Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

An Electronic Tool for the Evaluation and Treatment of Sepsis in the ICU: A Randomized Controlled Trial.

OBJECTIVES: To determine whether addition of an electronic sepsis evaluation and management tool to electronic sepsis alerting improves compliance with treatment guidelines and clinical outcomes in septic ICU patients. DESIGN: A pragmatic randomized trial. SETTING: Medical and surgical ICUs of an academic, tertiary care medical center. PATIENTS: Four hundred and seven patients admitted during a 4-month period to the medical or surgical ICU with a diagnosis of sepsis established at the time of admission or in response to an electronic sepsis alert. INTERVENTIONS: Patients were randomized to usual care or the availability of an electronic tool capable of importing, synthesizing, and displaying sepsis-related data from the medical record, using logic rules to offer individualized evaluations of sepsis severity and response to therapy, informing users about evidence-based guidelines, and facilitating rapid order entry. MEASUREMENTS AND MAIN RESULTS: There was no difference between the electronic tool (218 patients) and usual care (189 patients) with regard to the primary outcome of time to completion of all indicated Surviving Sepsis Campaign 6-hour Sepsis Resuscitation Bundle elements (hazard ratio, 1.98; 95% CI, 0.75-5.20; p = 0.159) or time to completion of each element individually. ICU mortality, ICU-free days, and ventilator-free days did not differ between intervention and control. Providers used the tool to enter orders in only 28% of available cases. CONCLUSIONS: A comprehensive electronic sepsis evaluation and management tool is feasible and safe but did not influence guideline compliance or clinical outcomes, perhaps due to low utilization.

Randomized trial of automated, electronic monitoring to facilitate early detection of sepsis in the intensive care unit*.

OBJECTIVE: To determine whether automated identification with physician notification of the systemic inflammatory response syndrome in medical intensive care unit patients expedites early administration of new antibiotics or improvement of other patient outcomes in patients with sepsis. DESIGN: : A prospective randomized, controlled, single center study. SETTING: Medical intensive care unit of an academic, tertiary care medical center. PATIENTS: Four hundred forty-two consecutive patients admitted over a 4-month period who met modified systemic inflammatory response syndrome criteria in a medical intensive care unit. INTERVENTION: Patients were randomized to monitoring by an electronic "Listening Application" to detect modified (systemic inflammatory response syndrome) criteria vs. usual care. The listening application notified physicians in real time when modified systemic inflammatory response syndrome criteria were detected, but did not provide management recommendations. MEASUREMENTS AND MAIN RESULTS: The median time to new antibiotics was similar between the intervention and usual care groups when comparing among all patients (6.0 hr vs. 6.1 hr, p = .95), patients with sepsis (5.3 hr vs. 5.1 hr; p = .90), patients on antibiotics at enrollment (5.2 hr vs. 7.0 hr, p = .27), or patients not on antibiotics at enrollment (5.2 hr vs. 5.1 hr, p = .85). The amount of fluid administered following detection of modified systemic inflammatory response syndrome criteria was similar between groups whether comparing all patients or only patients who were hypotensive at enrollment. Other clinical outcomes including intensive care unit length of stay, hospital length of stay, and mortality were not shown to be different between patients in the intervention and control groups. CONCLUSIONS: Realtime alerts of modified systemic inflammatory response syndrome criteria to physicians in one tertiary care medical intensive care unit were feasible and safe but did not influence measured therapeutic interventions for sepsis or significantly alter clinical outcomes.

In response: Letter on update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT03509350. Registered on 26 April 2018.

The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed. METHODS: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed. DISCUSSION: VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.

Nodular granulomatous Pneumocystis jiroveci pneumonia consequent to delayed immune reconstitution inflammatory syndrome.

Although Pneumocystis jiroveci pneumonia (PCP) is a frequent manifestation of acquired immune deficiency syndrome (AIDS), the granulomatous form is uncommon. Here, we present an unusual case of granulomatous PCP consequent to immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy. A 36-year-old woman with human immunodeficiency virus (HIV) presented with cough and dyspnea that were attributed to typical PCP associated with AIDS. She was successfully treated with antibiotic, steroid, and antiretroviral therapies. After six months, however, she presented with consolidating lung lesions caused by bronchial obstruction from PCP granulomatous disease. Although antibiotics were ineffective, the effectiveness of steroid therapy suggested a diagnosis of granulomatous IRIS caused by persistent PCP antigens. Physicians should strongly suspect PCP in HIV-positive patients with nodular lung lesions and must remain aware that these lesions, if immune in origin, might not respond to antimicrobial therapy.

Sepsis: Current Definition, Pathophysiology, Diagnosis, and Management.

Sepsis is a clinical syndrome that results from the dysregulated inflammatory response to infection that leads to organ dysfunction. The resulting losses to society in terms of financial burden, morbidity, and mortality are enormous. We provide a review of sepsis, its underlying pathophysiology, and guidance for diagnosis and management of this common disease. Current established treatments include appropriate antimicrobial agents to target the underlying infection, optimization of intravascular volume to improve stroke volume, vasopressors to counteract vasoplegic shock, and high-quality supportive care. Appropriate implementation of established treatments combined with novel therapeutic approaches promises to continue to decrease the impact of this disease.

Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.

BACKGROUND: The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries. METHODS: In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome. RESULTS: There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P < .001). CONCLUSIONS: Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.

Normocaloric versus hypocaloric feeding on the outcomes of ICU patients: a systematic review and meta-analysis.

INTRODUCTION: Current clinical practice guidelines recommend providing ICU patients a daily caloric intake estimated to match 80-100 % of energy expenditure (normocaloric goals). However, recent clinical trials of intentional hypocaloric feeding question this approach. METHODS: We performed a systematic review and meta-analysis to compare the outcomes of ICU patients randomized to intentional hypocaloric or normocaloric goals. We included randomized controlled trials that enrolled ICU patients and compared intentional hypocaloric with normocaloric nutritional goals. We included studies that evaluated both trophic feeding as well as permissive underfeeding. Data sources included MEDLINE, Cochrane Register of Controlled Trials and citation review of relevant primary and review articles. The outcomes of interest included hospital acquired infection, hospital mortality, ICU length of stay (LOS) and ventilator-free days (VFDs). RESULTS: Six studies which enrolled 2517 patients met our inclusion criteria. The mean age and body mass index (BMI) across the studies were 53 ± 5 years and 29.1 ± 1.5 kg/m(2), respectively. Two studies compared normocaloric feeding (77% of goal) with trophic feeding (20% of goal), while four studies compared normocaloric feeding (72% of goal) with permissive underfeeding (49% of goal). Overall, there was no significant difference in the risk of infectious complications (OR 1.03; 95% CI 0.84-1.27, I(2) = 16%), hospital mortality (OR 0.91; 95% CI 0.75-1.11, I(2) = 8%) or ICU LOS (mean difference 0.05 days; 95% CI 1.33-1.44 days; I(2) = 37%) between groups. VFDs were reported in three studies with no significant difference between the normocaloric and intentional hypocaloric groups (data not pooled). CONCLUSION: This meta-analysis demonstrated no difference in the risk of acquired infections, hospital mortality, ICU length of stay or ventilator-free days between patients receiving intentional hypocaloric as compared to normocaloric nutritional goals.

Controversies and Misconceptions in Intensive Care Unit Nutrition.

The early initiation of enteral nutrition remains a fundamental component of the management of critically ill and injured patients in the intensive care unit. Trophic feeding is equivalent, if not superior, to full-dose feeding. Parenteral nutrition has no proved benefit over enteral nutrition, which is the preferred route of nutritional support in intensive care unit patients with a functional gastrointestinal tract. Continuous enteral and parental nutrition inhibits the release of important enterohormones. These changes are reversed with intermittent bolus feeding. Whey protein, which is high in leucine, has a greater effect on insulin release and protein synthesis than does a soy- or casein-based enteral formula.

An overview of the diagnosis and management of Clostridium difficile infection.

The diagnosis and treatment of Clostridium difficile infection are becoming increasingly complex with the introduction of novel diagnostic techniques and new pharmacologic and nonpharmacologic treatments. The integration of these new approaches with older, established methods is a challenge to individual clinicians and hospital systems. This article provides an overview of the current methods for the diagnosis and treatment of C difficile infection.