Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial.

Importance: Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors. Objective: To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial. Design, Setting, and Participants: This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022. Interventions: The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo. Main Outcomes and Measures: Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization. Results: After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups. Conclusions and Relevance: In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Neurocognitive Function Changes Following Kidney Transplant: A Prospective Study.

Rationale & Objective: Patients with advanced kidney disease are at risk for cognitive impairment, which may persist after kidney transplantation. We sought to understand changes in neurocognitive function domains utilizing comprehensive cognitive assessments. Study Design: Prospective cohort study. Setting & Population: Single-center study of patients undergoing kidney transplantation. Exposure: Kidney transplantation. Outcomes: Changes in neurocognitive function as measured by the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and the Trail Making Test Parts A and B (TRAIL A and B) before transplantation (baseline) and compared to 3 months and 12 months posttransplant. Analytical Approach: Wilcoxon signed-rank and linear mixed effect models were utilized to assess changes in neurocognitive scores at 3 months and 12 months compared to baseline. Results: Thirty-two patients were included with a mean age of 45 years, 47% female, 85% White, and 62% with at least some college education. Hypertension and diabetes were etiologies of kidney disease in 31% and 25% of patients, respectively. Baseline RBANS and TRAIL A and B scores averaged 84.7 ± 14, 40.4 ± 9.9, and 41 ± 11.5, respectively. Although there were posttransplant improvements in immediate and delayed memory at 3 months, these were not sustained at 12 months. There were no significant differences from baseline at 3 months and 12 months in RBANS index scores for language, visuospatial/constructional abilities, and attention. Compared to baseline, TRAIL A scores were not significantly different at 3 months but were significantly improved at 12 months, whereas TRAIL B scores improved significantly at both 3 months and 12 months. Limitations: Single-center design and small sample size. Conclusions: Utilizing comprehensive cognitive assessments, we found improvements in attention and executive function in the first posttransplant year as measured by TRAIL A and B. However, there was no significant change in global cognition as measured by RBANS. These findings identify cognitive domains for potential intervention in the posttransplant population.

Instruments Assessing Cognitive Impairment in Survivors of Critical Illness and Reporting of Race Norms: A Systematic Review.

To conduct a systematic review to summarize cognitive instruments being used in long-term outcome studies of survivors of adult critical illness, as well as evaluate whether these measures are reported as using patient demographic norms, specifically race norms. DATA SOURCES: A comprehensive search was conducted in PubMed (National Center for Biotechnology Information), Excerpta Medica dataBASE (Ovid), Psychological Information Database (ProQuest), and Web of Science (Clarivate) for English language studies published since 2002. STUDY SELECTION: Studies were eligible if the population included adult ICU survivors assessed for postdischarge cognitive outcomes. DATA EXTRACTION: Two independent reviewers screened abstracts, examined full text, and extracted data from all eligible articles. DATA SYNTHESIS: A total of 98 articles (55 unique cohorts: 22 general ICU, 14 Acute respiratory distress syndrome/Acute respiratory failure/Sepsis, 19 COVID-19 and other subpopulations) were eligible for data extraction and synthesis. Among general ICU survivors, the majority of studies (n = 15, 68%) assessed cognition using multiple instruments, of which the most common was the Mini-Mental State Examination. Only nine of the 22 studies (41%) explicitly reported using patient demographic norms for scoring neuropsychological cognitive tests. Of the nine, all reported using age as a norming characteristic, education was reported in eight (89%), sex/gender was reported in five (55%), and race/ethnicity was reported in three (33%). Among Acute respiratory distress syndrome/Acute respiratory failure/Sepsis survivors, norming characteristics were reported in only four (28%) of the 14 studies, of which all reported using age and none reported using race/ethnicity. CONCLUSIONS: Less than half of the studies measuring cognitive outcomes in ICU survivors reported the use of norming characteristics. There is substantial heterogeneity in how studies reported the use of cognitive instruments, and hence, the prevalence of the use of patient norms may be underestimated. These findings are important in the development of appropriate standards for use and reporting of neuropsychological tests among ICU survivors.

Effect of Early High-Dose Vitamin D3 Repletion on Cognitive Outcomes in Critically Ill Adults.

BACKGROUND: Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition. RESEARCH QUESTION: Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function? STUDY DESIGN AND METHODS: This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group. RESULTS: Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42). INTERPRETATION: In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov.

Feasibility of Videophone-Assisted Neuropsychological Testing For Intensive Care Unit Survivors.

BACKGROUND: Most hospitals lack neuropsychologists, and this lack has hampered the conduct of large-scale, multicenter clinical trials to evaluate the effect of interventions on long-term cognition in patients in intensive care units (ICUs). OBJECTIVE: To evaluate the feasibility of videophone-assisted neuropsychological testing administered by using an inexpensive high-definition web camera and a laptop. METHODS: This prospective, single-center observational study, conducted at a tertiary care academic hospital, included ICU survivors aged 18 years or older. Participants were seated in a quiet room with a proctor who provided neuropsychological testing forms and addressed technical difficulties. The neuropsychological rater was in a room 100 yd (90 m) from the participant. Skype was used for videoconferencing via a wireless connection. After the testing session was completed, participants completed surveys. RESULTS: In April 2017, 10 ICU survivors (median age, 63 years; range, 51-73 years) were enrolled. All indicated that "Videophone-assisted neuropsychological testing is reasonable to use in research studies." When asked "What made the videophone-assisted cognitive testing difficult?" 1 participant (10%) reported occasionally becoming frustrated with the testing because the wireless internet speed was slower than usual and reduced the resolution of visual stimuli. Three participants (30%) reported difficulty with the line orientation task because the lines were "shaky" and the images were "hard to see." CONCLUSION: Videophone-assisted neuropsychological testing is feasible for evaluating cognition in multicenter studies of ICU patients. Feedback provided will be used to refine this telemedicine approach to neuropsychological testing.

Psychological Sequelae in Family Caregivers of Critically III Intensive Care Unit Patients. A Systematic Review.

Rationale: Family members of critically ill patients hospitalized in the intensive care unit (ICU) often become caregivers, and they are at risk to develop adverse psychological outcomes. There is a need to understand the psychological impact of critical illness on family caregivers. Objectives: The aim of this systematic review is to document the prevalence of depression, anxiety, and post-traumatic stress disorder (PTSD) in family caregivers of critically ill patients and identify potential risk factors for psychological outcomes to inform clinical and future research recommendations. Methods: A literature search for psychological outcomes for family caregivers of critically ill patients was conducted. A total of 1,148 studies from PsycINFO, CINAHL, Web of Science, SCOPUS, and Medline were identified. Results: Forty studies met inclusion criteria and were included in the review. The prevalence of psychological outcomes in family caregivers ranged from 4% to 94% for depression, 2% to 80% for anxiety, and 3% to 62% for PTSD. Caregiver depression, anxiety, and PTSD decreased in most studies that assessed longitudinal outcomes. Common risk factors identified for adverse psychological outcomes included younger caregiver age, caregiver relationship to the patient, lower socioeconomic status, and female sex. Conclusions: The prevalence of depression, anxiety, and PTSD varies greatly across studies of family caregivers of critically ill patients. This finding highlights the need for more systematic investigations of psychological outcomes and the implementation of clinical interventions to prevent or reduce depression, anxiety, and PTSD in family caregivers of critically ill patients.