Vitamin C May Improve Left Ventricular Ejection Fraction : A Meta-Analysis

Background: Vitamin C deprivation can lead to fatigue, dyspnea, oedema and chest pain, which are also symptoms of heart failure (HF). In animal studies vitamin C has improved contractility and mechanical efficiency of the heart. Compared with healthy people, patients with HF have lower vitamin C levels, which are not explained by differences in dietary intake levels, and more severe HF seems to be associated with lower plasma vitamin C levels. This meta-analysis looks at the effect of vitamin C on left ventricular ejection fraction (LVEF).Methods: We searched for trials reporting the effects of vitamin C on LVEF. We assessed the quality of the trials, and pooled selected trials using the inverse variance, fixed effect options. We used meta-regression to examine the association between the effect of vitamin C on LVEF level and the baseline LVEF level.Results: We identified 15 trials, three of which were excluded from our meta-analysis. In six cardiac trials with 246 patients, vitamin C increased LVEF on average by 12.0% (95% CI 8.1-15.9%; P < 0.001). In six non-cardiac trials including 177 participants, vitamin C increased LVEF on average by 5.3% (95% CI 2.0-8.5%; P = 0.001). In meta-regression analysis we found that the effect of vitamin C was larger in trials with the lowest baseline LVEF levels with P = 0.001 for the test of slope. The meta-regression line crossed the null effect level at a baseline LVEF level close to 70%, with progressively greater benefit from vitamin C with lower LVEF levels. Some of the included trials had methodological limitations. In a sensitivity analysis including only the four most methodologically sound cardiac trials, the effect of vitamin C was not substantially changed.Conclusions: In this meta-analysis, vitamin C increased LVEF in both cardiac and non-cardiac patients, with a strong negative association between the size of the vitamin C effect and the baseline LVEF. Further research on vitamin C and HF should be carried out, particularly in patients who have low LVEF together with low vitamin C intake or low plasma levels. Different dosages and different routes of administration should be compared.Peer reviewe

Association Between an Increase in Serum Sodium and In-Hospital Mortality in Critically Ill Patients*

OBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival. DESIGN: Retrospective cohort study. SETTING: Ten Dutch ICUs between January 2011 and April 2017. PATIENTS: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25]). CONCLUSIONS: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia

Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy

Objective: We wished to explore the use, diagnostic capability and outcomes of bronchoscopy added to noninvasive testing in immunocompromised patients. In this setting, an inability to identify the cause of acute hypoxaemic respiratory failure is associated with worse outcome. Every effort should be made to obtain a diagnosis, either with noninvasive testing alone or combined with bronchoscopy. However, our understanding of the risks and benefits of bronchoscopy remains uncertain. Patients and methods: This was a pre-planned secondary analysis of Efraim, a prospective, multinational, observational study of 1611 immunocompromised patients with acute respiratory failure admitted to the intensive care unit (ICU). We compared patients with noninvasive testing only to those who had also received bronchoscopy by bivariate analysis and after propensity score matching. Results: Bronchoscopy was performed in 618 (39%) patients who were more likely to have haematological malignancy and a higher severity of illness score. Bronchoscopy alone achieved a diagnosis in 165 patients (27% adjusted diagnostic yield). Bronchoscopy resulted in a management change in 236 patients (38% therapeutic yield). Bronchoscopy was associated with worsening of respiratory status in 69 (11%) patients. Bronchoscopy was associated with higher ICU (40% versus 28%; p<0.0001) and hospital mortality (49% versus 41%; p=0.003). The overall rate of undiagnosed causes was 13%. After propensity score matching, bronchoscopy remained associated with increased risk of hospital mortality (OR 1.41, 95% CI 1.08-1.81). Conclusions: Bronchoscopy was associated with improved diagnosis and changes in management, but also increased hospital mortality. Balancing risk and benefit in individualised cases should be investigated further

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Vitamin C and COVID-19

In numerous animal studies, vitamin C has prevented and alleviated viral and bacterial infections. In a few dozen placebo-controlled trials with humans, vitamin C has shortened infections caused by respiratory viruses, which indicates that the vitamin can also influence viral infections in humans. In critically ill patients, plasma vitamin C levels are commonly very low. Gram doses of vitamin C are needed to increase the plasma vitamin C levels of critically ill patients to the levels of ordinary healthy people. A meta-analysis of 12 trials with 1,766 patients calculated that vitamin C reduced the length of ICU stay on average by 8%. Another meta-analysis found that vitamin C shortened the duration of mechanical ventilation in ICU patients. Two randomized placebo-controlled trials found statistically significant reduction in the mortality of sepsis patients. The effects of vitamin C on acute respiratory distress syndrome (ARDS) frequently complicating COVID-19 pneumonia should be considered. Vitamin C is a safe and inexpensive essential nutrient.Peer reviewe

Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901