Should I Supplement Vitamin D in a Patient With Sepsis?

Abstract

Sepsis is a potentially fatal organ failure produced by the host’s immune response to infection. It is critical to identify risk factors associated with a poor prognosis in septic patients in order to develop new therapy options. Vitamin D deficiency (25-hydroxyvitamin cholecalciferol < 20 ng/mL) is common in critical and septic patients. Serum vitamin D concentrations are associated with an increased incidence of mortality in critically ill adult patients. In critically ill patients, vitamin D supplementation (a very high vitamin D ₃ or cholecalciferol loading dosage as a single bolus dose ranging from 400,000 to 540,000 IU) is feasible and safe. Some of the trials and their post-hoc analyses evaluating vitamin D supplementation in severely sick individuals, including septic patients, suggested possible benefits in mortality (reduced 28-day mortality in the range of 8.1%–17.5%), and other outcomes (reduction in hospital length in the range from 9 to 18 days, and decrease in duration of mechanical ventilation in the range from 5 to 10 days). Despite the fact that many studies support the provision of vitamin D to septic patients, there are still many studies that contradict this opinion, and there is still debate about the recommendation to use vitamin D in sepsis. A pragmatic clinical approach in severe sepsis could be supplementation of vitamin D if serum levels are diminished (< 30 ng/mL). It appears that a single ultrahigh dose of vitamin D ₃ (cholecalciferol) could be administered to the septic patient via an enteral tube, followed by daily or monthly maintenance doses. Parenteral administration might be reserved for a subgroup of septic patients with gastrointestinal, hepatic, or renal dysfunction. Future clinical trials designed exclusively for septic patients are required to assess the potential advantages of vitamin D. Possible impacts of selective activators of vitamin D receptors, such as paricalcitol, should be elucidated in sepsis. This emphasizes the requirement for more study and confirmation of any potential beneficial effects of vitamin D in sepsis.

Vitamin D Deficiency as a Novel Risk Factor for Stratification in Sepsis

Sepsis, a condition characterized by physiologic, pathological, and metabolic abnormalities caused by infection, is a potentially fatal organ malfunction produced by an unbalanced host response to infection and may advance to septic shock with dramatic severe failure of organs and death. 1 Patients suffering from sepsis have an extremely high death rate, and patients suffering from septic shock or multi-organ failure may have a fatality rate of more than 90%. 2 Despite many advances in treatment, sepsis is still a significant public health issue across the world. 3 In 2017, over 11 million sepsis-related fatalities have been documented, accounting for 19.7% of all worldwide mortality. 4 Sepsis pathogenesis is complex, and therefore, the treatment of sepsis is challenging. 5

Sepsis is frequent in critically ill patients. 6 Advanced age, increased use of invasive monitoring and treatment, antibiotic resistance, and the use of immunosuppressants are all well-known risk factors for the development of severe sepsis and septic shock in the critical care population. 7

Sepsis should be considered a treatable condition 8 and the identification of risk variables linked with poor outcomes in sepsis is critical for improved risk stratification and finding out possible therapeutic implications to develop novel treatment targets in sepsis. 9

Vitamin D is well known for its long-standing role in bone mineralization and calcium homeostasis, despite vitamin D receptors (VDRs) being found in practically all human body tissues and cells. 10

Consequently, vitamin D, as it mediates many physiological processes, including immune functions, 11 might be an important risk stratification tool and therapeutic target in sepsis.

In vitro , vitamin D has also been shown to modify levels of systemic inflammatory cytokines, such as interleukin 6 or tumor necrosis factor-alpha, and may boost the production of antimicrobial peptides such as cathelicidin and b-defensin, which have been regarded as the body’s initial line of defence against viral and bacterial infections. 12

Indeed, there are plenty of pieces of evidence that vitamin D deficiency has been related to an increase in sepsis incidence and death in a variety of patients. In general, critical patients admitted to the intensive care unit (ICU) have lower serum vitamin D concentrations. 13

Vitamin D insufficiency should be defined as a serum level of 25-hydroxyvitamin cholecalciferol (or 25[OH]D ₃ ) < 30 ng/mL and the term “deficiency” should be used for 25(OH)D ₃ levels < 20 ng/mL. 14

A recent study found that the prevalence of vitamin D deficiency, defined as a serum level of 25-hydroxyvitamin D ₃ (25-OH-cholecalciferol) level < 20 ng/mL, is very high in critically ill patients (59%). Furthermore, despite the fact that vitamin D deficiency was not linked to increased mortality rates, the use of ventilators and length of ICU stays were both increased in patients with vitamin D deficiency. 15 An observational study of 3,386 adult patients reported pre-admission 25-hydroxyvitamin D ₃ serum concentration ≤ 15 ng/mL as a major risk factor for sepsis in severely sick patients. 16

A meta-analysis of seven cohort studies involving 4,204 participants, including a significant number of septic patients, suggests that adult patients who are severely ill and have vitamin D insufficiency have an elevated risk of hospital death. 17 Another meta-analysis including 14 reports and involving 9,715 critically ill patients concluded that serum concentration levels of 25-hydroxyvitamin D ₃ less than 50 nmol/L (20 ng/mL) were associated with a rise in the 30-day mortality rate, sepsis rates, in-hospital mortality, and infection rates, which suggests that vitamin D deficiency raises the risk of fatal infections and death from critical illness. 18 Furthermore, a meta-analysis of 10 observational studies reported that vitamin D deficiency was associated with increased susceptibility to sepsis. 19

In the septic population, decreased levels of vitamin D are common findings. In a recent single-center study in 150 septic patients, the median serum concentration of 25-hydroxyvitamin D ₃ was 19.03 ± 13.08 ng/mL, so the frequency of vitamin D insufficiency was 100%. 20

The causal relationship between lower plasma vitamin D concentrations and sepsis is not entirely clear. There is a possibility that the state of sepsis itself leads to a metabolic disarrangement that is responsible for the reduction of plasmatic vitamin D concentration. Therefore, it is possible that vitamin D deficiency in septic patients is only one of the septic epiphenomena. Still, there is also evidence that decreased vitamin D levels among septic patients show significant associations with adverse outcomes. A surgical-ICU-based study demonstrated that vitamin D deficiency was inversely associated with mortality, cost of care, and length of stay. 21 Another study revealed a deficiency of 25-hydroxyvitamin D ₃ before hospital admission as a major risk factor for acute renal injury and death in a critically ill adult patient cohort (the A 25-hydroxyvitamin D ₃ deficiency was defined as less than 15 ng/mL). 22 A similar large 11-year multicenter observational study found that pre-admission 25(OH)D ₃ deficiency was a predictor of susceptibility to positive blood culture, a significant predictor of ICU and in-hospital mortality, which continued to be a predictor of survival following multivariate comorbidity adjustments. 23

In a retrospective cohort study among 121 adult patients, mortality was significantly higher in those with low vitamin D, and in a multivariate analysis, age and vitamin D deficiency were independently linked to a higher death rate. 24 A prospective observational study involving adult patients with severe sepsis or septic shock discovered a link between higher vitamin D levels and a more significant reduction in the degree of organ malfunction. 25 The same study found that a significant vitamin D deficiency affected 98% of sepsis patients. A study of 81 septic patients found that 79% had 25(OH)D ₃ levels of < 75 nmol/L (< 30 ng/mL), and such patients had a higher likelihood of having severe sepsis and higher sequential organ failure assessment scores. 26 In a report of 168 patients with sepsis, the average vitamin D ₃ serum level was 19.03 ± 13.08 ng/mL (considering 20–50 ng/mL the normal range, 61.6% had vitamin D deficiency), and the authors discovered a substantial relationship between mortality and serum vitamin D ₃ levels. 27 A similar study of 107 adult patients demonstrated vitamin D deficiency during ICU admission (≤ 20 ng/mL) in 93.5% of the subjects, and 53.3% showed levels < 7 ng/mL. Patients had a greater death rate from sepsis if vitamin D levels were < 7 ng/mL. The multivariate regression analysis demonstrated that vitamin D level < 7 ng/mL on ICU admission was an independent predictor of sepsis-related mortality. 28 Recently, a single-center prospective study on 164 patients with severe sepsis demonstrated that at admission time, severe vitamin D deficiency (25[OH]D ₃ < 12 ng/mL) was associated with higher mortality. 29

On the contrary, some reports of a correlation between vitamin D serum levels and outcomes in septic patients could not find a clear relationship. 30 An interesting prospective multicenter observational study (FINNAKI study) conducted on 610 patients with severe sepsis (of these, 29% had septic shock) measured vitamin D levels on admission to the ICU and showed vitamin D deficiency (< 50 nmol/L or 20 ng/mL) in 55% patients. According to their research, there was no difference in 90-day mortality between participants with and without vitamin D insufficiency. The multivariable regression model showed that 90-day mortality could not be predicted by low vitamin D levels, despite the fact that subjects who are vitamin D deficient more commonly showed diabetes, had higher levels of C-reactive protein, had more hospital infections, and more frequently experienced acute renal injury. 31

Nevertheless, a recent meta-analysis of 8 studies with 1,736 patients showed that lower 25 (OH)D ₃ was independently linked to a higher risk of death in septic patients upon admission. 32

Finally, it should be taken into account that 25(OH)D ₃ is an inactive circulating type of vitamin D measured in the studies mentioned above, and 25(OH)D ₃ has to be transformed into the active hormone named 1,25-dihydroxyvitamin-D3 or 1,25(OH) ₂ D ₃ , mostly by a renal 1α-hydroxylase enzyme. 33 Only active 1,25(OH) ₂ D ₃ can bind the nuclear VDR, resulting in the production of antimicrobial peptides, cathelicidin, and defensin by neutrophils. 34

One study aimed to determine the connection between vitamin D and outcomes in sepsis measured serum 1,25(OH) ₂ D ₃ and demonstrated a decrease in serum 1,25(OH) ₂ D ₃ in sepsis non-survivors versus survivors. Additionally, the serum 1,25(OH) ₂ D ₃ level, and not 25(OH)D ₃ , during the course of 72 hours, was an excellent indicator of outcome among septic patients and was considered related to increased mortality in sepsis patients. 35

In summary, the findings of the aforementioned studies strongly suggest that in septic patients, vitamin D deficiency may be a new independent predictor of death risk, as well as a novel risk stratification factor in sepsis. It is unclear whether low vitamin D levels in critical patients reflect disease severity or a general poor health status in obese, diabetic, elderly, and other patients, or whether they are an independent factor in sepsis morbidity and mortality.

Possible Therapeutic Approach for Vitamin D Deficiency in Sepsis

In an animal sepsis model, vitamin D deficiency was associated with defective macrophage phagocytosis and decreased local expression of the cathelicidin-related antimicrobial peptide. In the intratracheal lipopolysaccharide model, 1,500 IU of intraperitoneal cholecalciferol (D ₃ ) treatment 6 hours post-injury decreased cellular damage, hypoxia, and alveolar inflammation. 36 A similar study in an experimental model of rat sepsis demonstrated that pre-treatment with 1,25(OH) ₂ D ₃ reduced sepsis-induced thrombocytopenia, indicating a protective role for 1,25-dihydroxyvitamin D ₃ supplementation against the progression of sepsis-induced disseminated intravascular coagulation. 37

The results of the above-presented studies supported the theory that vitamin D administration might lower mortality in individuals with sepsis and severe vitamin D deficiency. 38

In critically ill patients, vitamin D supplementation is feasible and safe, and it has been shown to improve vitamin D deficiency in a matter of days.

Despite the majority of studies indicating potential benefits in terms of mortality or ICU stay, conflicting results have been found in randomized controlled trials examining the impact of vitamin D in critically ill individuals.

A randomized double-blind clinical trial found that a single bolus dose of 300,000 IU vitamin D ₃ helped reduce serum procalcitonin concentrations after seven days in patients with ventilator-associated pneumonia. 39 A meta-analysis of seven similar smaller studies published between 2011 and 2016 on a total of 716 patients was conducted to assess if giving vitamin D to very sick individuals lowers mortality and found that intervention, compared to placebo, had a considerably reduced death rate. 40 A meta-analysis of six studies including 695 patients was conducted to assess the therapeutic effects of vitamin D therapy in individuals with severe illnesses. The analysis found no reduction in mortality or other outcomes (ICU and hospital stays, infection rate, and ventilation days), and the authors concluded that daily doses of vitamin D greater than 300,000 IU did not improve mortality or ICU stay. 41

The large-scale PETAL-VIOLET trial was carried out at 44 hospitals across the United States and included 1,358 severe patients (more than 80% were admitted to the medical ICU) with vitamin D deficiency. The study protocol included very early vitamin D ₃ supplementation (a single enteral dose of 540,000 IU) in severely ill patients. The results showed that high-dose vitamin D ₃ supplementation in the early stages did not have an advantage over a placebo in preventing 90-day mortality or hospital stay, and there were no differences between the groups of participants. 42

The second large study, the VITdAL-ICU randomized clinical trial, was conducted among 492 seriously ill adult subjects with low vitamin D levels (20 ng/mL) chosen to receive either vitamin D ₃ administered orally or through nasogastric tube once at a dosage of 540,000 IU, followed by monthly maintenance doses of 90,000 IU for 5 months; or a placebo. 43 There was no difference between groups in hospital stay duration, hospital mortality, or 6-month mortality. In the analysis of the severe vitamin D deficiency (≤ 12 ng/mL) subgroup analysis, only hospital mortality decreased significantly for vitamin D ₃ recipients (28.6% died in the vitamin D ₃ treated group compared with 46.1% died in the placebo group). The authors came to the conclusion that high-dose vitamin D ₃ treatment vs. a placebo did not shorten hospital stays or decrease death among critically ill patients with vitamin D insufficiency. These findings would suggest that individuals with sepsis and severe vitamin D insufficiency might have a better chance of surviving with vitamin D therapy. Vitamin D ₃ therapy had no survival advantage for those with less severe vitamin D insufficiency. However, after 6 months, the authors report a significant improvement in hand grip strength and a physical performance scale, indicating a possible advantage of vitamin D in the healing and rehabilitation phase of post-intensive care syndrome. 44

A post-hoc analysis of the VITDAL-ICU study, excluding patients who died or were discharged within 7 days after study drug administration, among the remaining 410 patients, found that a high vitamin D intake was linked to a reduction in mortality (14.7% mortality in the treatment arm, and 22.8% in the placebo arm). 45

A recent meta-analysis of 10 randomized control trials with 2,058 patients was conducted to confirm the impact of vitamin D ₃ on critically ill individuals. Although a high vitamin D ₃ dose did not improve mortality in critically ill patients, it did dramatically shorten their time on the ventilator; for example, in one of the included studies, duration of mechanical ventilation was 27.72 ± 22.48 in control vs. 17.63 ± 14.00 days in intervention arm. 46

A very recent meta-analysis of 11 randomized control trials involving 2,187 critically ill patients concluded that vitamin D administration shortens mechanical ventilation and ICU stays. 47 There was no statistically significant difference in mortality or length of hospital stay. Interestingly, in subgroup analysis, the risk of death, the length of mechanical breathing, and ICU stays were all lower when vitamin D was administered via the parenteral route. Overall, the authors found a nonsignificant tendency toward a lower death rate in the vitamin D group.

The very last meta-analysis was conducted to ascertain the impact of vitamin D on significant clinical outcomes and included 16 randomized clinical trials with 2,449 critically ill patients. 48 It was discovered that supplementing with vitamin D was associated with lower overall mortality (in one report septic patients’ 90-day mortality was 34% in the vitamin D supplemented group vs. 66% in the placebo group), shorter lengths of stay in ICUs (according to one of the included trials 18.3 ± 8.4 vs. 25.4 ± 6.6 days in the intervention and placebo arms), and shorter durations of mechanical ventilation (15.7 ± 9.3 vs. 22.6 ± 9.1 days in vitamin D and placebo arms). Compared to enteral administration, parenteral administration had a larger impact on total mortality. The authors concluded that in severely ill individuals, vitamin D treatment may lower mortality, with additional benefits when administered parenterally.

However, the aforementioned systematic reviews and meta-analyses had some limitations, such as the large heterogeneity of the included population and intervention protocols. The only two large-scale studies were the VITdAL-ICU trial and the PETAL-VIOLET trial.

Finally, many of these studies on the ICU population included a mixed ICU population, including septic patients. Only a small number of the studies included in the meta-analyses were conducted specifically for the septic population. Consecutively, interventional studies on vitamin D replenishment in critical ICU populations should not be automatically extrapolated to septic patients and have to be evaluated cautiously for sepsis. Additionally, the VITdAL-ICU and PETAL-VIOLET trials included critically ill patients with a low sepsis prevalence at the time of enrolment (7.7% and 33.3%, respectively), so sepsis subgroup analyses did not allow a clear assessment of vitamin D supplementation’s effectiveness in septic patients.

However, some studies were conducted exclusively in a cohort of patients with sepsis. A randomized prospective double-blind placebo research was carried out in 57 septic patients in the ICU, with 29 patients supplemented with 300,000 IU of vitamin D ₃ for deficiency (25[OH]D ₃ 20–30 μg/L) or insufficiency (25[OH]D ₃ < 20 μg/L). There was no significant difference in the duration of mechanical ventilation, length of ICU stay, 28-day mortality, or 28-day accumulated survival between the D ₃ treatment group and the placebo group. The authors concluded that the outcomes of sepsis patients in ICUs cannot be improved by vitamin D ₃ treatment. 49 In an additional study on new-onset severe sepsis or septic shock patients receiving 200,000 IU and 400,000 IU of cholecalciferol versus placebo, within 24 hours, a rapid and safe improvement of bioavailable 25-hydroxyvitamin D ₃ levels was reported with concomitant increases in circulating cathelicidin. 50

Vitamin D can be delivered orally, intravenously, or intramuscularly. In previous studies, an enteral vitamin D ₃ excessive loading dosage (a single bolus dose from 400,000 to 540,000 IU) may quickly raise vitamin D levels, and there were very few negative effects observed. However, vitamin D ₃ therapy produced serum levels of 25-hydroxyvitamin D higher than 30 ng/mL only in 50% of the patients. 51 Furthermore, as some studies have shown, the route of administration of vitamin D may play an important role in the efficacy of vitamin D. Gao and co-workers 46 observed in their meta-analysis a substantial drop in mortality in the subset of subjects who received intramuscular injections of vitamin D ₃ . Similar conclusions in the meta-analysis by Singh and co-workers 47 on the reduction of mortality risk and ventilation were found in a subgroup analysis of participants with a parenteral route of vitamin D administration. The same conclusion arises from the last meta-analysis by Menger and co-workers 48 with a greater effect of parenteral vitamin D on overall mortality. Intramuscular supplementation may be a more efficient option than enteral vitamin D replacement due to the frequency of gastrointestinal dysfunction and unreliable enteral absorption in severely ill patients. Additionally, a recent prospective randomized trial included 36 ventilated ICU patients who received either a single intramuscular vitamin D injection of 300,000 IU or a placebo and found that the intervention arm lowered the length of stay (18.3 ± 8.4 vs. 25.4 ± 6.6 days) and mechanical ventilation duration (15.7 ± 9.3 vs. 22.6 ± 9.1 days). 52 As a result, patients with severe vitamin D deficiency who do not respond to oral vitamin D supplementation may benefit from a high parenteral dose of native vitamin D. It should be noted that in critical illness and sepsis, the gastrointestinal function is compromised, which impedes enteral absorption of vitamin D; in addition to renal failure or drug-related cytochrome P450 impairments in the liver, factors interfere with vitamin D ₃ hydroxylation. Specifically, supplementations are provided in a form that is inert and requires continuous metabolic processes to become active. However, many very sick patients are unable to properly activate natural vitamin D.

The timing of administration should also be considered an important issue, as the conversion of inactive vitamin D ₃ into the active form requires 2–3 days, and consecutively delayed administration might result in ineffective outcomes in critical patients with sepsis.

In conclusion, sufficient serum levels of vitamin D are important for immune system regulation and have the ability to prevent both a severe infection and an excessively active inflammatory response in sepsis. As the VDR is distributed in many organs and affects different signaling pathways, vitamin D could maintain the function of many organs affected by sepsis. 53

The results of some studies imply that vitamin D administration may be related to a probability of improving outcomes in critically ill individuals, including septic patients. For example, administration of vitamin D reduced serum procalcitonin, improved physical performance, lowered the length of stay, and decreased mechanical ventilation duration. Those studies that showed the benefit of vitamin D supplementation in critically ill patients demonstrated a significant reduction in hospital length in the range from 9 to 18 days, decrease in ICU length of stay to 7 days, and decrease in duration of mechanical ventilation in the range from 5 to 10 days. More importantly, some of these studies and their post-hoc analyses proved that vitamin D supplementation reduced 28-day mortality in the range of 8.1%–17.5%, and 90-day mortality by 32.3%. These favourable effects are particularly demonstrated if vitamin D is administered parenterally. However, it should be emphasized that not all studies have shown the beneficial effect of vitamin D supplementation in septic patients. The effect of vitamin D supplementation on reducing mortality in patients with sepsis is less clear. Most studies have not demonstrated the effect of vitamin D supplementation in septic patients on mortality reduction, although some studies have shown that in a subpopulation of patients with extremely low initial plasmatic vitamin D levels, administration of vitamin D has an impact on mortality reduction.

Therefore, it is impossible to provide an unequivocal recommendation for vitamin D administration in septic patients due to the conflicting findings of the studies. A reasonable clinical approach in severe sepsis could be supplementation of vitamin D in cases of diminished serum levels (< 30 ng/mL), ideally during the first admission day. It appears that a single ultrahigh dose of up to 540,000 IU of vitamin D ₃ (cholecalciferol), which has been shown to be both safe and effective, could be administered to the septic patient via an enteral tube or peroral, followed by a daily maintenance dose of no more than 4,000 IU (or monthly maintenance doses of 90,000 IU). Parenteral administration might be reserved for the subgroup of septic patients with gastrointestinal, hepatic, or renal dysfunction, bearing in mind that the clinical effects of vitamin D parenteral supplementation in septic patients appear to be related to accentuated beneficial effects.

To assess the potential advantages of vitamin D in sepsis, future clinical trials with significant sample sizes and subjects with severe vitamin D insufficiency are required. The ongoing VITDALIZE study, in which ICU patients with severe vitamin D deficiency (25-hydroxyvitamin D ₃ ≤ 12 ng/mL) were given a loading dose of 540,000 IU of cholecalciferol within 72 hours of ICU admission, followed by 4,000 IU daily for 90 days or a placebo, will provide answers to some of the arising questions in this field. 54

Also, in the future, it will be necessary to investigate the possible impact of selective activators of VDR (for example, paricalcitol) among the population of patients with sepsis, as it is well known that paricalcitol has beneficial anti-inflammatory and antioxidant properties on the renal and cardiovascular systems. 55