Steroid, ascorbic acid, and thiamine in adults with sepsis and septic shock: a systematic review and component network meta-analysis.
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SUBMITTER: Fong KM
PROVIDER: S-EPMC8338943 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSepsis 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.MethodsWe 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).ResultsNine 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).ConclusionsThe 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 registrationPROSPERO, CRD42020203166.
| S-EPMC8684090 | biostudies-literature
Project description:ImportanceThe combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock.ObjectiveTo determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock.Design, setting, and participantsRandomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019.InterventionsPatients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102).Main outcomes and measuresThe primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses.ResultsAmong 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively).Conclusions and relevanceIn patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock.Trial registrationClinicalTrials.gov Identifier: NCT03389555.
| S-EPMC7435341 | biostudies-literature
Project description:For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15-25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30-50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.
| S-EPMC5538252 | biostudies-other
Project description:Patients who experience sepsis often have long-term effects that may impact health-related quality of life. This study aimed to investigate whether the combination of ascorbic acid, corticosteroids, and thiamine compared with placebo improves health-related quality of life in patients with septic shock.DesignSecondary analysis of the Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis randomized controlled trial (NCT03389555).SettingThirteen tertiary-care hospitals in the United States.PatientsPatients who were enrolled in Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis, survived to 90 days post enrollment and were able to be contacted by telephone.InterventionsPatients were randomly assigned to parenteral ascorbic acid (1,500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days or placebo.Measurements and main resultsOne hundred seventeen patients (59%) survived to 90 days and were administered the Short Form 36 questionnaire; of these, 72 (62%) completed the Short Form 36 (38 [53%] in the intervention group, 34 [47%] in placebo). Sixty-six (92%) completed all survey questions (36 [95%] in the intervention group, 30 [88%] in placebo). There was no significant difference in overall Short Form 36 score between intervention and placebo group (median score: 39.4 [interquartile range, 31.2-45.4] vs 43.2 [37.0-46.7], respectively, p = 0.18). We found no statistically significant difference between the two groups in any of the other health-related quality of life domains used.ConclusionsWe found no difference in the health-related quality of life in patients with septic shock treated with a combination of ascorbic acid, corticosteroids, and thiamine compared to placebo.
| S-EPMC7685963 | biostudies-literature
Project description:Thiamine (vitamin B1) is a water-soluble vitamin essential for human health. Thiamine deficiency is causal and/or contributory in a number of debilitating diseases including beri-beri, the Wernicke-Korsakoff syndrome, optic neuropathy, and others. While thiamine deficiency is relatively rare in developed nations as a result of dietary supplementation, thiamine deficiency is more common in nutritionally compromised populations. Thiamine pyrophosphate, a thiamine derivative, is essential to the citric acid cycle and thiamine deficiency can result in impaired aerobic respiration and cellular energy production. Thiamine also plays an important role in the pentose phosphate pathway and other key metabolic processes. Although thiamine deficiency is a known cause of lactic acidosis, it has been recently evaluated as a potential contributor to refractory lactic acidosis and organ injury in septic shock and other shock states. In this article, we review the epidemiology of thiamine deficiency in septic shock and the existing evidence base supporting thiamine supplementation. We conclude that specific sepsis phenotypes may stand to benefit the most from thiamine supplementation, and efforts might be made to identify and supplement these patients early in their hospital course.
| S-EPMC7024754 | biostudies-literature
Project description:AbstractBackground: Acute kidney injury (AKI) occurs frequently in septic patients and correlates with increased mortality. Because clinical studies investigating hydrocortisone, ascorbic acid, and thiamine (HAT) have demonstrated discordant results, studies were performed using mortality stratification for therapy to identify candidates for therapy and determine mechanisms of organ injury. Methods: Sepsis was induced using the cecal ligation and puncture (CLP) model of sepsis with fluid and antibiotic support. Heart rate (HR) measurements obtained 6 hours after CLP stratified mice into live predicted (P-Live) or die predicted (P-Die). Stratified mice were then randomized for treatment with HAT or vehicle given 7 hours after CLP. Physiologic measurements were taken again at 24 hours, and mice were killed to collect blood and organs. Results: The following five groups were created: (1) P-Live vehicle, (2) P-Live HAT, (3) P-Die vehicle, (4) P-Die HAT, and (5) naive mice. Comparisons were made to test the hypotheses that (1) P-Die vehicle mice will have significant deterioration compared with P-Live mice targeting the kidney and (2) HAT will correct these deleterious changes in P-Die mice. Compared with P-Live, P-Die mice had a significant decline in all measured physiologic parameters (HR, cardiac output, breath rate, and temperature), which were corrected with HAT therapy (P < 0.05 for all parameters). The P-Die mice had declines in the ascorbic acid within the blood, peritoneal lavage, and kidney homogenate compared with P-Live mice indicating consumption, and the decline was corrected with HAT. Elevated IL-6, KC, Macrophage Inflammatory Protein-2, and IL-1RA were found in P-Die mice and decreased with HAT. Markers of endothelial cell injury (glypican 1 and glypican 4) were elevated in the P-Die mice, and these values were decreased with HAT therapy. Low oxygen levels with subsequent oxidative stress (OS) in the kidney were visualized in histologic sections using hypoxyprobe and also with carbonyl proteins and 8-iso-prostaglandin F2α in kidney homogenates. The P-Die mice had significant elevations of renal OSs, which was ameliorated with HAT. Kidney injury was evident in the P-Die mice compared with P-Live mice with elevations in blood urea nitrogen and cystatin C, which were significantly reduced with HAT. There was no evidence of global hypoxia or organ injury because hepatic parameters remained normal. Conclusions: Our data show that in CLP-induced sepsis, P-Die mice have increased inflammation, OS, and kidney injury. Hydrocortisone, ascorbic acid, and thiamine therapy decreased renal OS and injury in the P-Die group when given after the onset of sepsis-induced physiologic changes.
| S-EPMC9713586 | biostudies-literature
Project description:Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind, placebo-controlled trial aimed to investigate whether a high dose of intravenous ascorbic acid (AA) might improve microcirculation and affect glycocalyx in septic patients. In our study, 23 septic patients were supplemented with a high dose (50 mg/kg every 6 h) of intravenous AA or placebo for 96 h. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field (IDF) video microscope. A sidestream dark field video microscope (SDF), connected to the GlycoCheck software (GlycoCheck ICU®; Maastricht University Medical Center, Maastricht, the Netherlands), was employed to observe glycocalyx. We found a significantly higher proportion of perfused small vessels (PPV) 6 h after the beginning of the trial in the experimental group compared with placebo. As an indicator of glycocalyx thickness, the perfused boundary region was lower in capillaries of the 5-9 μm diameter in the AA group than placebo after the first dose of AA. Our data suggest that high-dose parenteral AA tends to improve microcirculation and glycocalyx in the early period of septic shock. The study was retrospectively registered in the clinicaltrials.gov database on 26/02/2021 (registration number NCT04773717).
| S-EPMC10496271 | biostudies-literature
Project description:We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, - 29.8 h [95% CI - 44.1 to - 15.5]) and ICU stay (incremental mean difference, - 1.3 days [95% CI - 2.2 to - 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality.
| S-EPMC8724116 | biostudies-literature
Project description:ObjectiveTo identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock.DesignA consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations.MethodsEach committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science.ResultsThe Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?ConclusionsWhile the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.
| S-EPMC7095388 | biostudies-literature
Project description:BackgroundSerum procalcitonin (PCT) evaluation has been proposed for early diagnosis and accurate staging and to guide decisions regarding patients with sepsis, severe sepsis and septic shock, with possible reduction in mortality.ObjectivesTo assess the effectiveness and safety of serum PCT evaluation for reducing mortality and duration of antimicrobial therapy in adults with sepsis, severe sepsis or septic shock.Search methodsWe searched the Central Register of Controlled Trials (CENTRAL; 2015, Issue 7); MEDLINE (1950 to July 2015); Embase (Ovid SP, 1980 to July 2015); Latin American Caribbean Health Sciences Literature (LILACS via BIREME, 1982 to July 2015); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCO host, 1982 to July 2015), and trial registers (ISRCTN registry, ClinicalTrials.gov and CenterWatch, to July 2015). We reran the search in October 2016. We added three studies of interest to a list of 'Studies awaiting classification' and will incorporate these into formal review findings during the review update.Selection criteriaWe included only randomized controlled trials (RCTs) testing PCT-guided decisions in at least one of the comparison arms for adults (≥ 18 years old) with sepsis, severe sepsis or septic shock, according to international definitions and irrespective of the setting.Data collection and analysisTwo review authors extracted study data and assessed the methodological quality of included studies. We conducted meta-analysis with random-effects models for the following primary outcomes: mortality and time spent receiving antimicrobial therapy in hospital and in the intensive care unit (ICU), as well as time spent on mechanical ventilation and change in antimicrobial regimen from a broad to a narrower spectrum.Main resultsWe included 10 trials with 1215 participants. Low-quality evidence showed no significant differences in mortality at longest follow-up (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.65 to 1.01; I2 = 10%; 10 trials; N = 1156), at 28 days (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; four trials; N = 316), at ICU discharge (RR 1.03, 95% CI 0.50 to 2.11; I2 = 49%; three trials; N = 506) and at hospital discharge (RR 0.98, 95% CI 0.75 to 1.27; I2 = 0%; seven trials; N = 805; moderate-quality evidence). However, mean time receiving antimicrobial therapy in the intervention groups was -1.28 days (95% CI to -1.95 to -0.61; I2 = 86%; four trials; N = 313; very low-quality evidence). No primary study has analysed the change in antimicrobial regimen from a broad to a narrower spectrum.Authors' conclusionsUp-to-date evidence of very low to moderate quality, with insufficient sample power per outcome, does not clearly support the use of procalcitonin-guided antimicrobial therapy to minimize mortality, mechanical ventilation, clinical severity, reinfection or duration of antimicrobial therapy of patients with septic conditions.
| S-EPMC6353122 | biostudies-literature