Table 2.
Human randomized controlled trials targeting endothelium and microcirculation in sepsis and septic shock.
| Tested intervention | Study | Study design | Microcirculatory assessment | Primary outcome | Results/status |
|---|---|---|---|---|---|
| Oxidative stress | |||||
| Vitamin C | The Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock Trial (VITAMINS) (34) |
216 patients High dose Vitamin C (6 g/d), Thiamine (400 mg/d) and Hydrocortisone (200 mg/d) vs. Hydrocortisone alone |
NA | Vasopressor-free days | Not significant |
| Hydrocortisone, vitamin C, and thiamine for the treatment of sepsis and septic shock (HYVCTTSSS) [NCT03258684] |
80 patients Vitamin C 1.5 g/6 h, hydrocortisone 50 mg/6 h and thiamine 200 mg/12 h vs. saline |
NA | Hospital mortality | Completed Awaiting results | |
| Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in Sepsis (ORANGES) [NCT03422159] |
140 patients Vitamin C (4 g/d), Hydrocortisone (200 mg/d), thiamine (400 mg/d) for 4 days vs. placebo |
NA | – Time to vasopressor independence – Change in SOFA score at day 4 |
Completed Awaiting results | |
| Vitamin C and Thiamine in Sepsis [NCT03592277] |
120 patients Vitamin C (4 g/d) and Thiamine (400 mg/d) vs. placebo |
NA | 60-day mortality | Recruiting | |
| Ascorbic acid, Corticosteroids, and thiamine in sepsis (ACTS) trial [NCT03389555] |
205 patients Vitamin C 1.5 g/6h, Thiamine 100 mg/6 h and Hydrocortisone 50 mg/6 h for 4 days vs. placebo |
NA | SOFA score at 72 h | Completed, not published | |
| Clinical trial of antioxidant therapy in patients with septic shock [NCT03557229] |
131 patients Vitamin C 4g/d, vitamin E 1,200 UNT/d, N-acetyl cysteine 2,400 mg/d and melatonin 50 mg/d for 5 days vs. placebo |
Oxidative stress and inflammatory biomarker | SOFA score at day 7 | Not yet recruiting | |
| Evaluation of Hydrocortisone, Vitamin C and Thiamine for the Treatment of Septic Shock (HYVITS) [NCT03380507] |
106 patients Vitamin C 6 g/d, hydrocortisone 200 mg/d and thiamine 400mg/d vs. placebo |
NA | 60-day mortality | Terminated due to futility | |
| Ascorbic acid and thiamine effect in septic shock (ATESS) [NCT03756220] |
116 patients Vitamin C 100 mg/kg/d, Thiamine 400 mg/d vs. placebo |
NA | Change in SOFA score at 72 h | Completed Awaiting results | |
| Para-tyrosine | Efficacy of Para-Tyrosine Supplementation on the Survival and Clinical Outcome in Patients With Sepsis [NCT03278730] |
296 patients Para-tyrosine 2 g x 3/d oral or enteral for 7 days vs. placebo |
NA | 30-day mortality | Not yet recruiting |
| Melatonin | Efficacy of Melatonin in Patients With Severe Sepsis or Septic Shock [NCT01858909] |
110 patients 30 mg/12 h 28 days vs. placebo |
Oxidative stress and inflammatory biomarkers | 28-day mortality and organ dysfunction | Unknown status |
| Effects of Melatonin as a Novel Antioxidant and Free Radicals Scavenger in Neonatal Sepsis [NCT03295162] |
55 patients Melatonin 10 mg x 2/days vs. placebo |
NA | Free radicals scavenge | Awaiting results | |
| Inflammation | |||||
| Evolocumab (anti-PSCK9) | Evolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study) [NCT03869073] |
36 patients Low dose (420 mg) vs. high dose (840 mg) vs. placebo in 3 SC injections |
NA | Decrease bacteria LPS levels | Recruiting |
| Atorvastatin | Study the Impact of Statins in Septic Shock [NCT02681653] |
80 patients Atorvastatin 40 mg/d or placebo for 7 days |
Cytokines | 28-day mortality | Awaiting results |
| Nitric oxide/Vasoreactivity | |||||
| NOS inhibitor | Nitric oxide synthase inhibitor 54C88 in patients with septic shock (35) |
797 patients NOS inhibitor vs. placebo for 7 or 14 days |
NA | Mortality | Increased mortality in intervention group |
| NO | Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis (36) |
49 patients Inhaled NO 40 parts per million for 6 h vs. placebo |
Sublingual microcirculation using sidestream dark field videomicroscopy | – Change in SOFA score – Change in sublingual microcirculation flow index |
Not significant |
| Nitroglycerin | Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial (37) |
70 patients Nitroglycerin at 4 mg/h for 30 min then 2 mg/h for 24 h or placebo |
Sublingual microcirculatory blood flow using SDF imaging | Sublingual microcirculatory flow index | No significant differences |
| Methylene blue | Effect of methylene blue on hemodynamic and metabolic response in septic shock patients (38) |
64 patients Methylene blue vs. placebo |
NA | Septic shock resolution | Unknown status |
| Methylene Blue in Early Septic Shock (SHOCKEM-Blue) [NCT04446871] |
91 patients I.V. infusion of 100mg of methylene blue for 6 hours x3 doses a day vs. placebo |
NA | Vasopressor requirement | Awaiting results | |
| Methylene Blue and Microcirculation in Septic Shock [NCT04295993] |
32 patients Methylene blue 2 mg/kg over 10 min vs. standard of care |
Sublingual microcirculation | Microvascular flow index at 6 hours | Not yet recruiting | |
| Ilomedin | Ilomedin in Septic Shock With Persistent Microperfusion Defects (I-MICRO) [NCT03788837] |
235 patients I.V. ilomedin at 0.5 ng/kg/min with increments of 0.5 ng/kg/min every 30 min up to a maximum of 1.5 ng/kg/min for 48 h vs. placebo |
Mottling, cutaneous laser Doppler, NIRS, videomicroscopy, tissular PCO2, perfusion index | Change in SOFA score at day 7 | Recruiting |
| Co-administration of Iloprost and Eptifibatide in Septic Shock Patients (CO-ILEPSS) [NCT02204852] |
18 patients Iloprost 1 ng/kg/min + Eptifibatide 0.5 ug/kg/min for 48 h continuously vs. placebo |
Biomarkers of inflammation, coagulation, adhesion molecules | Biomarkers of endothelial activation and dysfunction | Awaiting results | |
| Infusion of Prostacyclin (Iloprost) vs. Placebo for 72-hours in Patients With Septic Shock Suffering From Organ Failure (COMBAT-SHINE) [NCT04123444] |
380 patients Continuous infusion of 1 ng/kg/min for 72 h vs. placebo |
NA | Change in SOFA score | Recruiting | |
| Citrulline | Citrulline in Severe Sepsis [NCT01474863] |
72 patients Low dose vs. high dose vs. placebo |
NA | Vasopressor dependency index | Not published |
| Effect of Citrulline on the Clinical and Biochemical Evolution of Patients With Sepsis. (CITRUSEP) [NCT02370030] |
176 patients Citrulline malate 10g/day for 7 days vs. placebo |
NA | Multiple organ failure | Unknown status | |
| Coagulation/hemostasis | |||||
| Thrombomodulin | Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy (SCARLET study) |
800 patients I.V. thrombomodulin at 0.06 mg/kg/d vs. placebo for 6 days |
Biomarkers | 28-day mortality | Not significant |
| Protein C | Drotrecogin Alfa (Activated) in Adults with Septic Shock (39) |
1,697 patients Drotrecogin alfa or placebo for 96 hours |
NA | 28-day mortality | Not significant |
| Human protein C concentrates in patients with sepsis and septic shock [NCT01411670] |
60 patients with protein C activity <60% Human Protein C concentrate of activated protein C vs. placebo |
Sublingual microcirculatory blood flow | Sublingual microcirculatory blood flow assessed by SDF | Awaiting results | |
| Modulation of vasoreactivity in septic shock: impact of recombinant protein C [NCT02885168] |
30 patients Recombinant activated protein C during 96 h vs. placebo |
Near-infrared spectroscopy with reactive hyperemia | Vascular reactivity | Awaiting results | |
| Recombinant antithrombin | Recombinant human Antithrombin (ATryn) in the treatment of patients with DIC associated with severe sepsis [NCT00506519] |
25 patients High dose or low dose of I.V. antithrombin vs. placebo for 5 days |
Inflammatory markers | Improvement in the DIC score by 2 points at day 28 | Awaiting results |
| Antithrombin + recombinant human thrombomodulin | The efficacy and safety of antithrombin and recombinant human thrombomodulin combination therapy in patients with severe sepsis and disseminated intravascular coagulation (40) |
129 patients Antithrombin + thrombomodulin vs. antithrombin alone |
NA | Platelet count and D-dimer levels at day 7 | Intervention group had significant improvement of platelet count and D-dimer levels at day 7 |
| Heparin | Efficacy and Safety of Unfractionated Heparin on Severe sepsis With Suspected Disseminated Intravascular Coagulation [NCT02654561] |
700 patients Heparin 12,500 units/d for 7 days |
NA | ICU mortality | Recruiting |
| Heparin Anticoagulation to Improve Outcomes in Septic shock: The HALO Pilot [NCT01648036] |
76 patients Unfractionated heparin 18 UI/kg/h continuous I.V. for 7 days vs. Dalteparin 5000IU subcutaneous daily |
Biomarkers | Unknown | Not published | |
| Annexin 5 | SY-005(Recombinant Human Annexin A5)in Patients With Sepsis [NCT04898322] |
96 patients Annexin 5 vs. placebo for 5 days |
Biomarkers | Safety and tolerability | Not yet recruiting |
| Aspirin | ASpirin for Patients With SEPsis and SeptIc Shock (ASP-SEPSIS) [NCT01784159] |
240 patients 200 mg/day of placebo for 7 days |
NA | Change in SOFA score at day 7 | Recruiting |
| Heart rate control | |||||
| Landiolol | LANdiolol MIcrocirculatory Effects During Septic shOck (MILANOS) [NCT04931225] | Landiolol (Rapibloc) perfusion will be started at T0 at 0.5 mcg/kg/min and increased by 0.5 mcg/kg/min every 30 min in order to achieve a 15% (T1) decrease in heart rate | Laser Doppler coupled with iontophoresis of acetylcholine | Microcirculatory reactivity | Not yet recruiting |
| Ivabradine | Ivabradine for Heart Rate Control In Septic Shock (IRISS) [NCT04031573] |
429 patients Ivabradine 2.5 to 7.5 mg/12 h via enteral administration, to achieve a heart rate of 80–94 bpm vs. placebo |
NA | – Succeed in heart rate control – 28-day mortality |
Recruiting |
d, day; DIC, Disseminated intravascular coagulation; h, hours; ICU, Intensive care unit; I.V., intravenous; LPS, Lipopolysaccharide; NIRS, Near Infrared Spectrometry; NA, not available;NO, Nitric Oxide; NOS, Nitric oxide synthase; PCO2, partial pressure of carbon dioxide; SDF, Sidestream Dark Field; SOFA, Sequential Organ Failure Assessment; SC, subcutaneous.