Vitamin C, Thiamine, and Hydrocortisone in the Treatment of Sepsis: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials.

BACKGROUND: There is a conflicting body of evidence regarding the benefit of vitamin C, thiamine, and hydrocortisone in combination as an adjunctive therapy for sepsis with or without septic shock. We aimed to assess the efficacy of this treatment among predefined populations. METHODS: A literature review of major electronic databases was performed to include randomized controlled trials (RCTs) evaluating vitamin C, thiamine, and hydrocortisone in the treatment of patients with sepsis with or without septic shock in comparison to the control group. RESULTS: Seven studies met our inclusion criteria, and 6 studies were included in the final analysis totaling 839 patients (mean age 64.2 ± 18; SOFA score 8.7 ± 3.3; 46.6% female). There was no significant difference between both groups in long term mortality (Risk Ratio (RR) 1.05; 95% CI 0.85-1.30; P = 0.64), ICU mortality (RR 1.03; 95% CI 0.73-1.44; P = 0.87), or incidence of acute kidney injury (RR 1.05; 95% CI 0.80-1.37; P = 0.75). Furthermore, there was no significant difference in hospital length of stay, ICU length of stay, and ICU free days on day 28 between the intervention and control groups. There was, however, a significant difference in the reduction of SOFA score on day 3 from baseline (MD -0.92; 95% CI -1.43 to -.41; P < 0.05). In a trial sequential analysis for mortality outcomes, our results are inconclusive for excluding lack of benefit of this therapy. CONCLUSION: Among patients with sepsis with or without septic shock, treatment with vitamin C, thiamine, and hydrocortisone was not associated with a significant reduction in mortality, incidence of AKI, hospital and ICU length of stay, or ICU free days on day 28. There was a significant reduction of SOFA score on day 3 post-randomization. Further studies with a larger number of patients are needed to provide further evidence on the efficacy or lack of efficacy of this treatment.

Borrelia burgdorferi harbors a transport system essential for purine salvage and mammalian infection.

Borrelia burgdorferi is the tick-borne bacterium that causes the multistage inflammatory disease Lyme disease. B. burgdorferi has a reduced genome and lacks the enzymes required for de novo synthesis of purines for synthesis of RNA and DNA. Therefore, this obligate pathogen is dependent upon the tick vector and mammalian host environments for salvage of purine bases for nucleic acid biosynthesis. This pathway is vital for B. burgdorferi survival throughout its infectious cycle, as key enzymes in the purine salvage pathway are essential for the ability of the spirochete to infect mice and critical for spirochete replication in the tick. The transport of preformed purines into the spirochete is the first step in the purine salvage pathway and may represent a novel therapeutic target and/or means to deliver antispirochete molecules to the pathogen. However, the transport systems critical for purine salvage by B. burgdorferi have yet to be identified. Herein, we demonstrate that the genes bbb22 and bbb23, present on B. burgdorferi's essential plasmid circular plasmid 26 (cp26), encode key purine transport proteins. BBB22 and/or BBB23 is essential for hypoxanthine transport and contributes to the transport of adenine and guanine. Furthermore, B. burgdorferi lacking bbb22-23 was noninfectious in mice up to a dose of 1 × 10(7) spirochetes. Together, our data establish that bbb22-23 encode purine permeases critical for B. burgdorferi mammalian infectivity, suggesting that this transport system may serve as a novel antimicrobial target for the treatment of Lyme disease.

The long-term burden of severe sepsis and septic shock: Sepsis recidivism and organ dysfunction.

BACKGROUND: Severe sepsis and septic shock mortality has improved; however, rates of persistent (28-90 days) and long-term (>90 day) organ dysfunction in sepsis survivors are unknown. METHODS: Secondary analysis of a prospective cohort of adult emergency department patients with severe sepsis. RESULTS: Of 110 sepsis admissions, we obtained follow-up on 51 of 78 survivors of whom 41% (21 of 51) had persistent organ dysfunction: pulmonary, 18% (9 of 51); renal, 22% (11 of 51); coagulopathy, 10% (5 of 51); cardiovascular, 6% (3 of 51); hepatic, 2% (1 of 51); and neurologic, 3% (3 of 51). We obtained follow-up on 40 of 73 survivors at more than 90 days of whom 38% (15 of 40) had long-term organ dysfunction: pulmonary, 13% (5 of 40); renal, 18% (7 of 40); coagulopathy, 3% (1 of 40); cardiovascular, 5% (2 of 40); hepatic, 0%; and neurologic, 5% (2 of 40). Readmission rate within 90 days was 32% (25 of 78), and recurrent sepsis was the cause of readmission in 52% (13 of 25). Baseline SOFA scores from the index sepsis admission were compared using Wilcoxon rank-sum test and were significantly different in participants with organ dysfunction versus those without organ dysfunction at less than 90 days (z, -2.51; p = 0.01). CONCLUSION: Readmission with recurrent sepsis and organ dysfunction occurs frequently in sepsis survivors. Baseline SOFA score may be predictive of sepsis recidivism and persistent or recurrent organ dysfunction. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level IV.