ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10089-0031 |
Outcome of Septic Shock Patients treated with Vitamin C and Thiamine: A Prospective Cohort Study
1-6Department of Critical Care, Manipal Hospital Yeshwanthpur, Bengaluru, Karnataka, India
Corresponding Author: Ipe Jacob, Department of Critical Care, Manipal Hospital Yeshwanthpur, Bengaluru, Karnataka, India, Phone: +91 809844208268, e-mail: ipe.jacob@gmail.com
Received on: 03 October 2022; Accepted on: 19 November 2022; Published on: 31 December 2022
ABSTRACT
Background: Although there has been great progress in the field of medicine, mortality associated with the age-old problem of sepsis still remains high. One of the newer modalities to treat sepsis is the hydrocortisone, ascorbic acid (AA), and thiamine (HAT) therapy, using HAT, which is proposed to reduce organ failure and mortality by restoring dysregulated host immune response and mitochondrial function as well as neutralizing reactive oxygen species (ROS). Studies evaluating the treatment of severe sepsis, burns, and trauma with vitamin C administration have shown inconsistent results. Several studies have also shown the detrimental effect of a positive fluid balance on patients with sepsis, including an increased risk of mortality. This study aims to evaluate the effect of vitamin C with thiamine on improving the outcome of septic shock.
Materials and methods: This prospective cohort study was conducted at a tertiary care intensive care unit (ICU) and enrolled adult septic shock patients admitted over a 6-month period between April and September 2018. They formed an intervention group that received intravenous (IV) vitamin C 1.5 gm every 6 hours and thiamine 200 mg every 12 hours in addition to antibiotics. This was compared with a retrospective cohort of patients admitted between July to December 2017, which received only antibiotics. Both vitamin C and thiamine were initiated within 6 hours of admission and given for a period of 4 days. Hydrocortisone, as an infusion of 200 mg over 24 hours, was used in all patients on vasopressor support. The primary outcome evaluated was ICU mortality and secondary outcomes, ICU length of stay (LOS), hospital LOS, mechanical ventilation-free days (MVFDs), vasopressor-free days (VFDs), and cumulative fluid balance after 4 days.
Results: A total of 30 patients fulfilled the inclusion criteria and formed the intervention group. This was compared with a retrospective group which was equally matched in their baseline characteristics and acute physiology and chronic health evaluation (APACHE) II scores (20 vs 21), as well as antibiotics, are given. ICU mortality was 19% in the intervention group and 34.1% in the retrospective group (p = 0.115). ICU LOS was higher in the intervention group (5 vs 4 days, p = 0.014). There was no difference in the other secondary outcome parameters, namely, hospital LOS (10 vs 8 days, p = 0.141), MVFDs (5 vs 6, p = 0.493), VFDs (4 vs 6, p = 0.415), and cumulative fluid balance (+583 mL vs +450 mL, p = 0.209).
Conclusion: Intravenous (IV) administration of vitamin C and thiamine may not be beneficial in improving the outcome in patients with septic shock.
How to cite this article: Mallappa M, Reddy SS, Kunwar S, et al. Outcome of Septic Shock Patients treated with Vitamin C and Thiamine: A Prospective Cohort Study. J Acute Care 2022;1(2):56-60.
Source of support: Nil
Conflict of interest: Dr Pradeep Rangappa and Dr Karthik Rao are editorial board members, and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of the Editor-in-Chief and his/her research group.
Keywords: Ascorbic acid, Ascorbic acid and thiamine protocol, Hydrocortisone, Mortality, Sepsis, Septic shock, Vitamin C.
INTRODUCTION
Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection.1 Sepsis associated with overwhelming circulatory, cellular, and metabolic abnormalities is referred to as septic shock and carries a higher risk of mortality than sepsis alone. Parameters to diagnose septic shock include requiring vasopressor support to maintain a mean arterial pressure of 65 mm Hg or higher and hyperlactatemia of >2 mmol/L.
Hospital mortality has been shown to be about 17% for sepsis and 26% for severe sepsis.2 Annually, sepsis accounts for >5 million deaths worldwide.3 Even in high-income countries, there is a high incidence of sepsis ranging from 194 to 580 cases/100,000 population. Given this background, there are concerted efforts to develop newer, inexpensive, but effective modalities in treating sepsis.
The underlying pathophysiology of sepsis is an excess production of oxidants, mainly nitric oxide (NO), overwhelming the protective role of antioxidants. This imbalance is referred to as oxidative stress. This leads to increased vascular permeability, cardiac dysfunction, and mitochondrial malfunction. Vitamin C is one of the antioxidants purported to restore the redox balance in sepsis by preventing the oxidation of lipids, proteins, and deoxyribonucleic acid. AA is the redox form of vitamin C. Administration of vitamin C in animal models is shown to reduce edema and hypotension.4 Capillary density is noted to be decreased in sepsis, in addition to imbalances in perfusion due to poorly perfused and well-perfused capillaries in close proximity, altogether leading to hypoperfusion of tissues.5 These observations have been seen in bacterial peritonitis as well as proven experimentally by the administration of endotoxins or live bacteria in animal studies. Improvement in the vascular density of perfused capillaries may lead to a favorable outcome. The release of NO at the endothelial level is also impaired in sepsis and may contribute to the microcirculatory dysfunction seen in sepsis. Understanding this pathophysiology has given rise to the premise that focusing on improving microcirculation is more important than increasing overall blood flow to the organ. Endothelial NO synthase (eNOS), required for the production of NO, is the target of new therapies to improve blood flow at the microcirculatory level. Tetrahydrobiopterin (BH4) is an essential cofactor required for eNOS activity, and the ratio of BH4 to dihydrobiopterin determines the production of NO rather than free radicals such as superoxide and peroxynitrite. Vitamin C administration increases BH4 levels and may lead to the activation of eNOS. This has been experimentally proven when given in rats with peritonitis and shown to improve microcirculation.
It is known that vitamin C levels are low in sepsis.6 Animal studies show that IV administration of vitamin C improves microvascular blood flow and responsiveness of arterioles to vasoconstrictors and stabilizes the permeability barrier, leading to increased survival. Vitamin C, given with IV, acts as a scavenger of ROS within the microvascular endothelium and facilitates NO production by eNOS by increasing BH4 levels. In a small study on multi-organ failure in ICU patients, vitamin C levels were consistently lower as compared to other antioxidants such as vitamin E, copper, and zinc.7
Endothelial dysfunction, defined as loss of endothelium-mediated vasodilation, is related to the decreased generation of NO by eNOS. NO bioavailability can be restored only by administration of supraphysiological doses of IV vitamin C.8 High-dose vitamin C is also shown to reverse vaso-hyporeactivity in humans and sepsis-induced microcirculatory dysfunction in rodents. Additionally, it can reduce the volumes of fluids required for the resuscitation of both animals and humans in severe burn injuries.
The glycocalyx, which is a layer on the luminal surface of the endothelium, helps to maintain the vascular permeability barrier, mediates shear stress-dependent NO production, and houses vascular protective enzymes.9 Excessive activity of ROS may damage integral proteins and lipids of the endothelial glycocalyx and cell membranes with disruption of tight intercellular junctions, resulting in increased capillary permeability and cellular and organ dysfunction. Vitamin C may ameliorate this inflammatory process through its antioxidant function and by facilitating the synthesis of inflammatory modulators such as cortisol, catecholamines, and vasopressin. It prevents the uncoupling of eNOS and further formation of ROS, thereby restoring endothelial function.10 It acts as a cofactor for dopamine B hydroxyls which in turn convert dopamine to norepinephrine. Hence, endogenous norepinephrine levels decrease when vitamin C levels fall, as in sepsis, leading to protracted shock. Many studies have shown shock reversal on supplementing treatment with vitamin C. It acts by scavenging free radicals, restoring BH4 and α-tocopherol, which are useful for cell viability and, importantly, increases the tight junctions, which maintains endothelial integrity within the vessel wall and prevents intracellular and paracellular leakage from the blood vessel. This serves to reduce the cumulative balance and enhance the function of lymphocytes and macrophages.
Thiamine is an antioxidant that prevents lipid peroxidation and oleic acid oxidation.11 It acts as a cofactor for several enzymatic reactions that are key to aerobic carbohydrate metabolism, maintaining the cellular redox state and production of adenosine triphosphate by oxidative phosphorylation. Thiamine stores may be depleted within 2 weeks unless adequately supplemented in the diet. Thiamine is a cofactor for the pyruvate dehydrogenase complex (PDHC), an enzyme of the Kreb’s cycle, which converts pyruvate to acetyl CoA. Thiamine deficiency leads to dysfunction of the PDHC and shunting of pyruvate into anaerobic metabolism, resulting in the production of lactate. Sepsis which is marked by severe oxidative stress may deplete thiamine stores, leading to the deficiency seen in about 20% of sepsis patients. Animal studies have shown that thiamine deficiency is associated with increases in inflammatory and oxidative stress markers, suggesting that inadequate thiamine stores may worsen the body’s stress response to sepsis.
Thiamine is required for the metabolism of glyoxals, which are reactive α-oxoaldehydes formed endogenously from sugars.12 High levels of this metabolite may lead to the oxidation of glutathione (GSH) present in hepatocytes by hydrogen peroxide, which consequently increases cytotoxicity by GSH depletion, oxidative stress, and mitochondrial toxicity. This cytotoxicity can be prevented by thiamine supplementation.
The main side effects from the use of IV vitamin C include renal oxalate stones and pseudohyperglycemia.13 Urinary excretion of oxalate, which is formed from the breakdown of vitamin C, is increased following the administration of high doses of IV vitamin C. However, most studies on high-dose IV vitamin C in sepsis limited its usage to 4 days and did not report increased rates of nephrolithiasis.
Hydrocortisone is used in septic shock to attenuate the inflammatory response and reverse shock.14 It has been shown to lead to a quicker resolution of shock, more MVFDs, and shorter ICU LOS, although without a beneficial effect on mortality. It is also suggested that the infusion regimen rather than bolus doses may minimize the potentially harmful metabolic effects of glucocorticoids.
The HAT therapy, as envisaged by Marik et al., was based on a small study that compared a cohort of septic shock patients treated with IV vitamin C, hydrocortisone, and thiamine with a retrospective group treated with other standard medications.15 The study found improved hospital mortality, decreased sequential organ failure assessment (SOFA) scores, and more VFDs, and concluded that the combination of IV vitamin C, corticosteroid, and thiamine, when used early on in sepsis and septic shock, may prevent the progression of organ failure and reduce mortality. The positive results could be attributed to the synergism between hydrocortisone and vitamin C. The role of thiamine in this cocktail is as a coenzyme for vitamin C metabolism.
However, the benefits of the Marik et al. study have not been replicated in other studies, including the present one. In the VITAMINS trial, patients received the same dose of HAT as in the present study but failed to show any improvement.16
The trial concluded that HAT therapy might not resolve septic shock any faster than hydrocortisone alone. In the present study, the effectiveness of IV vitamin C (AA) and thiamine in improving all-cause mortality was investigated. Cumulative fluid balance was taken as another endpoint, as a positive balance has detrimental effects on patients with septic shock. A study by Sakr et al. shows the benefit of aiming for a negative fluid balance after 3 days in the ICU.17 Fluid balance was noted to be less positive in survivors than in nonsurvivors after 3 days in ICU, proving an independent association between higher cumulative fluid balance at day 3 and an increased hazard of death. Another study has shown that mortality was higher in patients with positive fluid balance for 3 consecutive days.18 Vitamin C administration has been shown to stabilize the capillary endothelial glycocalyx, thus reducing vascular permeability and edema, thus theoretically contributing to a negative fluid balance.9
MATERIALS AND METHODS
Study Design and Setting
This was a prospective cohort study investigating the effectiveness of IV vitamin C and thiamine on improving outcomes in patients with septic shock admitted to a single tertiary care hospital between April and September 2018. Adult, nonpregnant patients with septic shock and initiated on inotropic support not later than 6 hours were eligible for recruitment. Patients excluded from the study were those with burns, acute liver failure, terminally ill, with a known history of nephrolithiasis, and shock occurring after cardiac arrest. The study also included a group of septic shock patients admitted between July and December 2017, which received only antibiotics and formed the nonintervention, retrospective arm. Consent was obtained from the institutional ethics committee of Columbia Asia Hospitals with registration no ECR/105/Inst/KA/2013/4416, dated 3rd October 2017. The research conducted adhered to the strengthening of the reporting of observational studies in epidemiology guidelines.
Data Collection
Data were retrieved from the electronic medical records and included age, sex, diagnosis, comorbidities, Glasgow Coma Scale scores, APACHE II scores, procalcitonin, duration of vasopressor use, duration of mechanical ventilation, length of ICU and hospital stay, and fluid balance. Analysis was performed based on the intention to treat. For categorical values, statistical significance was assessed using a chi-squared test or Fisher’s exact test. The median test was used for continuous variables.
Data Analysis
Data were analyzed using statistical software Statistical Package for the Social Sciences Inc. released in 2009. PASW statistics for Windows, Version 18.0. Chicago, United States of America: mortality data were summarized in terms of percentage. The Chi-squared test was used to compare the mortality proportion between the two groups. Whenever the chi-square assumption failed, Fisher’s exact test was used. A p-value of <0.05 was considered for statistical significance.
Sample Size
Following a prior study,15 which showed a >30% reduction in mortality (risk difference) with vitamin C therapy, the target of the present study was a minimum of 20% reduction in absolute ICU mortality between the groups. Data from this institution shows mortality rates of about 30% for septic shock. Using this baseline mortality rate and employing a two-tailed α of 0.05, it was estimated that a minimum of sixty subjects would be needed to detect a 20% decrease in absolute mortality with 80% power.
Outcome Measures
The primary outcome evaluated was all-cause mortality between the intervention and the retrospective groups. The secondary endpoints were cumulative fluid balance in both groups, VFDs, MVFDs, and durations of ICU and hospital stay.
Intervention
Patients in the intervention arm received IV vitamin C 1.5 gm every 6 hours and thiamine 200 mg every 12 hours, for 5 days, in addition to a standard regimen of antibiotics for septic shock. The first doses of the drugs were administered within 6 hours of the onset of septic shock/admission. Vitamin C was administered over 60 minutes using a photolysis-preventing infusion set. This intervention group was compared with a retrospective cohort of septic shock patients, which was equally matched in terms of number and APACHE II scores, as well as antibiotics given for septic shock. Normal saline was used to resuscitate all patients, according to surviving sepsis campaign guidelines.1 A IV hydrocortisone was also used in all patients in both groups as they were on vasopressor support at admission. The infusion of vitamin C and thiamine was concluded either after 5 days or when the subject was off vasopressors for 24 consecutive hours.
RESULTS
A total of 30 patients met the inclusion criteria and formed the intervention group, with another 30 in the retrospective group. Demographic data, APACHE II scores, and comorbidities are enumerated in Table 1. There was no benefit in either primary or secondary outcomes parameters, as shown in Table 2. ICU mortality among the treatment group was 19% as against 34% in the retrospective group, a nonsignificant difference. The median ICU and hospital LOS were 5 and 10 days, respectively, in the treatment group, compared to 4 and 8 days, respectively, in the retrospective arm. The treatment group has a median of five MVFDs and four VFDs, as against six MVFDs and six VFDs in the retrospective group. The treatment group had a positive cumulative fluid balance of 583 mL at the end of 3 days in the ICU vs a positive balance of 450 mL in the retrospective group (Fig. 1).
| Parameter/comorbidity | Treatment (n = 30) | Control (n = 30) | p-value | |
|---|---|---|---|---|
| Age | 64 | 65 | 0.573 | |
| Median (IQR) in years | (57, 74) | (54, 74) | ||
| Gender | Male | 16 (53%) | 17 (57%) | |
| Female | 14 (47%) | 13 (43%) | ||
| Hypertension | 23 (76%) | 16 (54%) | 0.032 | |
| DM | 19 (62%) | 14 (46%) | 0.127 | |
| CKD | 6 (21%) | 4 (13.0%) | 0.296 | |
| APACHE II | 20 (14.75, 25) | 21 (15, 26) | 0.428 | |
DM, diabetes mellitus; CKD, chronic kidney disease
| Outcome measure | Treatment (n = 30) median (IQR) | Control (n = 30) median (IQR) | p-value |
|---|---|---|---|
| ICU mortality | 6 (19.0 %) | 10 (34 %) | 0.115 |
| ICU LOS | 5 (5, 7.25) | 4 (3, 8.5) | 0.014 |
| Hospital LOS | 10 (6, 15.25) | 8 (4, 15.5) | 0.141 |
| MVFDs | 5 (4, 7) | 6 (1.25, 9.75) | 0.493 |
| VFDs | 4 (3, 6.25) | 6 (1.25, 9.75) | 0.415 |
| Cumulative balance (mL) after 4 days mean ± standard deviation | +583.5 (−348.8– +2346.3) | 450.0 (−150.0– +900.0) | 0.209 |
Chi-square, 2.48
Fig. 1: Box plot showing cumulative fluid balance at the end of day 3 in ICU
DISCUSSION
In this study of vitamin C and thiamine therapy for septic shock, the absolute risk of ICU mortality was reduced by 19% (p = 0.115) in the interventional arm, which did not meet the primary outcome measure of reducing ICU mortality by 20%. There was a modest increase in fluid administration in the intervention arm, which was of unclear clinical significance. There are several studies of vitamin C-based therapies for sepsis and septic shock that have been concluded recently. Amongst these, the maximum reduction in 28- or 30-day absolute mortality observed has been 7.5%, and none were significant. Some trials suggest that initiating HAT therapy within 48 hours of the onset of sepsis may reduce 28-day mortality as well as lead to a quicker resolution of shock19; however, these findings have not been replicated elsewhere.
In the vitamin C infusion for treatment in sepsis-induced acute lung injury trial of vitamin C monotherapy for patients with sepsis and acute lung injury, the primary endpoints of reduction in SOFA score and plasma levels of inflammatory markers were not achieved, although a reduction in 28-day absolute mortality of 16.6%(p = 0.03) was demonstrated.20 A post hoc analysis of this study suggests a mortality benefit for patients requiring positive-pressure ventilation relative to the general study population. However, concluding whether vitamin C may benefit patients with septic shock and sepsis-induced respiratory dysfunction would require further trials incorporating ICU mortality as a primary endpoint. The vitamin C, thiamine, and steroids in the sepsis trial in 2021 did not show a significant increase in either ventilator or VFDs within 30 days, but this trial was terminated early.21
The multicenter, randomized, controlled lessening organ dysfunction with vitamin C study was carried out in 35 medical-surgical ICUs in Canada, France, and New Zealand.22 The primary outcome, a composite of death or persistent organ dysfunction at 28 days, was higher in the vitamin C group compared to the control group (44.5 vs 38.5%; 95% confidence interval, 1.04–1.40, p = 0.01). The SOFA scores at specific time intervals from days 1–28, 6-month survival, and health-related quality of life were also similar between the two groups. This study clearly demonstrated a lack of beneficial effects and possible harm from the use of high-dose vitamin C in patients with severe sepsis.
Limitations
This is a single-center study with a small sample size, and hence the result may not be generalized to the population. Secondly, as serum vitamin C levels were not measured, the degree of preexisting hypovitaminosis, if any, could not be assessed, nor the degree to which vitamin C levels were increased by supplementation. Thirdly, the exact time of onset of shock in a subject prior to admission was unclear, leading to inconsistencies in the duration between shock onset and study drug initiation.
CONCLUSION
The findings of this study corroborate that of other major and larger studies. While vitamin C and thiamine are theoretically and experimentally beneficial in improving septic shock at the microcirculatory level, the actual administration of IV vitamin C and thiamine may not show any benefit in patients with septic shock admitted to the ICU.
ORCID
Pradeep Rangappa https://orcid.org/0000-0002-2187-8950
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