Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care. 2020;8:15.
Meta-regression analysis of controlled trials that compared the duration of mechanical ventilation between vitamin C and control groups, including trials where vitamin C administration was the only difference between the 2 groups
Trials could be randomized or not, placebo or not, and included all doses of vitamin C. The investigators searched MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials on November 13, 2019. They did a prior search on January 20, 2019, of the same databases for trials on vitamin C and length of ICU (intensive care unit) stay.
Two trials used ventilator-free days, a term that could not be converted to duration of mechanical ventilation.
Trial Data Used for Analysis
Nine controlled trials reported on vitamin C administration and length of mechanical ventilation; 8 were included in the meta-analysis with 685 patients. Total number of patients in the 9 trials was 975, with 810 in 6 cardiac surgery trials, 128 patients in 2 sepsis trials, and 37 patients in 1 burn trial. Vitamin C was administered orally in 4 cardiac trials and intravenously in 5 trials (2 cardiac, 2 sepsis, and the 1 burn trial). The burn trial administered 90 grams of vitamin C over a single day. Three cardiac trials administered 1, 2, or 3 grams per day over 2 to 5 days. One sepsis trial administered 6 grams per day until discharge, while the other sepsis trial administered 6 grams per day once. Eight trials encompassing 685 patients were used for the final analysis. One cardiac trial recruited 500 patients but 210 dropped out and thus it was not included in the final meta-analysis.
Among the 8 included trials allocation was random in 5 cardiac trials; but not described in 1 of the cardiac trials. One sepsis trial was random while 1 sepsis trial and 1 burn trial used an undescribed alternative allocation that was not described.
Vitamin C, oral or intravenous, in patients receiving mechanical ventilation
The investigators used chi-square and I2 statistics to assess statistical heterogeneity among trials in the meta-analysis. I2 ranged from 0% to 100%, where 0% is a low-level heterogeneity, >50% is moderate heterogeneity, and >75% is high-level heterogeneity.
They also used ratio of means (RoM) to estimate the effect of vitamin C and the Taylor series–based approach to calculate the log of RoM. They pooled select trials with the metagen function of the meta-package of the R statistical software (R Core Team, R Project for Statistical Computing, 2019, accessed January 5, 2020), using inverse variance.
Ventilation time with vitamin C was reduced an average of 14% (P=0.00001) across the 8 trials. The investigators didn’t expect meaningful benefit from intravenous vitamin C if ventilation time was less than 10 hours. In the burn trial, vitamin C shortened the length of ventilation time an average of 25% (P<0.0001); burn patients tend to be quite ill. Overall residual heterogeneity was small with I2=12%.
Five cardiac trials administered vitamin C orally at 1 (1 trial), 2 (2 trials) and 3 (2 trials) g/day. Both sepsis trials administered 6 g/day intravenously and the 1 burn trial administered 90 g/day intravenously. The length of mechanical ventilation was shortened by an average of 14% (P=0.0001, but there was considerable heterogeneity (I2=83%, P=0.000048). The heterogeneity was explained by the length of mechanical ventilation in the untreated control group, (P=000001). If the ventilation time was under 10 hours regression indicated no benefit, but if it were 100 hours regression indicated ventilation time would be reduced an average of 31%. The highest dose use in 1 burn trial reduced ventilation time an average of 25% (P=0.000000001).
The more ill the patient was, the more likely they were to benefit from vitamin C; and if they received it, they spent less time under mechanical ventilation.
Among trials excluded, vitamin C with vitamin E was given in 3 trials with a decreased ventilation time of 20%. These trials used a combination of oral and intravenous administrations. In these 3 trials, the combined effect of vitamin C plus vitamin E was quite close to the predicted reduction in ventilation time with vitamin C alone found in this meta-analysis. Thus the authors argued that vitamin E may have been of little or no benefit.
Mechanical ventilation varies from routine to essential depending on disease severity. Bradypnea, acute respiratory syndrome, tachypnea, acute lung injury, vital capacity less than 15 mL/kg, or minute ventilation greater than 10 L/min all require mechanical ventilation. The authors’ meta-regression of the vitamin C effect, by looking at the control group, took this into account and found both low heterogeneity and an accurate prediction of which patients would benefit most from vitamin C. The more ill the patient was, the more likely they were to benefit from vitamin C; and if they received it, they spent less time under mechanical ventilation. Vitamin C also reduced the length of time spent in the ICU. If the time spent in ICU was 3 or more days, the time reduction was 10.1% (P=0.0001) versus stays of 1 to 2 days where the reduction was 5.7% (P=0.03), which is less of a reduction but still statistically significant.1
This paper again raised the negative specter of vitamin C causing death when too much is given (e.g, 80-224 g/d), but the researchers did not discuss the essential need to assess for G6PD deficiency before administering doses above 15 grams orally or intravenously.2-7 G6PD deficiency is the most common human enzyme deficiency with over 300 genetic variations found in about 7.5% of the world’s population. G6PD deficiency is a protection against Plasmodium falciparum and is divided into 5 classes with a higher incidence of deficiency in such populations as Kurdish Jews, 10% of African North Americans, Central and Western Africans, those from the Indian subcontinent, and those from the Mediterranean Basin.6
The more ill a patient is, the greater the clinical benefit vitamin C may have. A meta-analysis of exercise-induced bronchoconstriction found that vitamin C halved the decline in forced expiratory volume 1 (FEV1) caused by exercise, with the greatest effect in those with the greatest bronchoconstriction.8 In common-cold patients, vitamin C had the most benefit in those with the greatest bronchial hypersensitivity to histamine.9,10 The dose was 2 grams per day oral or chewed,8 while the doses ranged from 1 to 5 grams per day orally in the meta-analysis.9
Vitamins C and E interact both in vitro and in vivo such that vitamin C can rescue low vitamin E antioxidant levels.11,12 This was shown in a study with 11 male smokers where supplemental vitamin C (500 mg orally bid for 2 weeks) sustained vitamin E levels10 and in a study where dietary vitamin C (at a median of 90 mg/day) in 21,657 male Finnish smokers also sustained vitamin E levels.11 Vitamin C alone may prevent post-operation atrial fibrillation (AF) in some patients, but not others.13 The dose was typically 2 grams in the 12 hours prior to coronary artery bypass (CAB) and 1 to 2 grams per day for 5 to 7 days post-procedure. Vitamin C reduced the risk of AF by 27% and the duration of hospital stay by an average of 10.1% (P=0.0001), 16% if vitamin C was intravenous and 6% if vitamin C was oral. ICU length of stay was shortened by 8% (P=0.002).
Sepsis and septic shock affect about 15 million to 19 million people worldwide annually, with a mortality rate of about 60%, particularly in low-income countries.14 These patients are nearly always ventilated. In a 2017 study of septic patients in which those receiving standard care over a 7-month period served as controls (n=47) and were compared to those receiving HAT (hydrocortisone, ascorbic acid, and thiamine) over the following second 7-month period (n=47), hospital mortality was 40.4% in the controls (19 of 47) and 8.5% (4 of 47) in the treatment group (P<0.001.1).13,15 In each group 28% were positive for Escherichia coli.13 None in the treatment group developed progressive organ failure.
Septic patients enter the ICU with very low serum vitamin C and have an increased risk of death up to 5 years after the acute event. Approximately 50% of them suffer from post-sepsis syndrome, characterized by the development of new psychiatric and cognitive deficits.14,16 The treatment of septic patients consisted of broad-spectrum antibiotics empirically; norepinephrine as the vasopressor at 20 µg/min, targeting an arterial pressure of >65 mmHg; enteral nutrition using a whey-based formula; deep venous prophylaxis with enoxaparin or heparin based on creatinine clearance; intravenous vitamin C 1.5 grams every 6 hours for 4 days or until discharge; hydrocortisone 50 milligrams every 6 hours for 7 days or until discharge; and IV thiamine 200 milligrams every 12 hours for 4 days or until discharge.13 Vitamin C was delivered over 30 to 60 minutes in D5W (dextrose 5%) or normal saline, and thiamine was delivered in a piggyback of D5W or normal saline over 30 minutes.13 Mechanical ventilation was required for 22 individuals in the treatment group and 26 in the control group. The 3 predictors of mortality were vitamin C treatment, APACHE IV (acute physiology and chronic health evaluation) score, and need for mechanical ventilation (P=0.05).13
The CITRIS-ALI randomized clinical trial assessed the effect of intravenous vitamin C in patients with sepsis and severe acute respiratory failure at 7 ICUs in the United States from September 2014 to November 2017; the patients were enrolled within 24 hours of the onset of sepsis and ARDS (acute respiratory distress syndrome).17 Intravenous vitamin C was 50 mg/kg in D5W (n=84) or D5W as placebo (n=83) every 6 hours for 96 hours.15 Pneumonia was the most commonly presumed cause of sepsis: 82% in the treatment group versus 70% in the control group. On day 28 mortality was 46.3% in the placebo group and 29.8% in the treatment group (P=0.03), and Kaplan-Meier survival curves were significantly different, with the vitamin C group having better survival (P=0.01). There was no significant difference in the primary outcome, Sequential Organ Failure Assessment Score, from baseline to 96 hours (P=0.86); C-reactive protein levels (P=0.33); or thrombomodulin levels at 168 hours (P=0.70). However, the number of ventilator-free days was 13.1 for the vitamin C group and 10.6 for the placebo group (P=0.15); and the number of ICU-free days to day 28 was 10.7 days in the vitamin C group and 7.7 days in the placebo group (P=0.03). Transfer out of ICU by 168 hours (7 days) or less was 25% in the vitamin C group and 12.5% in the placebo group (P=0.03); and number of hospital-free days over the 28-day period was 22.6 in vitamin C recipients and 15.5 in placebo recipients (P=0.04). In secondary outcomes the vitamin C group fared significantly better.
Mechanical ventilation and septic conditions are dominated by excess production of reactive oxygen species (ROS), xanthine oxidase, lipoxygenase, cyclooxygenase, hydrogen peroxide, superoxide, hydroxyl radicals, peroxynitrite, and hypochlorous acid and the induction of such enzymes as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, elevation of nitric oxide, and uncoupling of mitochondrial oxidative phosphorylation. Vitamin C can scavenge free radicals, inhibit activation of xanthine oxidase and NADPH oxidase, protect mitochondria from oxidative stress, inhibit nitric oxide synthase activation, and decrease activation of nuclear factor kappa B (NF-кB).14,18
Humans, apes, guinea pigs, and salmon lack the ability to produce vitamin C and must obtain it from the diet.14,17 As seen above, vitamin C can rescue low vitamin E levels,10,11 combine with thiamine to scavenge free radicals and superoxide, inhibit activation of xanthine oxidase and NADPH oxidase, and with hydrocortisone synergistically decrease activation of NF-кB.14 Thiamine increases activation of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase and, thus, adenosine triphosphate (ATP). 17 Vitamin C also assists in microcirculation and immune function, decreases platelet activation and tissue factor expression, increases thrombomodulin, and is a cofactor in the synthesis of catecholamines and important in wound healing.14
Vitamin C can be a pro-oxidant when free iron is released from ferritin, a situation common in sepsis. This was demonstrated in rats when vitamin C doses of 30 mg/kg and 100 mg/kg decreased oxidative injury, while doses of 300 mg/kg and 1,000 mg/kg increased oxidative injury.19 This has led the Marik research and clinical treatment team to propose a U-shaped response curve to intravenous vitamin C in sepsis, with the optimal dose set at 6 grams per day based on over 800 patients and their procalcitonin values, and paralleling the findings of others.14,17 This is well discussed in a review of ischemia/reperfusion injury for both internal organs and the brain and the timing and dosing strategy for intravenous vitamin C.14,17 At least a dozen trials are underway to further test these concepts. Thus, vitamin C could be beneficial in septic and mechanically ventilated patients. Vitamin C doses typically used in patients with cancer can range from antioxidant levels of 1 to 15 grams to pro-oxidant levels of 100 grams in a single sitting, depending on the therapeutic goal.20 It is worth noting that in cancer patients, like septic and ventilation patients, at least 63% of them are deficient in vitamin C when presenting for initial treatment.13,14,17
This paper was well written by an individual whose published work on vitamin C dates back to at least 1997, including a 2013 Cochrane review on the use of vitamin C in the common cold with the same coauthor.21 He raised the possibility of vitamin C as a treatment for SARS because of its effects on T lymphocytes and production of interferon.22 He has been criticized, along with others, for publishing too many reviews on intravenous vitamin C in critical-care patients.23
This meta-analysis identified 9 trials but pooled data from 8 trials and 685 patients to find that vitamin C reduced the duration of mechanical ventilation by 14%, P=0.0001, with the illest patients obtaining the greatest value from infusions of vitamin C at 1 to 6 grams per day and a shortening of ventilation times by an average of 25%. These figures clearly demonstrate that vitamin C should be clinically considered and used in mechanically ventilated critical-care patients, patients who receive cardiac surgery, are septic, or have suffered burns, and especially among these who are the illest. One begins to wonder how long it will take conventional medicine to adopt a safe, simple, and significant life-saving intervention that has a very sound biochemical basis with conventional protocols.