Hydrocortisone, Vitamin C and thiamine for the treatment of sepsis and septic shock following cardiac surgery.

BACKGROUND AND AIMS: The effect of vitamin C on vasopressor requirement in critically ill patients have been evaluated previously. We aimed to evaluate the effect of vitamin C, hydrocortisone and thiamine on vasopressor requirement and mortality in post-operative adult cardiac surgical patients with septic shock.
METHODS: About 24 patients with septic shock were randomised into Group 1 (receiving matching placebo per day for 4 days) and Group 2 (receiving 6 g vitamin C, 400 mg thiamine and 200 mg hydrocortisone per day for 4 days). Vasopressor dose over 4 days of therapy was the primary endpoint, whereas in-hospital mortality was the secondary endpoint.
RESULTS: APACHE IV and EUROSCORE II scores were similar between both the groups. Significant reductions in the requirement of vasopressin (difference from day 1 - 0.0008 ± 0.00289 vs 0.0033 ± 0.00492 units/kg/min; P = 0.019) and noradrenaline (difference from day 1 - 0.0283 ± 0.040 vs 0.023 ± 0.035 μg/kg/min; P = 0.006) were observed with vitamin C treatment as compared to control group. PCT levels on Day 3 (68.11 ± 33.64 vs 33.2 ± 27.55 ng/mL; P = 0.0161) and Day 4 (70.03 ± 29.74 vs 26.3 ± 23.08 ng/mL; P = 0.0009) were significantly lower in treatment group as compared to control. However, there was no difference in the Sepsis-Related Organ Failure Assessment (SOFA) score and mortality between the studied groups.
CONCLUSION: Combination of vitamin C, thiamine and hydrocortisone reduces vasopressor requirement in adult cardiac surgical patients with septic shock.

INTRODUCTION

Sepsis affects an estimated 15–19 million cases per year worldwide;[1] the vast majority of these cases occur in low-income countries. Timely diagnosis and improvements in supportive care has led to a decrease in mortality rates by 25%.[234] Sepsis following cardiac surgeries has been known to have catastrophic consequences.[5] A cheap and effective treatment is the need of the hour to reduce mortality and financial burden. Our institute faces sepsis rates as high as 8–10% with mortality rates as high as 80%. Studies have shown that vitamin C, which is a cofactor for the production of catecholamines and cortisol, hormones needed for the survival of shock.[67] is depleted during sepsis. To compound the problems, cardiac failure is also known to be a state of catecholamine depletion.[8] Studies have shown that vitamin C given in a dose of 6 g per day is safe and devoid of side effects. Doses as high as 100–150 g have been safely administered to patients with burns and malignancy.[9] Intravenous thiamine (vitamin B1) was added to the vitamin C to prevent renal side effect of large dose of vitamin C and hydrocortisone is used to increase the endogenous production of catecholamine. A recent retrospective, before-after study found a dramatic decrease mortality in patients with sepsis treated with of high-dose vitamin C, hydrocortisone and thiamine.[10] This study evaluates the effects of high-dose vitamin C, hydrocortisone and thiamine given together in adult patients with sepsis and septic shock following cardiac surgery.

METHODS

This study was a double-blinded randomised control study and approved by the Institutional Ethical Committee. Twenty-four patients were randomised into two groups [Group 1 control (placebo) and Group 2 study (vitamin C)] by methods of permuted block randomisation. The method consisted of six blocks, each containing four patients in random manner. Treating clinicians, researchers and nurses were blinded to this study protocols. The computerised randomisation chart was prepared by the statistician. Blinding was achieved by preparing the drug solutions in black syringes. Primary endpoint was vasopressor- free days. Secondary endpoint was in hospital mortality. The sample size was calculated as 12 patients per group based on one previously reported study[11] stating that the mean dose of norepinephrine was 7.44 ± 3.65 mcg/min in the treatment group in contrast to 13.79 ± 6.48 mcg/min in the control group. The alpha error of 0.05 and a dropout rate of 15% were assumed. Patients diagnosed with septic shock and a procalcitonin (PCT) level >7 ng/mL were included in the study. Informed consent form was taken from all the patients or from their relatives when the patient was unable to give consent. The lower limit of PCT detection was 0.05 ng/mL. Septic patients with a PCT level <7 ng/mL within the first 24 h of ICU admission were not eligible for inclusion in the study. We used a threshold PCT level of 7 ng/mL because studies show that patients have a higher risk of morbidity and mortality above this level. The Sequential Organ Failure Assessment (SOFA http://clincalc.com/IcuMortality/SOFA.aspx) score and blood or endotracheal cultures were done to further evaluate the patients. EUROSCORE II (http://www.euroscore.org/calc) were used to predict the mortality after cardiac surgery. Acute Physiology and Chronic Health Evaluation (APACHE http://clincalc.com/IcuMortality/APACHEII.aspx) IV scores were used to assess the severity and prognosis of the patients. Their clinical and demographic data, including age, sex, admitting diagnosis, comorbidities, requirement for mechanical ventilation, use of vasopressors (values averaged over the entire day), daily urine output (for the first 4 days), fluid balance after 24, 72 and 96 h were collected. Patients were randomised if the mean arterial pressure (MAP) was <65 mmHg despite adequate fluid administration (according to the Surviving Sepsis Guideline) and were given vasopressor drug (norepinephrine). Patients <18 years of age, pregnant women, chronic renal failure and immunocompromised were excluded from the study. Patients were considered immunocompromised, if they were taking >10 mg of prednisone-equivalent per day for at least 2 weeks, were receiving cytotoxic therapy or were diagnosed with an acquired immunodeficiency syndrome. Serum creatinine, WBC, platelet count, total bilirubin, PCT and lactate levels were recorded daily for the first 4 days. The SOFA (Sepsis-Related Organ Failure Assessment) score was calculated daily for 4 days. The SOFA score was designed to sequentially assess the severity of organ dysfunction in patients who were critically ill from sepsis (incrementing score of 0–24). The overall treatment of patients with sepsis during the control and treatment periods were similar except for the administration of the combination of vitamin C, hydrocortisone and thiamine during the treatment period. The treatment and referral patterns given to patients during their ICU stay were according to institutional protocols. Patients with sepsis and septic shock were started empirically on third generation cephalosporins in our institute. Antibiotics were escalated based on blood or endotracheal cultures and sensitivity. Haemodynamics were maintained by giving vasopressors and crystolloids and a central venous pressure (CVP) of 8–12 mmHg was targeted. Patients were ventilated according to a lung-protective strategy avoiding hypoxia and with the limited use of sedative agents. (Combination of fentanyl and midazolam was used.) Norepinephrine was the vasopressor of first choice and was titrated to achieve a MAP >65 mmHg. Among patients failing to achieve this target despite norepinephrine of 0.15 μg/kg/min, fixed-dose vasopressin was added at 0.04 units/min followed by epinephrine. Enteral nutrition was started once bowel sounds were audible and patient was able to tolerate feeds. After diagnosing sepsis or septic shock and a PCT level >7 ng/mL patients randomised to Group 2 were treated with intravenous vitamin C (ascorbic acid – Systochem Laboratories Ltd, India) (1.5 g every 6 h for 4 days), hydrocortisone (Pilcort H – Psychotropic India Ltd, India) (50 mg every 6 h for 4 days) as well as intravenous thiamine (ABF inj. Kachhela MeDex Pvt. Ltd.) (200 mg every 12 h for 4 days). The vitamin C was administered as an infusion over 30–60 min and mixed in a 50 mL solution of either dextrose 5% in water (D5W) or normal saline. The control group consisted of a similar number of patients admitted to our ICU using the same inclusion and exclusion criteria as the treatment group. Patients in the control group did not receive the vitamin C protocol, and received saline in a black syringe.

All statistical studies were carried out using the SPSS program v 20 (Chicago, IL, USA). Quantitative variables were expressed as the mean ± standard deviation and qualitative variables were expressed as frequency (%). The groups were compared using the Chi-square or Student's t-test for continuous and categorical data, respectively. A level of significance was accepted as a two-tailed P value <0.05.

RESULTS

In this prospective double-blinded study, 24 patients were randomised into two groups. The baseline characteristics with regards to weight, age, admission EUROSCORE II and APACHE IV SCORE were comparable between both the groups [Table 1].

Table 1

Comparison of baseline characteristics between both the groups

Blood cultures were positive in 13 patients and endotracheal cultures were positive in 7 patients. Significantly lower PCT level was observed in Group 2 patients (68.11 ± 33.64) as compared to Group 1 patients (33.2 ± 27.55) at day 3 (P = 0.016) and day 4 (70.03 ± 29.04 vs 26.3 ± 23.08; P = 0.0009) [Figure 1].

Figure 1

Trends in procalcitonin levels in Group 1 versus Group 2 patients. (PCT: procalcitonin)

The trend in vasopressor requirements in both the groups is presented in Figures 2 and 3. The dose of noradrenaline and vasopressin over 4 days was significantly lower in Group 2 compared to Group 1 during the study period. The difference in vasopressin and noradrenalin from baseline to various other time interval was plotted where significant improvement was observed in Group 2 population at all-time points [Table 2].

Figure 2

Difference in vasopressin requirement in Group 1 versus Group 2 patients at various time intervals. (b/w: between)

Figure 3

Difference in noradrenalin requirement in Group 1 versus Group 2 patients at various time intervals. (b/w: between)

Table 2

Comparison of the biochemical parameters between the groups

The trends in the SOFA score between both the groups were assessed and were found to be comparable at all-time intervals [Figure 4].

Figure 4

Difference in the SOFA score in Group 1 versus Group 2 patients at various time intervals. (b/w: between)

DISCUSSION

We herewith report that in cardiac surgical patients suffering from sepsis and septic shock, vitamin C treatment reduces dose and duration of vasopressors as compared to placebo treatment. During critical illness, severe ascorbic acid deficiency (serum ascorbate level <27 μmol/L) is well reported,[1213] where up to 3000 mg/day ascorbic acid was required to normalize the plasma level of ascorbic acid (68 μmol/L).[14] Oral supplementation is ineffective hence parenteral supplementation is advocated.[151617] In catecholamine synthesis pathway, vitamin C is an essential cofactor for the copper-containing enzyme dopamine β-hydroxylase.[181920] This enzyme has a critical role in norepinephrine synthesis from dopamine. Deficiency of ascorbic acid is associated with decreased norepinephrine in adrenal glands as per the previous reports.[2122] Insufficiency in adrenal hormone synthesis has also been observed in critically ill patients. Vitamin C is a potent antioxidant that directly scavenges oxygen free radicals; restores other cellular antioxidants, including tetrahydrobiopterin and α-tocopherol; and is an essential cofactor for iron- and copper-containing enzymes. Both drugs inhibit nuclear factor-kB activation and down-regulating the production of proinflammatory mediators; increase tight junctions between endothelial and epithelial cells; preserve endothelial function and microcirculatory flow; are required for the synthesis of catecholamines; and increase vasopressor sensitivity.[232425] Vitamin C plays a major role in preserving endothelial function and microcirculatory flow.[26] In addition, vitamin C haem oxygenase (HO)-1 pathway, which plays a critical role in antioxidant defences and enhances T-cell and macrophage function. The overall benefit of ascorbic acid, thiamine and hydrocortisone is most likely due to their overlapping pathways and their interaction in the body. Furthermore, we believe that vitamin C and corticosteroids act synergistically.[27] Clinical studies suggesting that hydrocortisone and vitamin C alone have little impact on the clinical outcome of patients with sepsis.[2829] The HYPRESS (Hydrocortisone for Prevention of Septic Shock) study failed to demonstrate a favourable outcome or benefit from a hydrocortisone infusion in patients with severe sepsis. In order to achieve normal serum vitamin C levels in critically ill patients, a daily dose of >3 g is required. On the basis of pharmacokinetic data and preliminary dose–response curves the daily dose of 6 g combined with hydrocortisone is optimal. When high dosages of vitamin C are given intravenously, metabolic conversion to oxalate increases. Oxalate is normally excreted by the kidney, and serum levels will increase with renal failure. Patients with renal failure receiving mega dose vitamin C can lead to deposition of oxalate crystals in the kidney and tissues.[30] Worsening renal function is therefore a concern with mega dose vitamin C. It is noteworthy that renal function is improved in all the patients with acute kidney injury (AKI). Glyoxylate, a byproduct of intermediary metabolism, is either reduced to oxalate or oxidised to carbon dioxide by the enzyme glyoxylate aminotransferase; thiamine pyrophosphate is a coenzyme required for this reaction. Thiamine deficiency increases the conversion of glyoxylate to oxalate. Thiamine deficiency is common in septic patients and is associated with an increased risk of death.[31]

PCT is produced as a precursor to calcitonin in the C cells of the parathyroid. The normal value is <0.1 ng/mL.[32] During sepsis, however, sites like lung, intestine, kidney and liver are known to produce PCT.[33] Cardiac surgery especially those conducted using CPB incite a systemic inflammatory response syndrome with raised PCT. This can be explained by exposure of blood to a foreign surface, translocation of gut endotoxins and ischaemia reperfusion injury after removal of aortic cross clamp.[34] Higher levels were seen in patients with positive blood cultures. Despite a higher PCT level in cardiac surgeries a level of >7 ng/mL was recommended by Jain and colleagues.[1035]

The sample size was adequate for evaluating the difference in primary endpoint, however, the difference in secondary endpoints was non-significant and hence higher patient numbers are needed to substantiate the difference in these parameters. Small sample size, short period of intervention and no assessment of the patients' serum ascorbate baseline level are the major limitations of our study. Further randomised controlled studies with sufficient sample size and assessment of baseline serum ascorbate level, serum antioxidant capacity and proinflammatory cytokines may be considered in future studies.

CONCLUSION

Early use of intravenous vitamin C, together with hydrocortisone and thiamine, may prove to be effective in the reduction of vasopressors dosage and mortality of patients with severe sepsis and septic shock.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.