Abstract:A
bstract
Aims and objective
To study the effects of various components of “metabolic resuscitation” on the shock reversal among patients with septic shock
Introduction
Sepsis is characterized by dysregulated host response to infection. Mitochondrial dysfunction which occurs early in sepsis is associated with multiorgan dysfunction. Therapies such as adequate resuscitation, early administration of antibiotics, and aggressive monitoring reduced… Show more
“…Unlike in the study of Marik et al [13], we did not observe any improvement in ICU mortality in the AT group compared to the control group. This is in line with several recently conducted RCTs which were unable to reproduce the remarkable survival benefit described by Marik et al [27][28][29][30][31][32][33].…”
Background Sepsis and septic shock are common causes of ICU admission with devastating outcomes. Adjunctive therapies are urgently needed, and the use of high dose of vitamin B1 and C have recently gained interest. However, on the basis of a perceived possible synergic effect, most trials have never tested the combination of thiamine and ascorbic acid, with a separate assessment of the effect of each individual component. In this context, while the association of thiamine and ascorbic acid was not found to improve survival rates, potentially harmful effects were found when administering ascorbic acid alone. We have conducted a retrospective cohort study, comparing ICU mortality of septic shock patients receiving standard treatment, thiamine alone or a combination of thiamine and ascorbic acid. Results A total of 1800 patients were included, 1260 receiving standard care, 436 receiving only thiamine and 104 patients receiving a thiamine / ascorbic acid combination. Using doubly robust estimation of the treatment effect, combining propensity score weighting and variables adjustment, we found thiamine alone to be associated with a decrease in ICU mortality compared to the use of a thiamine / ascorbic acid combination (Hazar Ratio equal to 0.60, 95% Confidence Interval [0.36;0.99], p=0.048). Conclusions In septic shock patients, administration of thiamine is associated with improved ICU mortality when used alone rather than when associated with ascorbic acid. This result strengthens the evidence showing a lack of effectiveness of the ascorbic acid / thiamine combination reported in recent randomized controlled trials. Furthermore, it argues in favor of the need for further trials investigating the effect of thiamine in septic ICU patients as an adjunctive therapy.
“…Unlike in the study of Marik et al [13], we did not observe any improvement in ICU mortality in the AT group compared to the control group. This is in line with several recently conducted RCTs which were unable to reproduce the remarkable survival benefit described by Marik et al [27][28][29][30][31][32][33].…”
Background Sepsis and septic shock are common causes of ICU admission with devastating outcomes. Adjunctive therapies are urgently needed, and the use of high dose of vitamin B1 and C have recently gained interest. However, on the basis of a perceived possible synergic effect, most trials have never tested the combination of thiamine and ascorbic acid, with a separate assessment of the effect of each individual component. In this context, while the association of thiamine and ascorbic acid was not found to improve survival rates, potentially harmful effects were found when administering ascorbic acid alone. We have conducted a retrospective cohort study, comparing ICU mortality of septic shock patients receiving standard treatment, thiamine alone or a combination of thiamine and ascorbic acid. Results A total of 1800 patients were included, 1260 receiving standard care, 436 receiving only thiamine and 104 patients receiving a thiamine / ascorbic acid combination. Using doubly robust estimation of the treatment effect, combining propensity score weighting and variables adjustment, we found thiamine alone to be associated with a decrease in ICU mortality compared to the use of a thiamine / ascorbic acid combination (Hazar Ratio equal to 0.60, 95% Confidence Interval [0.36;0.99], p=0.048). Conclusions In septic shock patients, administration of thiamine is associated with improved ICU mortality when used alone rather than when associated with ascorbic acid. This result strengthens the evidence showing a lack of effectiveness of the ascorbic acid / thiamine combination reported in recent randomized controlled trials. Furthermore, it argues in favor of the need for further trials investigating the effect of thiamine in septic ICU patients as an adjunctive therapy.
“…In another three studies [ 19 – 21 ], intensivists were allowed to order open-label corticosteroid therapy as deemed necessary. In three other studies [ 22 – 24 ], patients in the control group were routinely given low doses of glucocorticoids. In addition, the severity of sepsis was varied.…”
Section: Resultsmentioning
confidence: 99%
“…In addition, the severity of sepsis was varied. Four trials focused on patients with sepsis including those with septic shock [ 11 , 12 , 19 , 21 ] and the others only focused on patients with septic shock [ 13 , 20 , 22 – 24 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Incidence of new onset of AKI 5. ICU and hospital LOS HAT protocol did not reduce hospital mortality in patients with septic shock HAT group has higher incidence of culture positivity for Klebsiella and Candida; significant reduction of hock reversal time, PCT level on day 3, PCT clearance at 72 h and ICU length of stay Control 45 59.37 32/11 standard of care for septic shock The use of hydrocortisone and vitamin supplements in the control group was at the treating physician’s discretion Reddy 2020 [ 24 ] India Septic shock Age ≥ 18 years Pregnancy have new onset acute coronary syndrome H 7 55.4 3/4 Hydrocortisone:200 mg over 24 h infusion Primary outcome: 1. Time to shock reversal Secondary outcomes: 1. time to vasopressor reduction (minutes) from SOFA(h) 4–3 H group has non-significantly longer shock reversal time than other groups No significant difference in time to initiation of metabolic resuscitation among groups Did not include the length of stay, ventilator-free days, and mortality in outcomes HA 7 56.5 3/4 Hydrocortisone:200 mg over 24 h infusion ascorbic acid 1.5 g IV q6 hour HAT 7 53.8 4/3 Hydrocortisone:200 mg over 24 h infusion ascorbic acid 1.5 g IV q6 hour thiamine:200 mg IV q12 hours Sevransky [ 21 ] US Age ≥ 18y Acute respiratory and/or cardiovascular dysfunction caused by sepsis ICU admission Age < 18y Weight < 40 kg Organ dysfunction no longer present Cardiovascular/respiratory organ failure caused by other disease DNR, DNI hospitalization > 30 days indication or contraindication of any study drug HAT 252 62 139/113 IV vit...…”
Background
Sepsis is a primary global health threat and costs a lot, requiring effective and affordable treatments. We performed this meta-analysis to explore the treatment of hydrocortisone, ascorbic acid, and thiamine (HAT) in sepsis and septic shock.
Methods
We searched Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to August 14, 2021. We included randomized controlled trials (RCTs) that evaluated the HAT treatments in sepsis and septic shock. The primary outcome was the change in SOFA score over the 72 h. The second outcomes were the hospital, and 28-/30-day mortality, the duration of vasopressors, PCT clearance, hospital length of stay (LOS), and ICU LOS. We performed a subgroup analysis and a trial sequential analysis (TSA). The Der Simonian–Laird random-effects models were used to report the pooled risk ratios (RR) or mean difference (MD) with confidence intervals (CI).
Results
Nine RCTs, enrolling 1427 patients of sepsis and septic shock treated with HAT (717) or only standard care (710), were included. There was a significant difference between the two groups in the change in SOFA score over the first 72 h (MD 0.65, 95% CI 0.30 to 1.00), the duration of vasopressors (MD − 18.16, 95% CI − 25.65 to − 10.68) and the PCT clearance (MD 14.54, 95% CI 0.64 to 28.43). In addition, there was no significant difference in the hospital mortality (RR 1.07, 95% CI 0.85 to 1.34), the 28-/30-day mortality (RR 0.96, 95% CI 0.80 to 1.15), the hospital LOS (MD 0.78, 95% CI − 0.30 to 1.86), and ICU LOS (MD 0.12, 95% CI − 0.53 to 0.78).
Conclusions
The HAT combination improves the SOFA score in the first 72 h and reduces the duration of vasopressors in patients with sepsis. Given the minor mean difference of the change in SOFA score, the mortality benefit has not been observed.
Trial registration
PROSPERO, CRD42020203166.
“…To achieve supraphysiological plasma concentrations, 10 g will be used as a second dose regimen. This dose is in between 6 g and 16 g vitamin C a day, as used in previous studies [ 17 – 23 , 25 – 28 , 44 – 46 ]. Currently, the optimal length of vitamin C supplementation is also unknown.…”
Background
High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients.
Methods
This is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations.
Discussion
Vitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest.
Trial registration
ClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL
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