Table 1 Table showing population, intervention, control, and endothelial assessment of the included studies

(1) Septic shock

 Macdonald et al. (2023) [19]

Randomised controlled trial (biomarkers sub-study of the restricted fluid resuscitation in sepsis-associated hypotension, REFRESH, clinical trial)

Septic shock (sepsis-3 criteria) in adults over 18 years

Treatment (restricted fluid arm—early vasopressor and 250-mL intravenous fluid if MAP < 65 mmHg) versus control (usual care comprising initial fluid boluses 1000 mL and additional 500 mL, if required and later introduction of vasopressors)

95 patients randomised: restricted fluid arm (n = 49) versus controls/usual care (n = 46)

Syndecan-1

Syndecan-4

Hyaluronan

heparan sulphate

ICAM

VCAM

VEGFR-1

E-selectin

-

 Fernández-Sarmiento et al. (2023) [20]

Single-centre, prospective cohort study

Septic shock in children from 1 month to 18 years old

N/A; standard resuscitation protocol for management of haemodynamic instability in paediatric septic shock patients (20 mL/kg) comparing balanced or unbalanced crystalloids

106 patients observed (divided into two groups): unbalanced fluid (0.9% saline), n = 58, and balanced fluids (lactated Ringer’s, Hartmann or Plasma-Lyte 148 solution), n = 48

Syndecan-1

ANGPT2

GlycoCheck™ analysis of the perfused boundary region (PBR)

 Saoraya et al. (2021a) [21]

Randomised controlled trial (post hoc analysis of the limited infusion rates on syndecan-1 Shedding, LIFE3S, clinical trial)

Septic shock (Sepsis-3 criteria) in adults over 18 years

Treatment (limited rate 10 mL/kg/h Ringer’s lactate) versus control (standard rate 30 mL/kg/h bolus or maximum rate of 2000 mL/h in the main LIFE3S trial)

95 participants (not divided into sub-groups in the post hoc analysis)

Syndecan-1

-

-

 Saoraya et al. (2021b) [22]

Randomised controlled trial

Septic shock in adults ≥ 18 years

Initial bolus lactated Ringer’s solution

Standard rate group (30 mL/kg/h, max. 2000 mL/h) vs limited-rate group (10 mL/kg/h)

96 patients randomised: standard-rate group (n = 48) versus limited-rate group (n = 48)

Syndecan-1

-

-

 Hippensteel et al. (2019) [23]

Observational cohort study (based on patients in the Protocolized Care for Early Septic Shock, ProCESS, clinical trial)

Septic shock in adults ≥ 18 years

ProCESS cohort (n = 56)

Syndecan-1

sTM

sFLT-1

tPA

ANGPT2

-

 Rovas et al. (2019) [24]

Prospective observational cross-sectional study

Septic shock in children and adults

Treatment standard resuscitation (Sepsis-3 criteria of septic shock) versus healthy controls

40 participants observed (divided into two groups): septic shock (n = 30) and healthy controls, adults only (n = 10)

Syndecan-1

-

GlycoCheck™ analysis of the perfused boundary region (PBR)

 Wu et al. (2017) [25]

Prospective observational case–control study of post-operative patients

Septic shock in adults who had undergone open chest surgery

N/A; standard resuscitation protocol for septic shock patients

26 patients who had undergone thoracotomy: patients who had been admitted to ICU with severe sepsis post-op (n = 15) versus patients who had recovered (n = 11)

Syndecan-1

-

-

 Bourcier et al. (2017) [26]

Prospective observational cohort study

Septic shock in patients aged 18 years or more

Standard resuscitation for septic shock using intravenous volume expansion and vasopressor treatment

37 participants observed (divided into two groups): with septic shock (n = 26) and without septic shock (n = 11)

-

-

Laser Doppler flowmetry

 Meng et al. (2016) [27]

Non-blinded randomised controlled trial

Septic shock-induced ARDS in patients over 18 years

Treatment (early initiated continuous venovenous hemofiltration, ECVVH) versus control (non-ECVVH)

51 participants (divided into two-groups): ECVVH (n = 24) and non-ECVVH (n = 27)

-

sE-selectin

-

 Müller et al. (2016) [28]

Observational cohort study (based on patients in the Scandinavian Starch for Severe Sepsis/Septic Shock, 6S, clinical trial)

Septic shock in patients over 18 years

Treatment (trial of hydroxyethyl starch 130/0.4, HES) versus control (Ringer’s acetate)

208 participants (divided into two groups): HES (n = 106) and Ringer’s acetate (n = 102)

Syndecan-1

sTM

sCD40L

Protein C

tPA

PAI-1

-

 Katundu et al. (2016) [29]

Prospective observational cohort study

Septic shock in adults (no age specified) admitted to ICU and surviving to 7 days

N/a (no vitamin C was administered during the study period—instead, plasma sampling was done to assess vitamin C levels and correlate with other outcomes)

25 participants (i.e. 15 survivors and 10 non-survivors)

-

sVCAM-1

sE-selectin

-

(2) Trauma and haemorrhagic shock

 Peng et al. (2020) [30]

Observational cohort study (based on patients in the Fibrinogen in the initial Resuscitation of Severe Trauma, FiiRST, clinical trial)

Haemorrhagic shock in adult trauma patients over 18 years

Treatment (fibrinogen concentrate, FC 6 g) versus placebo (normal saline)

45 participants (divided into wo-groups for the sub-study): FC (n = 21) and placebo (n = 24)

Syndecan-1

sTM

sE-selectin

-

 Lopez et al. (2020) [31]

Prospective observational cohort study

Haemorrhagic shock in patients over 16 years

All participants received FFP treatment for haemorrhagic shock resuscitation

125 participants (divided into two groups for the analysis): normal ATIII (n = 50) versus ATIII deficient (n = 75)

Syndecan-1

ATIII

-

 Welling et al. (2020) [32]

Retrospective observational cohort study

Endotheliopathy of trauma (EoT) and shock due to burns in patients over 16 years

Treatment volume replacement resuscitation for burns (i.e. using the modified Brooke formula 2 mL/kg/total body surface area) versus non-burn trauma controls (receiving volume replacement resuscitation of Ringer’s lactate and blood transfusion within 24 h)

458 participants (divided into two large groups): burn trauma (n = 68) and non-burn trauma (n = 390)

Syndecan-1

sTM

-

 Gruen et al. (2020) [33]

Observational cohort study (based on patients in the Prehospital Air Medical Plasma, PAMPer, cluster randomised clinical trial)

Haemorrhagic shock in pre-hospital air medical transport patients aged between 18 and 90 years

Treatment (two units of plasma given pre-hospital and then standard resuscitation) versus controls (standard treatment for haemorrhagic shock during air medical transport)

405 participants (divided into two groups): treatment (n = 188) and controls (n = 217)

Syndecan-1

sTM

VGEF

-

 Naumann et al. (2019) [34]

Prospective observational cohort study (based on the observational pilot study of the effects of traumatic haemorrhagic shock and resuscitation on the microcirculation, MICROSHOCK study)

Traumatic injury and haemorrhagic shock in patients over 18 years

Observational study with no test treatment, all patients received the standard resuscitation for haemorrhagic shock

20 participants observed with no sub-groups

Syndecan-1

sTM

Incident dark field (IDF) assessment of microcirculatory flow

 Naumann et al. (2018) [35]

Prospective observational cohort study (based on the Brain Biomarkers After Trauma Study, BBATS)

Haemorrhagic shock and endotheliopathy of trauma (EoT) in patients over 16 years

Pre-hospital tranexamic acid (TXA) for trauma patients

110 participants (divided into two large groups): trauma (n = 91) and non-trauma controls (n = 19)

Syndecan-1 (CD138)

sTM (CD141)

-

 Gonzalez Rodriguez et al. (2018) [36]

Prospective observational cohort study

Endotheliopathy of trauma (EoT) in adults with traumatic brain injury (TBI) and polytrauma

Standard resuscitation for shock

360 participants (divided into two large groups): trauma (n = 331) and healthy controls (n = 29)

Syndecan-1

sTM

-

 Stensballe et a. (2018) [37]

Randomised controlled trial (vasculopathic Injury and plasma as endothelial rescue-OCTAplasLG, VIPER-OCTA, trial)

Haemorrhagic shock in patients over 18 years

Treatment group (detergent-treated pooled plasma) versus control group (standard fresh frozen plasma, FFP)

44 participants (divided into two groups): OctaplastLG treatment (n = 23) and FFP controls (n = 21)

Syndecan-1

sTM

sE-selectin

sVE-cadherin

-

 Turk et al. (2014) [38]

Randomised controlled trial

Endotheliopathy of trauma (EoT) in patients aged 18 years to 50 years with partial- or full-thickness burns covering 20–70% of the body surface area

Standard resuscitation and treatment for burns based on Parkland’s formula

60 participants (divided into two groups): burn patients (n = 30) and controls (n = 30)

-

-

Indirect assessment of the microcirculatory function using FMD after occlusion of the brachial artery

 Tang et al. (2013) [39]

Prospective observational cohort study

Endotheliopathy of trauma (EoT) in patients older than 18-years

N/a (standard resuscitation practices for trauma patients)

82 participants (divided into two groups based on presence of coagulopathy): coagulopathy (n = 37) versus non-coagulopathy (n = 45)

-

von Willebrand factor (vWF) antigen

-

 Junger et al. (2012) [40]

Randomised controlled trial (a priori sub-group analysis within the Resuscitation Outcomes Consortium, ROC, clinical trial)

Haemorrhagic shock in patients older than 15 years

(1) 7.5% hypertonic saline (HS)

(2) 7.5% hypertonic saline + 6% dextran 70 (HSD)

(3) 0.9% normal saline (control)

34 participants (divided into the three treatment groups): HS (n = 9) versus HSD (n = 8) versus control (n = 17)

-

sI-CAM-1

sV-CAM-1

sE-selectin

sP-selectin

-

(3) Cardiogenic shock

 Meyer et al. (2020) [41]

Randomised controlled trial (endothelial dysfunction in resuscitated cardiac arrest, ENDO-RCA, sub-trial within the targeted temperature management, TTM, trial)

Cardiogenic shock in patients over 18 years with out-of-hospital cardiac arrest (OHCA), GCS < 8, and sustained ROSC for > 20 min

Treatment (iloprost infusion, 48 h of 1 ng/kg/min) versus placebo (0.9% saline infusion)

46 participants (divided into two groups for the ENDO-RCA sub-study): iloprost infusion (n = 13) and placebo (n = 33)

Syndecan-1

sTM

sE-selectin, sVEGF, VEcad

-

 Grand et al. (2020) [42]

Randomised controlled trial (ENDO-RCA, sub-trial within the TTM, trial)

Cardiogenic shock in patients over 18 years with out-of-hospital cardiac arrest (OHCA), GCS < 8, and sustained ROSC for > 20 min

Treatment (higher mean arterial pressure target of 72 mmHg, MAP 72) versus control (target mean arterial pressure of 65 mmHg, MAP65)

50 participants (divided into two groups for the sub-study): MAP72 (n = 24) and MAP65 (n = 26)

-

sTM

-

 Ohbe et al. (2017) [43]

Prospective observational cohort study

Cardiogenic shock in patients aged over 20 years

Resuscitation for out-of-hospital cardiac arrest (R-OHCA)

28 participants observed (classified into two groups based on their 28-day survival): non-survivors (n = 13) and survivors (n = 21)

-

sTM

vWF antigen

-

 Bro-Jeppesen et al. (2017) [44]

Prospective observational cohort study (based on the TTM trial)

Cardiogenic shock in patients over 18 years with out-of-hospital cardiac arrest (OHCA), GCS < 8, and sustained ROSC for > 20 min

24-h target temperature management of either 33 °C (TTM33) or 36 °C (TTM36)

163 participants (divided into two groups for the analysis): TTM33 (n = 82) and TTM36 (n = 81)

Syndecan-1

sTM

sE-selectin

sVE-cadherin

-

 Bro-Jeppesen et al. (2016) [45]

Prospective observational cohort study (based on the TTM trial)

Cardiogenic shock in patients over 18 years with out-of-hospital cardiac arrest (OHCA), GCS < 8, and sustained ROSC for > 20 min

24-h target temperature management of either 33 °C (TTM33) or 36 °C (TTM36)

163 participants (divided into two groups for the analysis): TTM33 (n = 82) and TTM36 (n = 81)

Syndecan-1

sTM

sE-selectin

sVE-cadherin

-

 Omar et al. (2013) [46]

Prospective observational cohort study

Cardiogenic shock and septic shock in adults ≥ 18 years

N/a (standard resuscitation practices for cardiogenic and septic shock patients)

55 participants (divided into three groups): cardiogenic shock (n = 30), sepsis (n = 16), and controls (n = 9)

-

sE-selectin

V-CAM

I-CAM

sVEGF

Microvascular flow index, MFI

(4) Others

 Monteiro et al. (2021) [47]

Prospective observational cohort study (based on the Randomised Evaluation of Sedation Titration for Respiratory Failure, RESTORE trial)

Acute respiratory failure (PALICC definition of ARDS) in patients aged 2 weeks to 17 years

Implementation of a nurse-implemented, goal-directed sedation protocol versus standard of care in the main RESTORE trial

432 participants (not divided into sub-groups in the post hoc analysis)

-

sTM

-

 Case et al. (2020) [48]

Case report

Systemic capillary leak syndrome (SCLS) in a 63-year-old man who developed profound shock post-resuscitation

Crystalloid volume resuscitation

-

-

-

Systemic capillary leak and impaired microvascular endothelial function

 Bøe et al. (2018) [49]

Case report

Systemic capillary leak syndrome (SCLS) in a 49-year-old woman with an upper respiratory tract infection who developed profound shock post-resuscitation

Crystalloid volume resuscitation

-

Syndecan-1 (CD138) and heparan sulphate

-

-

 Somasetia et al. (2014) [50]

Randomised controlled trial

Endothelial dysfunction in dengue shock syndrome in children aged 2 years to 14 years

Treatment (hypertonic sodium lactate, HSL) versus control (Ringer’s lactate)

46 participants (divided into two groups): HSL (n = 24) and Ringer’s lactate (n = 22)

-

sVCAM-1

-