Whole blood thiamine, intravenous thiamine supplementation and delirium occurrence in the intensive care unit: retrospective cohort analyses.

BACKGROUND: Thiamine di-phosphate is an essential cofactor in glucose metabolism, glutamate transformation and acetylcholinesterase activity, pathways associated with delirium occurrence. We hypothesised that a deficiency in whole blood thiamine and intravenous thiamine supplementation could impact delirium occurrence. AIM: To establish whether a deficiency in whole blood thiamine and/or intravenous thiamine supplementation within 72 h of intensive care admission is associated with delirium occurrence. METHOD: The first dataset was secondary analysis of a previous study in an intensive care unit in the Netherlands, reported in 2017. The second dataset contained consecutive intensive care admissions 2 years before (period 1: October 2014 to October 2016) and after (period 2: April 2017 to April 2019) routine thiamine supplementation was introduced within 72 h of admission. Delirium was defined as a positive Confusion Assessment Method-Intensive Care Unit score(s) in 24 h. RESULTS: Analysis of the first dataset (n = 57) using logistic regression showed no relationship between delirium and sepsis or whole blood thiamine, but a significant association with age (p = 0.014). In the second dataset (n = 3074), 15.1% received IV thiamine in period 1 and 62.6% during period 2. Hierarchical regression analysis reported reduction in delirium occurrence in the second period; this did not reach statistical significance, OR = 0.81 (95% CI 0.652-1.002); p = 0.052. CONCLUSION: No relationship was detected between whole blood thiamine and delirium occurrence on admission, at 24 and 48 h. It remains unclear whether routine intravenous thiamine supplementation during intensive care admission impacts delirium occurrence. Further prospective randomised clinical trials are needed.

Mixed-methods randomised study exploring the feasibility and acceptability of eye-movement desensitisation and reprocessing for improving the mental health of traumatised survivors of intensive care following hospital discharge: protocol.

INTRODUCTION: Post-traumatic symptoms are common among patients discharged from intensive care units (ICUs), adversely affecting well-being, increasing healthcare utilisation and delaying return to work. Non-pharmacological approaches (eg, music, therapeutic touch and patient diaries) have been suggested as candidate interventions and trauma-focused psychological interventions have been endorsed by international bodies. Neither category of intervention is supported by definitive evidence of long-term clinical effectiveness in patients who have been critically ill. This study assesses the feasibility and acceptability of using eye-movement desensitisation and reprocessing (EMDR) to improve the mental health of ICU survivors. METHODS AND ANALYSIS: EMERALD is a multicentre, two-part consent, pilot feasibility study, recruiting discharged ICU survivors from three hospitals in the UK. We are gathering demographics and measuring post-traumatic symptoms, anxiety, depression and quality of life at baseline. Two months after discharge, participants are screened for symptoms of post-traumatic stress disorder (PTSD) using the Impact of Events Scale-Revised (IES-R). Patients with IES-R scores<22 continue in an observation arm for 12 month follow-up. IES-R scores≥22 indicate above-threshold PTSD symptoms and trigger invitation to consent for part B: a randomised controlled trial (RCT) of EMDR versus usual care, with 1:1 randomisation. The study assesses feasibility (recruitment, retention and intervention fidelity) and acceptability (through semistructured interviews), using a theoretical acceptability framework. Clinical outcomes (PTSD, anxiety, depression and quality of life) are collected at baseline, 2 and 12 months, informing power calculations for a definitive RCT, with quantitative and qualitative data convergence guiding RCT refinements. ETHICS AND DISSEMINATION: This study has undergone external expert peer review and is funded by the National Institute for Health and Care Research (grant number: NIHR302160). Ethical approval has been granted by South Central-Hampshire A Research Ethics Committee (IRAS number: 317291). Results will be disseminated through the lay media, social media, peer-reviewed publication and conference presentation. TRIAL REGISTRATION NUMBER: NCT05591625.

Surgical Prehabilitation: Nutrition and Exercise.

Complications after major surgery account for a disproportionate amount of in-hospital morbidity and mortality. Recent efforts have focused on preoperative optimization in an attempt to modify the risk associated with major surgery. Underaddressed, but important, modifiable risk factors are physical fitness and nutritional status. Surgical patients are particularly at risk of 3 related, but distinct, conditions: frailty, sarcopenia, and reduced physical fitness. Exercise-based prehabilitation strategies have shown promise in terms of improving aerobic fitness, although their impact on key clinical perioperative outcome measures have not been fully determined. Preoperative nutritional status also has a strong bearing on perioperative outcome.

Effects of dietary nitrate on respiratory physiology at high altitude - Results from the Xtreme Alps study.

Nitric oxide (NO) production plays a central role in conferring tolerance to hypoxia. Tibetan highlanders, successful high-altitude dwellers for millennia, have higher circulating nitrate and exhaled NO (ENO) levels than native lowlanders. Since nitrate itself can reduce the oxygen cost of exercise in normoxia it may confer additional benefits at high altitude. Xtreme Alps was a double-blinded randomised placebo-controlled trial to investigate how dietary nitrate supplementation affects physiological responses to hypoxia in 28 healthy adult volunteers resident at 4559 m for 1 week; 14 receiving a beetroot-based high-nitrate supplement and 14 receiving a low-nitrate 'placebo' of matching appearance/taste. ENO, vital signs and acute mountain sickness (AMS) severity were recorded at sea level (SL) and daily at altitude. Moreover, standard spirometric values were recorded, and saliva and exhaled breath condensate (EBC) collected. There was no significant difference in resting cardiorespiratory variables, peripheral oxygen saturation or AMS score with nitrate supplementation at SL or altitude. Median ENO levels increased from 1.5/3.0  mPa at SL, to 3.5/7.4 mPa after 5 days at altitude (D5) in the low and high-nitrate groups, respectively (p = 0.02). EBC nitrite also rose significantly with dietary nitrate (p = 0.004), 1.7-5.1  µM at SL and 1.6-6.3 µM at D5, and this rise appeared to be associated with increased levels of ENO. However, no significant changes occurred to levels of EBC nitrate or nitrosation products (RXNO). Median salivary nitrite/nitrate concentrations increased from 56.5/786 µM to 333/5,194  µM  with nitrate supplementation at SL, and changed to 85.6/641 µM and 341/4,553 µM on D5. Salivary RXNO rose markedly with treatment at SL from 0.55 µM to 5.70 µM. At D5 placebo salivary RXNO had increased to 1.90 µM whilst treatment RXNO decreased to 3.26 µM. There was no association with changes in any observation variables or AMS score. In conclusion, dietary nitrate supplementation is well tolerated at altitude and significantly increases pulmonary NO availability and both salivary and EBC NO metabolite concentrations. Surprisingly, this is not associated with changes in hemodynamics, oxygen saturation or AMS development.

Oral Coenzyme Q10 supplementation does not prevent cardiac alterations during a high altitude trek to everest base cAMP.

Exposure to high altitude is associated with sustained, but reversible, changes in cardiac mass, diastolic function, and high-energy phosphate metabolism. Whilst the underlying mechanisms remain elusive, tissue hypoxia increases generation of reactive oxygen species (ROS), which can stabilize hypoxia-inducible factor (HIF) transcription factors, bringing about transcriptional changes that suppress oxidative phosphorylation and activate autophagy. We therefore investigated whether oral supplementation with an antioxidant, Coenzyme Q10, prevented the cardiac perturbations associated with altitude exposure. Twenty-three volunteers (10 male, 13 female, 46±3 years) were recruited from the 2009 Caudwell Xtreme Everest Research Treks and studied before, and within 48 h of return from, a 17-day trek to Everest Base Camp, with subjects receiving either no intervention (controls) or 300 mg Coenzyme Q10 per day throughout altitude exposure. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac morphology and function. Following altitude exposure, body mass fell by 3 kg in all subjects (p<0.001), associated with a loss of body fat and a fall in BMI. Post-trek, left ventricular mass had decreased by 11% in controls (p<0.05) and by 16% in Coenzyme Q10-treated subjects (p<0.001), whereas mitral inflow E/A had decreased by 18% in controls (p<0.05) and by 21% in Coenzyme Q10-treated subjects (p<0.05). Coenzyme Q10 supplementation did not, therefore, prevent the loss of left ventricular mass or change in diastolic function that occurred following a trek to Everest Base Camp.

Design and conduct of 'Xtreme Alps': a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude.

The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the 'Xtreme Alps' expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients.