Low rate of enrollment; publication of relevant results by other groups

This study has been approved as a nested substudy of a multicenter trial (CORVICTES, Clinicaltrials.gov Identifier: NCT03592693). The current, randomized, placebo-controlled study will compare steroids/vitamin C versus placebo/placebo in septic shock, with respect to cerebral autoregulation, biomarkers, and functional outcome. The following hypotheses will be tested: The steroids/vitamin C/thiamine intervention may result in attenuation of the septic shock-associated impairment in cerebral autoregulation; and 2) The increased frequency of intact cerebral autoregulation in the intervention group may result in more neurologic failure free days and ventilator free days during a 60-day follow-up; improved survival to hospital discharge with good functional outcome; and better patient-reported health-related outcomes at 90-day follow-up.

BACKGROUND AND RATIONALE Septic Encephalopathy is a serious complication of sepsis / septic shock. In postmortem, human brain samples, two forms of neuraxonal injury have been described, namely, scattered ischemic lesions and diffuse injury. Prior evidence suggests that cerebral autoregulation is impaired in patients with septic shock, and this may render the central nervous system more vulnerable to direct ischemic damage, especially during episodes of hypotension. Near-infrared spectroscopy (NIRS) constitutes an established method of noninvasive assessment of cerebral autoregulation and provides the capability of semiquantitative assessment of regional cerebral blood flow.

In the context of a multicenter randomized clinical trial (RCT) evaluating the effect of steroids and antioxidants on the outcome of septic shock, we aim to assess cerebral autoregulation and frontal cortex perfusion using NIRS in patients who will be enrolled in the 25-bed intensive care unit (ICU) of Evaggelismos Hospital, Athens, Greece.

The rationale of the main study is based on the following facts: A large body of experimental data has demonstrated that both corticosteroids and intravenous vitamin C reduce activation of nuclear factor kappa beta (NFƘB), thereby attenuating the release of pro-inflammatory mediators. This may result in reduced endothelial permeability and improved macrocirculatory flow, and augmentation of the release of endogenous catecholamines and enhanced vasopressor responsiveness. Furthermore, a combined attenuation of the systemic inflammatory response, reduced vascular leakage, and improved macrocirculatory flow may partly contribute to the preservation of cerebral autoregulation and effective, regional brain perfusion. In addition, recent evidence suggests that thiamine may be neuroprotective in severe shock states.

Regarding the rationale and hypotheses of the current substudy: Recent, observational data suggest that impaired cerebral autoregulation is independently associated with 3-month mortality in patients with septic shock. Therefore, the current project aims to test the following hypotheses: 1) The steroids/vitamin C/thiamine intervention may result in attenuation of the septic shock-associated impairment in cerebral autoregulation; and 2) The increased frequency of intact cerebral autoregulation in the intervention group may result in more neurologic failure free days and ventilator free days during a 60-day follow-up; improved survival to hospital discharge with good functional outcome; and better patient-reported health-related outcomes at 90-day follow-up.

METHODS

NIRS monitoring will be applied for 60 min at 2 levels of mean arterial pressure (MAP; ie, 65-70 mmHg and 95-100 mmHg) within 24-30 hours, and within 48-54 hours and 72-78 hours after the diagnosis of the septic shock. Autoregulation will be assessed by using tissue oxygenation index values and concurrently recorded MAP values in a regression analysis and will be considered as adequate if the pertinent Pearson correlation coefficient is lower than 0.3. Cerebral blood flow will be assessed by determination of the blood flow index after bolus injection of 5 mg of indocyanine green.

Patients will be randomized to the intervention or control group in subgroups of 4 using the "Research Randomizer" software, version 4 (https://www.randomizer.org/). Substudy intervention: In concordance with the main study protocol as approved by the Institutional Review Board (IRB; ie, the Scientific Council) of Evaggelismos Hospital, Athens Greece, the substudy intervention will comprise the following:

Hydrocortisone: Hydrocortisone 50 mg initial/single bolus (5-mL syringe containing 50 mg of hydrocortisone in normal saline), followed by a 24-hour continuous infusion of 200 mg/day for 4 days. The daily hydrocortisone dose of 200 mg will be diluted in a 50 or 100 mL bag of normal saline.

Hydrocortisone placebo will be provided as an identical syringe/50 or 100 mL bag of normal saline.

Vitamin C: Vitamin C is provided by the manufacturer as a 50 mL vial at a concentration of 500mg/mL. Three (3) ml of the vitamin C solution will be diluted in a 50 or 100 mL bag of normal saline (1500 mg vitamin C in a 50 mL bag) which will then be infused over 1 hour. The bag will be labeled by the study's pharmacy team as "vitamin C". The dosing schedule is 1500 mg every 6 hours for 4 days or until discharge from the ICU.

Vitamin C placebo will consist of an identical bag of 50 or 100 mL normal saline (but with no vitamin C) and will be labeled vitamin C. Placebo will be infused over 60 min as per the infusion instructions of the active vitamin.

Thiamine: As a high percentage of septic patients have been shown to be thiamine-deficient, patients will receive intravenous thiamine 200 mg every 12 hours for 4 days or until ICU discharge. Thiamine is also a cofactor for the metabolism of oxalate (a byproduct of vitamin C metabolism), with thiamine deficiency increasing oxalate levels. To simplify the study protocol both the intervention and the control group will receive thiamine.

The study inclusion and exclusion criteria are detailed in the dedicated subsections.

DOCUMENTATION AND PATIENT FOLLOW-UP

Monitoring of patients over the first 10 days after randomization will include: 1) Determination and recording of hemodynamic parameters and hemodynamic support, blood gases and fluid balance over the previous 24 hours as well as arterial blood lactate and central venous oxygen saturation; 2) Blood sampling at 24, 48 and 72 hours and 7 days after randomization for determination of cytokines' concentrations; 3) Daily, routine laboratory investigations' results and prescribed treatment data; 4) the results of 4 daily (1 / 6 hours) blood glucose measurements will be recorded and the incidence of hyperglycemia (defined as blood glucose over 200 mg/dL) will be analyzed; 5) Daily calculation of the Sequential Organ Dysfunction Assessment Score; and 6) The source of the infection, the results of blood cultures and other biological specimen cultures, and the antibiograms.

The time to first cessation of vasopressor support will also be documented. Follow-up until day 60 postresuscitation will include organ failure-free days and ventilator-free days. Finally, the ICU length of stay, the hospital discharge date, and the morbidity and complications / adverse events during hospital stay will be recorded.

ICU management protocol:

All septic patients enrolled in this study will be managed by a standardized approach which will comprise:

1. Empirical treatment with at least 2 broad spectrum antibiotics; antibiotic treatment will be deescalated according to microbiological data and clinical improvement
2. A conservative strategy of fluid management
3. A lung-protective ventilation strategy
4. Limited use of sedative agents according to pertinent guidelines
5. Enteral nutrition which will be started at 24 hours after ICU admission
6. Prophylaxis against deep venous thrombosis prophylaxis with both enoxaparin (or heparin in patients with a calculated creatinine clearance < 30 mL/min) and sequential compression/decompression stockings
7. Permissive hyperglycemia (ie, blood glucose of 150-200 mg/dL)

The study outcome measures are detailed in the dedicated subsection.

Sample size calculation: The previously reported frequency of impaired cerebral autoregulation is approximately 60% on day 2 after the diagnosis of sepsis/septic shock (3). The detection of a study intervention-related halving of the aforementioned proportion with an alpha value of 0.05 and a power of 0,80 would require the enrollment of 96 patients. As we estimate that at least 100 patients will be enrolled at Evagglismos hospital in the context of the steroids - vitamin C - thiamine multicenter RCT, we also propose a target enrollment of 100 patients for the current substudy.

G Power 3.1.9.2 Exact - Proportions: Inequality, two independent groups (Fisher's exact test) Options: Exact distribution Analysis: A priori: Compute required sample size Input: Tail(s) = Two Proportion p1 = 0.30 Proportion p2 = 0.60 α err prob = 0.05 Power (1-β err prob) = 0.80 Allocation ratio N2/N1 = 1 Output: Sample size group 1 = 48 Sample size group 2 = 48 Total sample size = 96 Actual power = 0.8004595 Actual α = 0.0290919

POSSIBLE SIGNIFICANCE OF STUDY RESULTS: In view of encouraging preliminary data on the corticosteroids / vitamin C, thiamine combination, we expect that the results of the current study will further elucidate important mechanisms underlying the (speculated) intervention-related benefit.

Inclusion Criteria:

• Diagnosis of septic shock within 12 hours of admission to the intensive care unit (ICU).

Exclusion Criteria:

• Age < 18 years
• Pregnancy
• Patients with a fatal underlying disease who are unlikely to survive to hospital discharge
• Patients with acquired immunodeficiency and a CD4 count of < 50 / μL
• Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.
• Patients with sepsis/septic shock transferred from another hospital
• Patients with features of sepsis/septic shock > 12 hours
• Patients who require treatment with corticosteroids for an indication other than sepsis
• Patients with any history of an allergic reaction

No specific plan

Participant, Care Provider, Investigator, Outcomes Assessor