Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports.

BACKGROUND: In the early literature, unintentional vitamin C deficiency in humans was associated with heart failure. Experimental vitamin C deficiency in guinea pigs caused enlargement of the heart. The purpose of this study was to collect and analyze case reports on vitamin C and pulmonary hypertension. METHODS: We searched Pubmed and Scopus for case studies in which vitamin C deficiency was considered to be the cause of pulmonary hypertension. We selected reports in which pulmonary hypertension was diagnosed by echocardiography or catheterization, for any age, sex, or dosage of vitamin C. We extracted quantitative data for our analysis. We used the mean pulmonary artery pressure (mPAP) as the outcome of primary interest. RESULTS: We identified 32 case reports, 21 of which were published in the last 5 years. Dyspnea was reported in 69%, edema in 53% and fatigue in 28% of the patients. Vitamin C plasma levels, measured in 27 cases, were undetectable in 24 and very low in 3 cases. Diet was poor in 30 cases and 17 cases had neuropsychiatric disorders. Right ventricular enlargement was reported in 24 cases. During periods of vitamin C deficiency, the median mPAP was 48 mmHg (range 29-77 mmHg; N = 28). After the start of vitamin C administration, the median mPAP was 20 mmHg (range 12-33 mmHg; N = 18). For the latter 18 cases, mPAP was 2.4-fold (median) higher during vitamin C deficiency. Pulmonary vascular resistance (PVR) during vitamin C deficiency was reported for 9 cases, ranging from 4.1 to 41 Wood units. PVR was 9-fold (median; N = 5) higher during vitamin C deficiency than during vitamin C administration. In 8 cases, there was direct evidence that the cases were pulmonary artery hypertension (PAH). Probably the majority of the remaining cases were also PAH. CONCLUSIONS: The cases analyzed in our study indicate that pulmonary hypertension can be one explanation for the reported heart failure of scurvy patients in the early literature. It would seem sensible to measure plasma vitamin C levels of patients with PH and examine the effects of vitamin C administration.

Vitamin C reduces the severity of common colds: a meta-analysis.

BACKGROUND: Randomized trials have shown that vitamin C shortens the duration of common colds. Some trials reported greater effects on severe cold symptoms compared with mild symptoms. This review systematically compares the effects of vitamin C on severe and mild common cold symptoms. METHODS: We included all placebo-controlled trials of orally administered vitamin C in doses of at least 1 g/day for the common cold for people in good health at baseline. The analysis was restricted to trials which reported both the total duration of the common cold, and the severity of the common cold measured using severity scales, the duration of more severe stages of the cold, or proxies for severe colds such as days indoors. Findings were pooled using the inverse variance, fixed effect options of the metacont function of the R package meta to calculate the ratio of means estimate. RESULTS: Fifteen comparisons from 10 trials which reported both mild and severe symptoms were identified. All trials were randomized and double-blind. Compared to placebo, vitamin C significantly decreased the severity of the common cold by 15% (95% CI 9-21%). The direct comparison of the effect of vitamin C on mild and severe symptoms was limited to five comparisons which found that vitamin C had a significant benefit on the duration of severe symptoms. In this subset, there was a significant difference in the size of the effect of vitamin C on the overall duration of colds versus the duration of severe colds (P = 0.002), and vitamin C had no significant effect on the duration of mild symptoms. CONCLUSIONS: The common cold is the leading cause of acute morbidity and a major cause of absenteeism from work and school. However, absenteeism is dependent on the severity of symptoms. The finding that vitamin C may have a greater effect on more severe measures of the common cold is therefore important. Further research on the therapeutic effects of vitamin C on the common cold should measure outcomes of differing levels of severity.

Vitamin C may reduce troponin and CKMB levels after PCI and CABG: a meta-analysis.

BACKGROUND: Ischemia/reperfusion injury contributes to periprocedural myocardial injury (PMI) in patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). PMI can be estimated by the elevation of troponin (Tn) and creatine kinase-MB (CKMB) plasma levels, and it is associated with increased risk of cardiovascular events and mortality. Vitamin C might have a beneficial effect on PMI by improving endothelial function, improving myocardial perfusion, and by reducing oxidative stress generated during/after reperfusion. In several small animal models of cardiac stress, vitamin C reduced the increase in Tn and CKMB levels. The aim of this meta-analysis was to investigate whether vitamin C administration may have an effect on Tn and CKMB levels in patients undergoing PCI or CABG. METHODS: We searched PubMed, Cochrane, Embase and Scopus databases for controlled clinical trials reporting on Tn and CKMB levels in adult patients who underwent PCI or CABG and received vitamin C. As secondary outcomes we collected data on biomarkers of oxidative stress in the included trials. In our meta-analysis, we used the relative scale and estimated the effect as the ratio of means. RESULTS: We found seven controlled trials which included 872 patients. All included trials administered vitamin C intravenously, with a range from 1 to 16 g/day, and all initiated vitamin administration prior to the procedure. Vitamin C decreased peak Tn plasma levels in four trials on average by 43% (95% CI: 13 to 63%, p = 0.01) and peak CKMB plasma levels in five trials by 14% (95% CI: 8 to 21%, p < 0.001). Vitamin C also significantly decreased the biomarkers of oxidative stress. CONCLUSIONS: Vitamin C may decrease cardiac enzyme levels in patients undergoing elective PCI or CABG. This may be explained partially by its antioxidant effects. Our findings encourage further research on vitamin C administration during cardiac procedures and in other clinical contexts that increase the level of cardiac enzymes. Future studies should search for an optimal dosing regimen, taking baseline and follow-up plasma vitamin C levels into account.

Abrupt termination of vitamin C from ICU patients may increase mortality: secondary analysis of the LOVIT trial.

BACKGROUND: The LOVIT trial examined the effect of vitamin C on sepsis patients, and concluded that in adults with sepsis receiving vasopressor therapy in the ICU, those who received 4-day intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. The aim of this study was to determine whether the abrupt termination of vitamin C administration could explain the increased mortality in the vitamin C group. METHODS: We used Cox regression with two time periods to model the distribution of deaths over the first 11 days in the LOVIT trial. RESULTS: Compared with a uniform difference between vitamin C and placebo groups over the 11-day follow-up period, addition of a separate vitamin C effect starting from day 5 improved the fit of the Cox model (p = 0.026). There was no difference in mortality between the groups during the 4-day vitamin C administration with RR = 0.97 (95% CI: 0.65-1.44). During the week after the sudden termination of vitamin C, there were 57 deaths in the vitamin C group, but only 32 deaths in the placebo group, with RR = 1.9 (95% CI: 1.2-2.9; p = 0.004). CONCLUSION: The increased mortality in the vitamin C group in the LOVIT trial is not explained by ongoing vitamin C administration, but by the abrupt termination of vitamin C. The LOVIT trial findings should not be interpreted as evidence against vitamin C therapy for critically ill patients.

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.

Quantile Treatment Effect of Zinc Lozenges on Common Cold Duration: A Novel Approach to Analyze the Effect of Treatment on Illness Duration.

Calculation of the difference of means is the most common approach when analyzing treatment effects on continuous outcomes. Nevertheless, it is possible that the treatment has a different effect on patients who have a lower value of the outcome compared with patients who have a greater value of the outcome. The estimation of quantile treatment effects (QTEs) allows the analysis of treatment effects over the entire distribution of a continuous outcome, such as the duration of illness or the duration of hospital stay. Furthermore, most of these outcomes have asymmetric distributions with fat tails, and censored observations are not uncommon. These features can be accounted for in the analysis of the QTE. In this paper, we use the QTE approach to analyze the effect of zinc lozenges on common cold duration. We use the data set of the Mossad (1996) trial with zinc gluconate lozenges, and three data sets of trials with zinc acetate lozenges. In the Mossad (1996) trial, zinc gluconate lozenges shortened common cold duration on average by 4.0 days (95% CI 2.3-5.7 days). However, the QTE analysis indicates that 15- to 17-day colds were shortened by 8 days, and 2-day colds by just 1 day, for the group taking zinc lozenges. Thus, the overall 4.0-day average effect of zinc gluconate lozenges in the Mossad (1996) trial is inconsistent with our QTE findings for both short and long colds. Similar results were found in our QTE analysis of the pooled data sets of the three zinc acetate lozenge trials. The average effect of 2.7 days (95% CI 1.8-3.3 days) was inconsistent with the effects on short and long colds. The QTE approach may have broad usefulness for examining treatment effects on the duration of illness and hospital stay, and on other similar outcomes.

Bias against Vitamin C in Mainstream Medicine: Examples from Trials of Vitamin C for Infections.

Evidence has shown unambiguously that, in certain contexts, vitamin C is effective against the common cold. However, in mainstream medicine, the views on vitamin C and infections have been determined by eminence-based medicine rather than evidence-based medicine. The rejection of the demonstrated benefits of vitamin C is largely explained by three papers published in 1975-two published in JAMA and one in the American Journal of Medicine-all of which have been standard citations in textbooks of medicine and nutrition and in nutritional recommendations. Two of the papers were authored by Thomas Chalmers, an influential expert in clinical trials, and the third was authored by Paul Meier, a famous medical statistician. In this paper, we summarize several flaws in the three papers. In addition, we describe problems with two recent randomized trial reports published in JAMA which were presented in a way that misled readers. We also discuss shortcomings in three recent JAMA editorials on vitamin C. While most of our examples are from JAMA, it is not the only journal with apparent bias against vitamin C, but it illustrates the general views in mainstream medicine. We also consider potential explanations for the widespread bias against vitamin C.

Carrageenan nasal spray may double the rate of recovery from coronavirus and influenza virus infections: Re-analysis of randomized trial data.

In this individual patient data meta-analysis we examined datasets of two randomized placebo-controlled trials which investigated the effect of nasal carrageenan separately on children and adults. In both trials, iota-carrageenan was administered nasally three times per day for 7 days for patients with the common cold and follow-up lasted for 21 days. We used Cox regression to estimate the effect of carrageenan on recovery rate. We also used quantile regression to calculate the effect of carrageenan on colds of differing lengths. Nasal carrageenan increased the recovery rate from all colds by 54% (95% CI 15%-105%; p = .003). The increase in recovery rate was 139% for coronavirus infections, 119% for influenza A infections, and 70% for rhinovirus infections. The mean duration of all colds in the placebo groups of the first four quintiles were 4.0, 6.8, 8.8, and 13.7 days, respectively. The fifth quintile contained patients with censored data. The 13.7-day colds were shortened by 3.8 days (28% reduction), and 8.8-day colds by 1.3 days (15% reduction). Carrageenan had no meaningful effect on shorter colds. In the placebo group, 21 patients had colds lasting over 20 days, compared with six patients in the carrageenan group, which corresponds to a 71% (p = .003) reduction in the risk of longer colds. Given that carrageenan has an effect on diverse virus groups, and effects at the clinical level on two old coronaviruses, it seems plausible that carrageenan may have an effect on COVID-19. Further research on nasal iota-carrageenan is warranted.

Comment on "Therapeutic target and molecular mechanism of vitamin C-treated pneumonia: a systematic study of network pharmacology" by R. Li, C. Guo, Y. Li, X. Liang, L. Yang and W. Huang, Food Funct., 2020, 11, 4765.

This Comment raises concerns about the article "Therapeutic target and molecular mechanism of vitamin C-treated pneumonia: a systematic study of network pharmacology".