 5.4 and considered two-sided p val- 36, 38, 44, 45, 52, 60, 61, 63, 66, 67], 16 studies as having
ues < 0.05 statistically significant. some concerns [6, 24, 28, 29, 35, 37, 41, 43, 48, 49, 51, 55,
Kotani et al. Critical Care (2024) 28:439 Page 4 of 14

Table 1 Characteristics of the included studies

First author, year No. of centers Country No. of patients Baseline Dose of non- Comparator Follow-up
noradrenaline adrenergic agents
equivalent dose,
µg/kg/min

Septic shock
Vasopressin
Malay MB, 1999 [39] 1 USA 10 0.33 0.04 U/min Placebo 24 h
Dunser MW, 2003 1 Austria 48 0.84 4 U/h Noradrenaline ICU stay
[29]
Lauzier F, 2006 [37] 2 Multinational 23 0.27 0.04–0.2 U/min Noradrenaline 48 h
Russell JA, 2008 [45] 27 Multinational 778 0.25 0.01–0.03 U/min Noradrenaline 90 days
Fonseca-Ruiz NJ, 1 Colombia 30 NR 0.01–0.04 U/min Noradrenaline 28 days
2013 [30]
Barzegar E, 2014 [26] 1 Iran 30 NR 0.03 U/min Noradrenaline 28 days
Gordon A, 2016 [31] 18 England 408 0.18 0.06 U/min Noradrenaline 28 days
Hajjar LA, 2019 [32] 1 Brazil 250 0 0.01–0.06 U/min Noradrenaline 90 days
Hussien RM, 2021 1 Egypt 90 NR 0.03 U/min Noradrenaline 28 days
[34]
Terlipressin
Albanese J, 2005 [24] 1 France 20 0 1 mg bolus Noradrenaline Hospital stay
Morelli A, 2008 [42] 1 Italy 39 NR 1 mg bolus Noradrenaline ICU stay
Svoboda P, 2012 [48] 1 Czech Republic 30 NR 4 mg/24 h for 72h Noradrenaline 90 days
Hua F, 2013 [33] 1 China 32 0 1.3 mg/kg/h for 48 h Dopamine 28 days
Choudhury A, 2016 1 India 84 NR 1.3–5.2 µg/min Noradrenaline 28 days
[28]
Xiao X, 2016 [50] 1 China 32 NR 1.3 mg/kg/h Noradrenaline 7 days
Liu ZM, 2018 [38] 21 China 526 0.55 20–160 µg/h Noradrenaline 28 days
Arora V, 2020 [25] 1 India 120 NR 2–12 mg/24 h Noradrenaline 28 days
Sahoo P, 2022 [46] 1 India 50 0.22 0.02 mg/kg/min Noradrenaline ICU stay
Wang J, 2022 [49] 1 China 22 0.29 1.3 mg/kg/h for 24 h Noradrenaline 28 days
Vasopressin & Terlipressin (3 arms)
Morelli A 2009 [43] 1 Italy 45 0 Vasopressin: 0.03 U/ Noradrenaline ICU stay
min Terlipressin:
1.3 µg/kg/min
for 48 h
Selepressin
Russell JA, 2017 [44] NR Multinational 50 0.28 1.25–3.75 ng/kg/min Placebo 28 days
Laterre PF, 2019 [36]c 63 Multinational 828 0.28 1.7–5 ng/kg/min Placebo 90 days
Angiotensin II
Chawla LS, 2014 [27] 1 USA 20 NR 20 ng/kg/min Placebo 30 days
Khanna A, 2017 [34] 75 Multinational 321 0.37 40 ng/kg/min Placebo 28 days
Methylene blue
Kirov MY, 2001 [35] 1 Russia 20 NR 2 mg/kg Placebo 28 days
bolus + 0.25–2 mg/
kg/h for 2 h
Memis D, 2002 [41] 1 Turkey 30 0 0.5 mg/kg/h for 6 h Placebo Hospital stay
Senthilnathan M, 1 India 30 NR 2 mg/kg Placebo 7 days
2017 [47]
Lu YP, 2019 [40] 1 China 54 NR 2 mg/kg Noradrenaline 28 days
Ibarra Estrada M, 1 Mexico 92 0.41 1.2 mg/kg/day Placebo 28 days
2023 [56]
Hydroxocobalamin
Patel JJ, 2023 [52] 2 Multinational 20 0.32 5g Placebo Hospital stay
Kotani et al. Critical Care (2024) 28:439 Page 5 of 14

Table 1 (continued)
First author, year No. of centers Country No. of patients Baseline Dose of non- Comparator Follow-up
noradrenaline adrenergic agents
equivalent dose,
µg/kg/min

Cardiac surgery
Vasopressin
Morales DLS, 2003 1 USA 27 0 0.03 U/min for 72 h Placebo ICU stay
[56]
Luckner G, 2006 [54] 1 Austria 18 0.70 4 U/h Noradrenaline ICU stay
Papadopoulos G, 1 Greece 50 0 0.03 U/min Placebo 48 h
2010 [59]
Okamoto Y, 2014 [57] 1 Japan 92 NR 1.8 U/min Placebo 30 days
Hajjar LA, 2017 [52] 1 Brazil 300 NR 0.01–0.06 U/min Noradrenaline 90 days
Angiotensin II
Bennett SR, 2001 [51] 1 UK 20 NR NR Phenylephrine 48 h
Coulson TG, 2022 2 Australia 60 0 1–40 ng/kg/min Noradrenaline Hospital stay
[65]
Sadjadi M, 2024 [59] 1 Germany 63 NR 20–80 ng/kg/min Placebo 90 days
Methylene blue
Levin RL, 2004 [53] 4 Argentina 56 0.71 1.5 mg/kg for 1 h Placebo Hospital stay
Ozal E, 2005 [58] 1 Turkey 100 0 2 mg/kg Placebo Hospital stay
Maslow AD, 2006 1 America 30 0 3 mg/kg Placebo ICU stay
[55]
Non-cardiac surgery
Vasopressin
Song T, 2015 [68] 1 Korea 60 0 0.2–1 U/min Epinephrine Hospital stay
Elgebaly AS, 2019 1 Egypt 30 0 0.1–0.4 U/min Noradrenaline 28 days
[61]
Terlipressin
Hong SH, 2012 [62] 1 Chorea 41 NR 1–4 μg/kg/h Placebo 10 days
Reddy MS, 2017 [67] 1 India 41 NR 1 mg + 2 µg/kg/h Placebo 30 days
for 72 h
Mahdy MM, 2019 1 Egypt 50 NR 1 mg bolus + 2 μg/ Placebo Hospital stay
[66] kg/h
Kohler A, 2020 [65] 1 Switzerland 130 0 1 mg Placebo 6 weeks
Zhang L, 2023 [69] 1 China 64 0 1 mg Placebo Hospital stay
Methylene blue
Koelzow H, 2002 [64] 1 England 38 NR 1.5 mg/kg Placebo 30 days
Deng Y, 2021 [60] 1 China 248 0 2 mg/kg Placebo 3 months
Huang J, 2022 [63] 1 China 70 0 2 mg/kg Placebo 6 months
ICU, intensive care unit; NR, not reported; UK, United Kingdom; USA, United States of America

57, 58, 62, 68, 69], and 18 studies as being at high risk of analyses except for the one addressing hydroxocobalamin
bias [25, 26, 30, 33, 34, 39, 40, 42, 46, 47, 50, 53, 54, 56, 59, (Fig. 2A and Fig. S1). The TSA confirmed the robustness
64, 65, 70] (Table S4). of evidence indicating reduced mortality with the use of
non-adrenergic agents (Fig. S2).
Primary outcome No significant mortality differences were observed
In septic shock studies (30 RCTs with 4122 patients), the in 11 cardiac surgery studies with 822 patients (34/410
administration of non-adrenergic vasopressors was asso- [8.3%] vs. 47/412 [11%]; RR, 0.82; 95% CI, 0.55 to 1.22;
ciated with a significantly reduced mortality (RR, 0.92; P = 0.32; ­I2 = 12%) and in 10 non-cardiac surgery stud-
95% CI, 0.86 to 0.97; P = 0.03; ­I2 = 0%) (Table 2 and Fig. 2). ies with 771 patients (9/388 [2.3%] vs. 18/383 [4.7%]; RR,
The primary outcome data were similar in the sensitivity 0.66; 95% CI, 0.31 to 1.44; P = 0.28; ­I2 = 24%) (Table 2,
Kotani et al. Critical Care (2024) 28:439 Page 6 of 14

None of the non-cardiac surgery studies reported base-

line vasopressor doses.

Secondary outcomes
Septic shock
The administration of non-adrenergic agents was associ-
ated with reduced risk of RRT (9 studies; RR, 0.68; 95%
CI, 0.57 to 0.81; ­I2 = 0%), reduced days of mechanical
ventilation (7 studies; MD, − 0.73 days; 95% CI, − 1.15
to − 0.31; ­I2 = 0%), reduced risk of atrial fibrillation (16
studies; RR, 0.65; 95% CI, 0.43 to 0.98; I­ 2 = 36%), increased
vasopressor-free days (8 studies; MD, 1.28; 95% CI, 0.54
to 2.03; I­ 2 = 25%), and reduced dose of noradrenaline (10
studies; SMD, − 1.17; 95% CI, − 1.75 to − 0.59; ­I2 = 93%).
No detectable differences were observed in days of ICU
stay or days of hospital stay (Table 3, Figs. S9–S15).

Cardiac surgery
Non-adrenergic vasopressors were associated with
reduced risk of RRT (4 studies; RR, 0.19; 95% CI, 0.07
to 0.48; I­2 = 0%), shortened days of ICU stay (6 stud-
ies; MD, − 0.66 days; 95% CI, − 1.22 to − 0.11; ­I2 = 73%),
Fig. 1 Flow chart of study selection shortened days of hospital stay (4 studies; MD, − 1.83
days; 95% CI, − 3.57 to − 0.09; ­I2 = 86%), reduced risk
of atrial fibrillation (6 studies; RR, 0.76; 95% CI, 0.67 to
Fig. 2B and C). Sensitivity analyses focused on stud- 0.87; ­I2 = 0%), increased vasopressor-free days (3 stud-
ies with low risk of bias were consistent with the main ies; MD, 0.29; 95% CI, 0.16 to 0.42; ­I2 = 0%), and reduced
analyses (Figs. S3–S4). The TSA for cardiac and non- dose of noradrenaline (4 studies; SMD, − 2.24; 95%
cardiac surgery settings showed the need for further CI, − 3.90 to − 0.59; ­I2 = 95%). No significant difference
RCTs to draw a definitive conclusion (required sample was observed in days of mechanical ventilation (Table 4,
size, 40,151 and 60,626, respectively). Visual inspection Figs. S16–S22).
of the funnel plot suggested potential small-study effects
in all the three settings (Figs. S5–S7). The timeframe to Non‑cardiac surgery
observe mortality at the longest follow-up is summa- Among secondary outcomes, non-adrenergic vasopres-
rized in Table S5a. A sensitivity analysis based on the sors were associated with shortened ICU stay (4 studies;
timeframe yielded similar findings with the main analysis MD, − 0.72 days; 95% CI, − 1.19 to − 0.24; ­I2 = 15%) and
(Table S5b). Results of the other sensitivity analyses for reduced dose of noradrenaline (4 studies; SMD, − 1.16;
mortality are summarized in Table S6. These sensitivity 95% CI, − 2.05 to − 0.28; ­I2 = 89%), while other outcomes
analyses did not materially change our findings. were not different (Table 5, Figs. S23–S28).
The effect modification by baseline vasopressor dose on The GRADE evaluation is shown in Table S7. Results of
mortality was explored in septic shock studies. 20 studies sensitivity analyses based on control treatment (placebo
contributed baseline vasopressor doses, and meta-regres- vs. adrenergic vasopressors) and baseline vasopressor
sion analysis showed no evident change in the mortality dose (high vs. low) are summarized in Tables S8 and S9.
risk ratio for a change in baseline vasopressor dose (Esti- These sensitivity analyses aligned with the main analysis.
mate 0.21 [95%CI, −0.15 to 0.58], tau = 0.05, ­I2 = 10.1%,
Fig. S8). As we applied continuity correction to one study Discussion
in the septic shock studies, we performed additional Key findings
analysis excluding the trial, which did not change the In this systematic review and meta-analysis of 51 RCTs,
findings. For cardiac surgery studies, only seven stud- we evaluated the effects of non-adrenergic vasopres-
ies reported baseline vasopressor doses, six of which sors on clinical outcomes in three distinct popula-
reported zero death in either or both groups. Given such tions. The use of non-adrenergic agents was associated
data do not provide reliable effect estimates, we did not with a reduced mortality risk in patients with septic
perform meta-regression analysis in this population. shock. It was also associated with reduced RRT use and
Kotani et al. Critical Care (2024) 28:439 Page 7 of 14

Table 2 Effects of non-adrenergic vasopressor administration on mortality

Group No. of studies Non-adrenergic agents Control Risk ratio (95% CI) P value I2

Septic shock 30 960/2232 (43%) 898/1890 (48%) 0.92 (0.86 to 0.97) 0.03 0%
Vasopressin 10 378/867 (44%) 392/838 (47%) 0.93 (0.85 to 1.02) 0.14 0%
Terlipressin 10 222/470 (47%) 254/485 (52%) 0.89 (0.77 to 1.02) 0.10 32%
Selepressin 2 247/591 (42%) 120/285 (42%) 0.98 (0.83 to 1.16) 0.84 0%
Angiotensin II 2 80/173 (46%) 91/168 (54%) 0.85 (0.69 to 1.06) 0.14 0%
Methylene blue 5 29/121 (24%) 37/104 (36%) 0.72 (0.49 to 1.04) 0.08 0%
Hydroxocobalamin 1 4/10 (40%) 4/10 (40%) 1.00 (0.34 to 2.93) 0.99 NA
Placebo as comparator 10 355/864 (41%) 249/554 (45%) 0.91 (0.81 to 1.03) 0.14 0%
Adrenergic agents as comparator 20 927/2101 (44%) 649/1336 (49%) 0.92 (0.86 to 0.98) 0.01 0%
Exclusion of studies assessing nitric oxide scaven- 24 927/2101 (44%) 857/1776 (48%) 0.92 (0.87 to 0.98) 0.008 0%
gers
Low risk of bias studies 9 771/1790 (43%) 671/1473 (46%) 0.95 (0.88 to 1.02) 0.14 0%
Cardiac surgery 11 34/410 (8.3%) 47/412 (11%) 0.82 (0.55 to 1.22) 0.32 12%
Vasopressin 5 32/248 (13%) 37/245 (15%) 0.89 (0.65 to 1.22) 0.48 0%
Angiotensin II 3 2/69 (2.9%) 2/74 (2.7%) 0.98 (0.15 to 6.38) 0.99 0%
Methylene blue 3 0/93 (0%) 8/93 (8.6%) 0.12 (0.02 to 0.95) 0.04 0%
Placebo as comparator 7 1/213 (0.5%) 14/211 (6.6%) 0.22 (0.06 to 0.77) 0.02 0%
Adrenergic agents as comparator 4 33/197 (17%) 33/201 (16%) 0.93 (0.68 to 1.28) 0.67 0%
Exclusion of studies assessing nitric oxide scaven- 8 34/317 (11%) 39/319 (12%) 0.90 (0.66 to 1.22) 0.48 0%
gers
Low risk of bias studies 3 25/208 (12%) 28/215 (13%) 0.91 (0.56 to 1.49) 0.71 0%
Non-cardiac surgery 10 9/388 (2.3%) 18/383 (4.7%) 0.66 (0.31 to 1.41) 0.28 0%
Vasopressin 2 0/45 (0%) 5/45 (11%) 0.09 (0.01 to 1.51) 0.09 NA
Terlipressin 5 1/164 (0.6%) 5/161 (3.1%) 0.34 (0.07 to 1.71) 0.19 0%
Methylene blue 3 8/179 (4.5%) 8/177 (4.5%) 1.00 (0.40 to 2.48) 0.99 0%
Placebo as comparator 8 9/343 (2.6%) 13/338 (3.8%) 0.77 (0.35 to 1.70) 0.52 0%
Adrenergic agents as comparator 2 0/45 (0%) 5/45 (11%) 0.09 (0.01 to 1.51) 0.09 NA
Exclusion of studies assessing nitric oxide scaven- 7 1/209 (0.5%) 10/206 (4.9%) 0.25 (0.06 to 0.998) 0.0497 0%
gers
Low risk of bias studies 5 3/220 (1.4%) 11/219 (5.0%) 0.44 (0.15 to 1.34) 0.15 0%
Abbreviations: CI = confidence interval; NA = not applicable

occurrence of atrial fibrillation both in patients with sep- the number of studies and sample size, while maintaining
tic shock and in those undergoing cardiac surgery. More- separate analyses according to study populations to take
over, we observed shortened ICU and hospital stays in into account the heterogeneity of treatment effects in dif-
cardiac surgery settings. Finally, noradrenaline dose was ferent settings.
decreased across all three settings.
Mortality
Relationship with previous literature In patients with septic shock, we observed a mortality
To our knowledge, this systematic review is the most reduction, which was mainly driven by vasopressin and
updated and comprehensive evaluation of the efficacy of methylene blue. This finding aligns with previous meta-
non-adrenergic vasopressors in various etiologies. Unlike analyses [9, 11, 71, 75]. However, it should be noted that
previous meta-analyses confined to specific vasopressors such significant mortality reduction was not confirmed
(vasopressin and its analogues [9, 10, 71–73], angiotensin when each non-adrenergic agent was analyzed separately.
II [74], or methylene blue [11, 75]) and specific popula- On the other hand, in cardiac and non-cardiac settings,
tions (septic shock [71, 74, 75], septic shock and cardiac similar to previous meta-analyses in surgical settings [72,
surgery [69, 70], cardiac surgery [72], or any surgery [73]), 73], mortality differences did not reach statistical sig-
our review included all non-adrenergic agents available in nificance. Nevertheless, the overall analysis and the vast
three different settings (septic shock, cardiac surgery, and majority of sensitivity analyses across three different pop-
non-cardiac surgery). This inclusive approach increased ulations found a pooled RR < 1 for mortality.
Kotani et al. Critical Care (2024) 28:439 Page 8 of 14

Fig. 2 Forest plot for mortality. A Septic shock. B Cardiac surgery. C Non-cardiac surgery

Secondary outcomes Implications for clinical practice and future research

Use of renal replacement therapy was significantly Our meta-analysis implies that the administration of
reduced in septic shock and in cardiac surgery, with a non-adrenergic vasopressors may reduce mortality in
similar point estimate in non-cardiac surgery settings. patients with septic shock. Since the annual sepsis-
Such benefits were mainly driven by vasopressin and related deaths are estimated to be 11 million worldwide
angiotensin II. The renal protection associated with vaso- [78], the relative risk reduction of 0.08 would potentially
pressin was consistent with a previous meta-analysis [76] translate into hundreds of thousands of lives saved every
and has been attributed to preferential post-glomerular year. Moreover, avoidance of RRT and facilitated libera-
vasoconstriction [76]. Angiotensin II seems to exert tion from mechanical ventilation would not only prevent
its renoprotective effects through its specific vasocon- various complications attributable to such interventions
strictive effects on efferent arterioles, since dilatation of but also save considerable healthcare resources and
efferent arterioles is a key pathological finding of sepsis- potentially improve long-term health-related quality of
associated AKI. Indeed, angiotensin II therapy might life.
confer survival benefits in refractory vasodilatory shock Another important implication is that non-adrenergic
patients on RRT [77]. vasopressors may reduce arrhythmia risks and noradren-
Duration of mechanical ventilation, ICU stay, and aline dosage across different settings. This observation
hospital stay appeared shortened with non-adrenergic suggests hemodynamic safety and efficacy for non-adren-
vasopressor administration. Given the increased vaso- ergic vasopressor strategy. Moreover, such observations
pressor-free days and reduced noradrenaline dose, it were consistent irrespective of drug type or comparator.
is plausible to think that adding a vasopressor with dis- From a research perspective, our meta-analysis
tinct mechanisms of action could restore blood pressure implies that phase III clinical trials dedicated to each
successfully while avoiding some of the complications agent and setting are warranted to draw a definitive
related to adrenergic vasopressors or preventing exces- answer. Moreover, precision approach is highly needed
sive fluid administration. These assumptions are sup- to identify which patient subgroups would most benefit
ported by the reduction of atrial fibrillation.
Kotani et al. Critical Care (2024) 28:439 Page 9 of 14

Table 3 Effects of non-adrenergic agents on secondary outcomes in septic shock settings

Secondary outcome No. of studies Non-adrenergic agents Control Risk ratio (95% CI) Mean difference/ P value I2
standardized mean
difference (95% CI)

Renal replacement 9 115/528 (22%) 170/509 (29%) 0.68 (0.57 to 0.81) < 0.0001 0%
therapy
Vasopressin 6 77/433 (18%) 112/414 (27%) 0.66 (0.51 to 0.84) 0.0009 0%
Terlipressin 2 35/85 (41%) 54/85 (64%) 0.48 (0.12 to 1.84) 0.28 54%
Hydroxocobalamin 1 3/10 (30%) 4/10 (40%) 0.75 (0.22 to 2.52) 0.64 NA
Days of mechanical 7 − 0.73 (− 1.15 to − 0.31) 0.0006 0%
ventilation
Vasopressin 1 − 1.00 (− 2.39 to 0.39) 0.16 NA
Terlipressin 2 − 1.00 (− 1.97 to − 0.03) 0.04 0%
Selepressin 1 − 0.20 (− 1.39 to 0.99) 0.74 NA
Methylene blue 3 − 0.72 (− 1.26 to − 0.17) 0.01 0%
Days of ICU stay 14 − 0.69 (− 1.49 to 0.12) 0.10 52%
Vasopressin 6 − 0.31 (− 2.08 to 1.47) 0.74 75%
Terlipressin 4 − 0.01 (− 1.12 to 1.11) 0.99 0%
Selepressin 1 − 0.70 (− 2.02 to 0.62) 0.30 NA
Methylene blue 3 − 1.62 (− 2.95 to − 0.30) 0.02 19%
Days of hospital stay 6 − 0.73 (− 3.42 to 1.96) 0.60 64%
Vasopressin 4 − 2.24 (− 5.69 to 1.20) 0.20 64%
Terlipressin 2 2.19 (− 0.29 to 4.67) 0.08 0%
Atrial fibrillation 16 82/813 (10%) 120/794 (15%) 0.65 (0.43 to 0.98) 0.04 36%
Vasopressin 8 45/461 (10%) 78/449 (17%) 0.40 (0.19 to 0.83) 0.01 55%
Terlipressin 5 13/150 (8.7%) 20/156 (13%) 0.80 (0.33 to 1.96) 0.63 27%
Selepressin 1 0/29 (0%) 1/21 (4.8%) 0.24 (0.01 to 5.72) 0.38 NA
Angiotensin II 2 24/173 (14%) 21/168 (13%) 1.16 (0.49 to 2.77) 0.74 10%
Vasopressor-free days 8 1.28 (0.54 to 2.03) 0.0007 25%
at day 28
Vasopressin 1 0.70 (− 1.81 to 3.21) 0.55 NA
Terlipressin 3 1.93 (1.43 to 2.43) < 0.0001 0%
Selepressin 1 − 0.40 (− 2.19 to 1.39) 0.66 NA
Methylene blue 2 0.94 (− 0.60 to 2.47) 0.23 0%
Hydroxocobalamin 1 − 1.40 (− 20.95 to 18.15) 0.89 NA
Dose of noradrenaline* 10 − 1.17 (− 1.75 to − 0.59) < 0.0001 93%
Vasopressin 4 − 1.29 (− 1.82 to − 0.76) < 0.0001 60%
Terlipressin 3 − 2.27 (− 6.63 to 2.08) 0.31 98%
Angiotensin II 2 − 0.39 (− 1.22 to 0.43) 0.35 69%
Hydroxocobalamin 1 − 0.65 (− 1.55 to 0.26) 0.16 NA
*
Indicates that the treatment effect is expressed with a standardized mean difference and 95% confidence interval
ICU, intensive care unit; NA, not applicable

from a non-adrenergic vasopressor [79]. For example, non-adrenergic agents are considered too expensive or
hyperreninemia might identify patients in whom angi- in resource-limited settings.
otensin II might increase the chance of survival [80].
Such personalized vasopressor therapy, rather than a Strengths and limitations
one-size-fits-all strategy, should also be evaluated in The strengths of this meta-analysis include the pre-reg-
future RCTs. Furthermore, cost-effectiveness analy- istered protocol, a statistical analysis which accounted
sis would help decision making in countries where for clinical heterogeneity, and comprehensive approach
Kotani et al. Critical Care (2024) 28:439 Page 10 of 14

Table 4 Effects of non-adrenergic agents on secondary outcomes in cardiac surgery settings

Secondary outcome No. of Non-adrenergic agents Control Risk ratio (95% CI) Mean difference/ P value I2
studies standardized mean
difference (95% CI)

Renal replacement 4 4/236 (1.7%) 26/243 (11%) 0.19 (0.07 to 0.48) 0.0005 0%
therapy
Vasopressin 1 4/149 (2.7%) 21/151 (14%) 0.19 (0.07 to 0.55) 0.002 NA
Angiotensin II 2 0/59 (0%) 3/64 (4.7%) 0.16 (0.01 to 3.02) 0.22 NA
Methylene blue 1 0/28 (0%) 2/28 (7.1%) 0.20 (0.01 to 3.99) 0.29 NA
Days of mechanical venti- 2 − 0.12 (− 0.61 to 0.36) 0.62 86%
lation (vasopressin only)
Days of ICU stay 6 − 0.66 (− 1.22 to − 0.11) 0.02 73%
Vasopressin 3 − 0.50 (− 1.41 to 0.41) 0.28 83%
Angiotensin II 2 − 1.04 (− 2.00 to − 0.07) 0.03 0%
Methylene blue 1 − 0.90 (− 1.26 to − 0.54) < 0.0001 NA
Days of hospital stay 4 − 1.83 (− 3.57 to − 0.09) 0.04 86%
Vasopressin 2 − 2.30 (− 6.22 to 1.62) 0.25 95%
Angiotensin II 1 0.20 (− 2.30 to 2.70) 0.88 NA
Methylene blue 1 − 2.30 (− 3.03 to − 1.57) < 0.0001 NA
Atrial fibrillation 6 125/292 (43%) 169/295 (57%) 0.76 (0.67 to 0.87) < 0.0001 0%
Vasopressin 1 112/190 (59%) 148/188 (78%) 0.76 (0.67 to 0.87) < 0.0001 0%
Angiotensin II 2 6/59 (10%) 8/64 (13%) 0.90 (0.36 to 2.26) 0.82 0%
Methylene blue 1 7/43 (16%) 13/43 (30%) 0.55 (0.14 to 2.21) 0.40 60%
Vasopressor-free days at 3 0.29 (0.16 to 0.42) < 0.0001 0%
day 28
Vasopressin 2 0.28 (0.15 to 0.41) < 0.0001 0%
Angiotensin II 1 1.00 (− 0.34 to 2.34) 0.14 NA
Dose of noradrenaline* 4 − 2.24 (− 3.90 to − 0.59) 0.008 95%
(vasopressin only)
*
Indicates that the treatment effect is expressed with a standardized mean difference and 95% confidence interval
ICU, intensive care unit; NA, not applicable

regarding non-adrenergic vasopressor types and clinical or studies published in high-impact journals did not
indications. find a statistically significant mortality reduction in any
We acknowledge several limitations. First, we aggre- setting assessed. Nonetheless, the point estimates were
gated data of studies using different non-adrenergic similar to the overall results, suggesting potential posi-
agents and comparators. Furthermore, there was consid- tive effects on survival. Fourth, there is intense debate on
erable heterogeneity in the way non-adrenergic agents whether nitric oxide scavengers are considered vasopres-
were initiated, titrated, weaned, and terminated among sors or not. However, these agents have gained growing
the included studies. However, we performed sensitiv- attention as a rescue therapy in refractory vasodilatory
ity analyses to evaluate their impacts on the effect size. shock. Furthermore, sensitivity analyses assessing these
Moreover, it was reassuring that none of the sensitivity agents separately or excluding them confirmed the find-
analyses found an increased mortality risk in the non- ings of the main analysis, suggesting that our findings are
adrenergic vasopressor group. Second, mortality was likely robust. Fifth, standard of care outside use of vaso-
reported at different time points. As a previous work pressors was not always well-defined. However, thanks to
showed that this approach does not affect the overall the randomized design, it seems plausible to assume that
treatment effects in critical care settings [81], we synthe- both groups were balanced regarding care outside the
sized mortality data at different time points. Moreover, intervention of interest and that this limitation had little
a sensitivity analysis based on the timing found consist- influence on the estimated effects. Sixth, the publication
ent results with the main analysis. Third, only one-third year of the included studies spanned 25 years. Complete
of the included studies were judged to be at low risk of data extraction was not always feasible in old studies.
bias or published in well-recognized journals. As a result, Standard intensive care may change over time. However,
sensitivity analyses focused on such high-quality studies a sensitivity analysis according to the publication year
Kotani et al. Critical Care (2024) 28:439 Page 11 of 14

Table 5 Effects of non-adrenergic agents on secondary outcomes in non-cardiac surgery settings

Secondary outcome No. of Non-adrenergic agents Control Risk ratio (95% CI) Mean difference/ P value I2
studies standardized mean
difference (95% CI)

Renal replacement 3 2/83 (2.4%) 3/82 (3.7%) 0.74 (0.15 to 3.74) 0.71 0%
therapy
Vasopressin 1 0/30 (0%) 0/30 (14%) Not estimable NA NA
Terlipressin 2 2/53 (3.8%) 3/52 (5.8%) 0.74 (0.15 to 3.74) 0.71 0%
Days of mechanical ven- 3 − 0.26 (− 1.72 to 1.19) 0.72 74%
tilation (terlipressin only)
Days of ICU stay 4 − 0.72 (− 1.19 to − 0.24) 0.003 15%
Terlipressin 3 − 0.56 (− 1.29 to 0.17) 0.14 34%
Methylene blue 1 − 0.90 (− 1.53 to − 0.27) 0.005 NA
Days of hospital stay 4 − 0.71 (− 2.28 to 0.87) 0.38 35%
Vasopressin 1 − 0.30 (− 1.30 to 0.70) 0.59 NA
Terlipressin 2 − 1.41 (− 5.25 to 2.43) 0.47 59%
Methylene blue 1 0.70 (− 3.56 to 4.96) 0.75 NA
Atrial fibrillation 4 5/240 (2.1%) 8/238 (3.4%) 0.65 (0.13 to 3.32) 0.61 38%
Vasopressin 1 0/30 (0%) 0/30 (14%) Not estimable NA NA
Terlipressin 2 5/86 (5.8%) 4/84 (4.8%) 1.22 (0.32 to 4.70) 0.78 0%
Methylene blue 1 0/30 (0%) 0/30 (14%) 0.11 (0.01 to 2.04) 0.14 NA
Dose of noradrenaline* 3 − 1.38 (− 2.67 to − 0.09) 0.04 93%
Terlipressin 1 − 0.46 (− 0.96 to 0.04) 0.07 NA
Methylene blue 2 − 1.94 (− 4.65 to 0.77) 0.16 96%
*
Indicates that the treatment effect is expressed with a standardized mean difference and 95% confidence interval
ICU, intensive care unit; NA, not applicable

did not find heterogeneity in effects on mortality. Finally, PRISMA Preferred reporting items for systematic reviews and meta-analyses
RCT​ Randomized controlled trial
most studies failed to clarify which noradrenaline for- RR Relative risk
mulation was used and whether they reported the dose TSA Trial sequential analysis
of noradrenaline base, which could result in inconsistent
dosage comparison. Future trials should use a uniform Supplementary Information
dose reporting with noradrenaline base [82]. The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s13054-​024-​05212-7.

Supplementary Material 1.
Conclusions
Use of non-adrenergic vasopressors was associated with
a mortality reduction in patients with septic shock, Acknowledgements
The authors wish to appreciate all the patients and investigators of the
though subgroup analyses of individual non-adrenergic included studies.
vasopressors did not show a significant survival benefit.
No significant mortality difference was observed in car- Author contributions
YK, ABe, FD, ABo, PMW, TF, AKK, GL, and RB conceived the study. YK, ABe, FD,
diac or non-cardiac surgery settings. Moreover, in both ABo, and GL designed the search strategy and did the literature search. YK,
septic shock and cardiac surgery patients, non-adrener- ABo, TF, and GL did the statistical analysis. YK, ABe, FD, PMW, TF, AKK, GL, and
gic agents were associated with reduced RRT use and less RB wrote the initial protocol. YK wrote the initial manuscript draft. All authors
shared the study data, gave a critical appraisal of the protocol, provided crucial
atrial fibrillation both in patients with septic shock and revisions, and approved the final manuscript.
in those undergoing cardiac surgery. Finally, across all
three settings, noradrenaline dose was decreased. These Funding
Department fund only.
findings justify the conduct of phase III trials comparing
these agents to usual care based on noradrenaline alone. Availability of data and materials
We collected the summary data from published randomized trials. This
Abbreviations published article and its supplementary files include all the data generated or
CI Confidence interval analyzed for this study. Further information is available from the correspond-
ICU Intensive care unit ing authors upon reasonable request.
Kotani et al. Critical Care (2024) 28:439 Page 12 of 14

Declarations 8. Belletti A, Musu M, Silvetti S, Saleh O, Pasin L, Monaco F, et al. Non-

adrenergic vasopressors in patients with or at risk for vasodilatory shock.
Ethics approval and consent to participate A systematic review and meta-analysis of randomized trials. PLoS ONE.
Not applicable. 2015;10:e0142605.
9. McIntyre WF, Um KJ, Alhazzani W, Lengyel AP, Hajjar L, Gordon AC, et al.
Consent for publication Association of vasopressin plus catecholamine vasopressors vs catecho-
Not applicable. lamines alone with atrial fibrillation in patients with distributive shock: a
systematic review and meta-analysis. JAMA. 2018;319:1889–900.
Competing interests 10. Nagendran M, Russell JA, Walley KR, Brett SJ, Perkins GD, Hajjar L, et al.
YK has received consultancy fees from Viatris. PMW previously received Vasopressin in septic shock: an individual patient data meta-analysis of
consultant fees from Viatris. AKK received consulting fees from Medtronic, randomised controlled trials. Intensive Care Med. 2019;45:844–55.
Edwards Life Sciences, Philips Research North America, Hillrom, GE Healthcare, 11. Pruna A, Bonaccorso A, Belletti A, Turi S, Di Prima AL, D’amico F, et al.
Potrero Medical, Viatris Pharma, Trevena Pharma, Fifth Eye Inc., Pharmazz Inc., Methylene blue reduces mortality in critically ill and perioperative
Retia Medical and Caretaker Medical. He is also funded with a Wake Forest patients: a meta-analysis of randomized trials. J Cardiothorac Vasc Anesth.
Clinical and Translational Science Institute (CTSI) grant on renin dysfunction 2023. https://​doi.​org/​10.​1053/j.​jvca.​2023.​09.​037.
in septic shock. GL has received speaker fees from Medis, Paion, and Viatris 12. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al.
and consultancy fees from Paion and Viatris. RB has received grants and con- Angiotensin II for the treatment of vasodilatory shock. N Engl J Med.
sultancy fees from La Jolla Pharmaceuticals, Paion AG, and Viatris. The other 2017;377:419–30.
authors have no competing interests. 13. Sadjadi M, von Groote T, Weiss R, Strauß C, Wempe C, Albert F, et al. A
pilot study of renin-guided angiotensin-ii infusion to reduce kidney stress
Author details after cardiac surgery. Anesth Analg. 2024. https://​doi.​org/​10.​1213/​ANE.​
1
Department of Intensive Care Medicine, Kameda Medical Center, 929 00000​00000​006839.
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