Methodological Rigor and Transparency in Clinical Practice Guidelines for Nutrition Care in Critically Ill Adults: A Systematic Review Using the AGREE II and AGREE-REX Tools.

Background: To evaluate the methodological quality of (1) clinical practice guidelines (CPGs) that inform nutrition care in critically ill adults using the AGREE II tool and (2) CPG recommendations for determining energy expenditure using the AGREE-REX tool. Methods: CPGs by a professional society or academic group, intended to guide nutrition care in critically ill adults, that used a systematic literature search and rated the evidence were included. Four databases and grey literature were searched from January 2011 to 19 January 2022. Five investigators assessed the methodological quality of CPGs and recommendations specific to energy expenditure determination. Scaled domain scores were calculated for AGREE II and a scaled total score for AGREE-REX. Data are presented as medians (interquartile range). Results: Eleven CPGs were included. Highest scoring domains for AGREE II were clarity of presentation (82% [76-87%]) and scope and purpose (78% [66-83%]). Lowest scoring domains were applicability (37% [32-42%]) and stakeholder involvement (46% [33-51%]). Eight (73%) CPGs provided recommendations relating to energy expenditure determination; scores were low overall (37% [36-40%]) and across individual domains. Conclusions: Nutrition CPGs for critically ill patients are developed using systematic methods but lack engagement with key stakeholders and guidance to support application. The quality of energy expenditure determination recommendations is low.

Protocol summary and statistical analysis plan for Intensive Nutrition Therapy comparEd to usual care iN criTically ill adults (INTENT): a phase II randomised controlled trial.

INTRODUCTION: It is plausible that a longer duration of nutrition intervention may have a greater impact on clinical and patient-centred outcomes. The Intensive Nutrition care Therapy comparEd to usual care iN criTically ill adults (INTENT) trial will determine if a whole hospital nutrition intervention is feasible and will deliver more total energy compared with usual care in critically ill patients with at least one organ system failure. METHODS AND ANALYSIS: This study is a prospective, multicentre, unblinded, parallel-group, phase II randomised controlled trial (RCT) conducted in 23 hospitals in Australia and New Zealand. Mechanically ventilated critically ill adult patients with at least one organ failure who have been in intensive care unit (ICU) for 72-120 hours and meet all of the inclusion and none of the exclusion criteria will be randomised to receive either intensive or usual nutrition care. INTENT started recruitment in October 2018 and a sample size of 240 participants is anticipated to be recruited in 2022. The study period is from randomisation to hospital discharge or study day 28, whichever occurs first, and the primary outcome is daily energy delivery from nutrition therapy. Secondary outcomes include daily energy and protein delivery during ICU and in the post-ICU period, duration of ventilation, ventilator-free days, total bloodstream infection rate and length of hospital stay. All other outcomes are considered tertiary and results will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: Ethics approval has been received in Australia (Alfred Hospital Ethics Committee (HREC/18/Alfred/101) and Human Research Ethics Committee of the Northern Territory Department of Health (2019-3372)) and New Zealand (Northern A Health and Disability Ethics Committee (18/NTA/222). Results will be disseminated in an international peer-reviewed journal(s), at scientific meetings and via social media. TRIAL REGISTRATION NUMBER: NCT03292237.

Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis.

We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, - 29.8 h [95% CI - 44.1 to - 15.5]) and ICU stay (incremental mean difference, - 1.3 days [95% CI - 2.2 to - 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality.

Pharmacokinetic data support 6-hourly dosing of intravenous vitamin C to critically ill patients with septic shock.

OBJECTIVES: To study vitamin C pharmacokinetics in septic shock. DESIGN: Prospective pharmacokinetic study. SETTING: Two intensive care units. PARTICIPANTS: Twenty-one patients with septic shock enrolled in a randomised trial of high dose vitamin C therapy in septic shock. INTERVENTION: Patients received 1.5 g intravenous vitamin C every 6 hours. Plasma samples were obtained before and at 1, 4 and 6 hours after drug administration, and vitamin C concentrations were measured by high performance liquid chromatography. MAIN OUTCOME MEASURES: Clearance, volume of distribution, and half-life were calculated using noncompartmental analysis. Data are presented as median (interquartile range [IQR]). RESULTS: Of the 11 participants who had plasma collected before any intravenous vitamin C administration, two (18%) were deficient (concentrations < 11 µmol/L) and three (27%) had hypovitaminosis C (concentrations between 11 and 23 µmol/L), with a median concentration 28 µmol/L (IQR, 11-44 µmol/L). Volume of distribution was 23.3 L (IQR, 21.9-27.8 L), clearance 5.2 L/h (IQR, 3.3-5.4 L/h), and half-life 4.3 h (IQR, 2.6-7.5 h). For the participants who had received at least one dose of intravenous vitamin C before sampling, T0 concentration was 258 µmol/L (IQR, 162- 301 µmol/L). Pharmacokinetic parameters for subsequent doses were a median volume of distribution 39.9 L (IQR, 31.4-44.4 L), clearance 3.6 L/h (IQR, 2.6-6.5 L/h), and half-life 6.9 h (IQR, 5.7-8.5 h). CONCLUSION: Intravenous vitamin C (1.5 g every 6 hours) corrects vitamin C deficiency and hypovitaminosis C and provides an appropriate dosing schedule to achieve and maintain normal or elevated vitamin C levels in septic shock.

Vitamin C therapy for patients with sepsis or septic shock: a protocol for a systematic review and a network meta-analysis.

INTRODUCTION: Vasoplegia is common and associated with a poor prognosis in patients with sepsis and septic shock. Vitamin C therapy in combination with vitamin B1 and glucocorticoid, as well as monotherapy in various doses, has been investigated as a treatment for the vasoplegic state in sepsis, through targeting the inflammatory cascade. However, the combination effect and the relative contribution of each drug have not been well evaluated. Furthermore, the best combination between the three agents is currently unknown. We are planning a systematic review (SR) with network meta-analysis (NMA) to compare the different treatments and identify the combination with the most favourable effect on survival. METHODS AND ANALYSIS: We will include all randomised controlled trials comparing any intervention using intravenous vitamin C, vitamin B1 and/or glucocorticoid with another or with placebo in the treatment of sepsis. We are interested in comparing the following active interventions. Very high-dose vitamin C (≥12 g/day), high-dose vitamin C (≥6 g/day), vitamin C (<6 g/day); low-dose glucocorticoid (<400 mg/day of hydrocortisone (or equivalent)), vitamin B1 and combinations of the drugs above. The primary outcome will be all-cause mortality at the longest follow-up within 1 year but 90 days or longer postrandomisation. All relevant studies will be sought through database searches and trial registries. All reference selection and data extraction will be conducted by two independent reviewers. We will conduct a random-effects NMA to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. We will use the surface under the cumulative ranking curve and the mean ranks to rank the various interventions. To differentiate between the effect of combination therapies and the effect of a component, we will employ a component NMA. ETHICS AND DISSEMINATION: This SR does not require ethical approval. We will publish findings from this systematic review in a peer-reviewed scientific journal and present these at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42018103860.