A Study of Vitamin D Level in Critically Ill Patients and Effect of Supplementation on Clinical Outcome.

BACKGROUND: Supplementation of Vitamin-D in Vitamin-D deficient patients may reduce morbidity and mortality in critically ill patients in ICU. AIMS AND
OBJECTIVES: The aim of this study is to investigate serum level of Vitamin-D in critically ill patients and supplementation of vitamin-D in deficient patients and finally to compare clinical outcomes between two groups. SETTINGS AND
DESIGN: Randomized, prospective and comparative study.
MATERIALS AND METHODS: In this study, serum vitamin-D level was investigated in recruited patients and vitamin-D deficient patients were randomly allocated into two groups viz; group-1, group-2. Vitamin-D (sachet CALCIROL 60,000 IU) supplementation was done once a week and twice a week in in group-1 and group-2 respectively, clinical outcomes between two groups were compared in terms of length of ICU stay, need for inotropic support, need for mechanical ventilation and 28 days ICU mortality. STATISTICAL ANALYSIS: Mean and standard deviation were calculated. Test of analysis between two groups was done by t-test and then P value was calculated.
RESULTS: No significant difference was found between two groups whether vitamin D supplementation done once or twice weekly (P = 0.24) in terms of length of ICU stay. Patients of group-2 required significantly less inotropic support as compared to group-1 (P = 0.037). There was no significant difference found in duration of mechanical ventilation (P = 0.138) and 28 days ICU mortality (P = 0.284).
CONCLUSION: From the above results we concluded that vitamin D supplementation in high dosages may be started in all critically ill patients, who are deficient in serum vitamin D level to get better clinical outcomes. Copyright:

INTRODUCTION

Vitamin D is a key regulator in calcium and phosphorus metabolism and likely confers physiologically relevant pleiotropic functions that include cardioprotective and immunomodulatory effects as well as improvement of antimicrobial actions.[12] To date, only few large interventional randomized trials have investigated the effect of Vitamin D on clinical outcomes. Hundreds of genes with Vitamin D receptor response elements directly or indirectly influence cell cycling, proliferation, differentiation, and apoptosis.[3]

Endogenous synthesis in the presence of ultraviolet B (UV-B) radiation is the main source of Vitamin D. Therefore, immobilized and elderly individuals are prone to develop Vitamin D deficiency. Low Vitamin D levels are highly prevalent in critically ill adults and children.[45] Over the last years, several groups have reported an inverse association between Vitamin D levels in critically ill patients and severity of disease including length of intensive care unit (ICU) stay (LOS) and mortality.[6] Moreover, Vitamin D levels decline further during ICU stay, which is explained by the insufficient replacement of Vitamin D via enteral or parenteral nutrition in the absence of UV-B exposure.

This study was proposed with the aims and objectives of determining Vitamin D level in critically ill patients, supplementing Vitamin D in people who are deficient, and finally comparing various clinical outcomes in two different groups allocated randomly.

MATERIALS AND METHODS

The present study entitled, “A study of Vitamin D level in critically ill and effect of supplementation on clinical outcome,” was a prospective, comparative, observational study conducted in the ICU of the department of anesthesiology and critical care of our tertiary care hospital and research center, for a period of 1 year, from August 2015 to August 2016. Before the beginning of the study, proper approval was taken from the institutional research ethical committee. Inclusion criteria were patients admitted to our ICU with the clinical diagnosis of severe sepsis according to the definition of Surviving Sepsis Campaign, those with age >18 years, those who are expected to stay at the ICU ≥48 h, and those with Vitamin D level 25(OH) D level ≤20 ng.m −1 (deficient). We had excluded the patients with life expectancy <24 h, those with severely impaired gastrointestinal motility (ileus, gastric volume >400 mL), those with contraindication to study drug application (orally or via feeding tube), those with readmission after participation in the study, those enrolled in another intervention trial or have documented hypercalcemia (total calcium >2.65 or ionized serum calcium >1.35 mmol.L−1), patients with a history of granulomatous disease (tuberculosis and sarcoidosis), those who recently had kidney stones (≤1 year), and pregnant or lactating women. On ICU admission, all patients were screened for study participation. Written informed consent was obtained directly from the patient or from a legal surrogate (in mechanically ventilated and encephalopathy patients). We had enrolled 72 patients for our study to get the number of patients around 30 in each group after dropouts. Out of the 72 patients, 8 died before 48 h of admission and 4 patients went left against medical advice. Finally, a total of sixty patients were randomly allocated in either of the two groups. Randomization was done by computer-generated tables. Patients of Group 1 received 60,000 IU Calcirol sachet (containing 60,000 IU Vitamin D3) once a week and Group 2 received the same amount of cholecalciferol twice a week either orally or through nasogastric tube. After admission to our Institutional ICU and satisfying inclusion criteria including Vitamin D level, all the critically ill patients were evaluated with a thorough physical examination and laboratory investigations such as complete blood count, renal function test, liver function test, serum electrolytes, blood culture, and sensitivity for aerobic and anaerobic bacteria from two sites, and chest X-ray was done in all patients. Arterial blood gas analysis was done at admission and followed up in the morning and evening during ICU stay according to need. At the time of admission, one researcher assessed the severity of illness by Simplified Acute Physiology Score II (SAPS II).[7] All the patients were given empirical antibiotics, fluids, inotropic support (to maintain mean arterial blood pressure >65 mmHg), and ventilatory support as per necessity to keep the patient hemodynamically stable. We have used noradrenaline as the first-choice drug in sepsis.[8] We considered ionotropic support when we used noradrenaline intravenously at doses of >0.2 μg.kg−1.min−1. Antibiotics were changed after blood culture report accordingly. Serial serum Vitamin D level measurement was done on days 10 and 28. Duration of mechanical ventilation was defined from starting of invasive mechanical ventilation to the day of weaning from mechanical ventilation.

Clinical data collected were age, sex, SAPS II score, LOS, need of ionotropic support, duration of mechanical ventilation, and 28-day mortality. Data were collected regularly from both groups and analyzed to compare clinical outcomes. At baseline, data on demographic and clinical characteristics of the patients were obtained. Simplified Acute Physiology Score (SAPS II), presence of comorbidities, medical history, admission diagnosis by category, and relevant medications were registered. In addition, the need for and the number of days of hemodynamic (inotropic) support and mechanical ventilation including noninvasive ventilation and tracheostomy as well as the quantity and formula of enteral/parenteral nutrition given were recorded. 25(OH) D serum levels were measured by ELISA Immunodiagnostic Systems (IDS-)iSYS 25(OH)D assay (Immunodiagnostic Systems Ltd, Boldon, United Kingdom).

Statistical analysis

We have taken the help of a pilot study that has been previously done before the present study, included a total of ten patients (five in each group) from our institute, and calculated the LOS and duration of mechanical ventilation in both the groups. The formula used for the sample size calculation is as follows:

Sample size (N) = (Zα/2 + Zβ) 2 (σ1 2 + σ2 2)/(μ1 − μ2) 2

Zα/2 = Desired level of significance. Typically 1.96 for 95% significance level

Zβ = Desired power of study. Typically 0.84 for 80% power.

σ1 and σ2 are standard deviations of Group 1 and Group 2, respectively. μ1 and μ2 are means of Group 1 and Group 2, respectively.

In the pilot study, ICU stay in Group 1 and 2 was found 25 ± 4.2 versus 21 ± 5.4 days. Duration of mechanical ventilation was found 17 ± 4.1 versus 14 ± 3.2 days. After calculation with the above formula, for ICU stay sample size was found 22 in each group and for duration of mechanical ventilation, it was found 25 in each group with 95% significance level and 80% power of study. Randomization was done using computer-generated random number table. The primary analysis for comparing length of hospital stay between the two groups was made using the independent Student's t-test. For secondary end points, differences between the two groups were evaluated with the t-test. For continuous variables and for categorical variables, the Chi-square test was used for analysis. The parametric data were expressed as mean ± standard deviation. P ≤ 0.05 was considered statistically significant, and P > 0.05 was not considered statistically significant.

RESULTS

A total of 72 patients were enrolled for the study, but only 60 patients were included for the final analysis [Figure 1].

Figure 1

Consort flowchart showing number of patients included and finally analyzed. ICU = Intensive care unit, LAMA = Left against medical advice

The overall mean age of the patients enrolled was 44.37 years versus 42.37 years for Group 1 versus Group 2 (P = 0.565) by independent sample t-test, as shown in Table 1, and was found statistically insignificant. The mean LOS in Group 1 was 27.23 ± 11.24 days, whereas in Group 2, it was 24.27 ± 7.89 days. The difference in the LOS between the two groups was not statistically significant. The mean reduction in ICU stay of 2.97%, 95% confidence interval (CI) = −2% to 8%, t = 1.183, P = 0.24, by the unpaired t-test is shown in Table 2. The mean duration of mechanical ventilation in Group 1 was 18.77 ± 9.619 days versus 15.03 ± 9.622 days in Group 2. A decrease in the mean duration of mechanical ventilation in Group 2 by 3.73 was not statistically significant with P = 0.138 and 95% CI (−1.239–8.706), as shown in Table 3. On comparison of need for inotropic support in both groups, it was found that 65.4% of Group 1 versus 34.6% of Group 2 patients required inotropic support during the ICU stay. The decrease in the percentage of people requiring inotropic support in Group 2 was statistically significant with χ2 = 4.34 and two-sided P = 0.037 by the Pearson's Chi-square test, as shown in Table 4. The difference in 28-day ICU mortality between the two groups was not statistically significant with χ2 = 0.098 and two-sided P = 0.284 by the Pearson's Chi-square test, as shown in Table 5.

Table 1

Demographic profile of the patients

	Mean±SD		P
	Group 1	Group 2
Age (years)	44.37±7.82	42.50±5.60	0.29
Sex (male: female)	21:9	20:10	0.78 (Chi-square test)

Data are mean±SD. No significant difference P>0.05. SD=Standard deviation

Table 2

Length of intensive care unit stay comparison

	Group 1	Group 2
Number of patients	30	30
Mean±SD (days)	27.23±11.24	24.27±7.89
P	0.24

Data are mean±SD. No significant difference P>0.05. SD=Standard deviation

Table 3

Comparison of duration of mechanical ventilation

	Group 1	Group 2
Number of patients	30	30
Mean±SD (days)	18.77±9.619	15.03±9.622
P	0.138

Data are mean±SD. No significant difference P>0.05. SD=Standard deviation

Table 4

Comparison of need for inotropic support

	Group 1	Group 2
Number of patients not needed inotropic support (%)	13 (43.33)	21 (70)
Number of patients needed inotropic support (%)	17 (56.66)	9 (30)
P	0.037

Data are in percentage %. Pearson’s Chi-square test was used. Significant difference P<0.05

Table 5

Comparison of 28-day mortality

	Group 1	Group 2
Number of patients	30	30
28-day mortality (%)	6 (20)	7 (23.3)
P	0.284

Data are in percentage. Pearson’s Chi-square test was used. No significant difference P<0.05

DISCUSSION

The primary end point of the study, that is, LOS, depicts that the mean LOS of Group 1 and Group 2 was 27.23 ± 11.24 days versus 24.27 ± 7.89 days. This small decrease in LOS was not statistically significant with P = 0.24. Amrein et al., 2014, conducted a randomized, double-blind, placebo-controlled, single-center trial from May 2010 to September 2012 at five ICUs that included a medical and surgical population of 492 critically ill adult patients with Vitamin D deficiency (≤20 ng.mL − 1) assigned to receive either Vitamin D3 (n = 249) or a placebo (n = 243). They intervened by giving Vitamin D3 or placebo either orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months.[9] They found that the median (interquartile range [IQR]) length of hospital stay was not significantly different between the groups (20.1 days [IQR, 11.1–33.3] for Vitamin D3 vs. 19.3 days [IQR, 11.1–34.9] for placebo; P = 0.98). From the above study, they concluded that among critically ill patients with Vitamin D deficiency, administration of high-dose Vitamin D3 compared with placebo did not reduce the hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe Vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study. In contrast to the above study, a recent study by Han et al., 2016, conducted a pilot, double-blinded, randomized controlled trial on mechanically ventilated adult ICU patients. The patients were administered either placebo, 50,000 IU Vitamin D3 or 100,000 IU Vitamin D3 daily for 5 consecutive days enterally (total Vitamin D3 dose = 250,000 IU or 500,000 IU, respectively).[10] There was a significant decrease in hospital length of stay over time in the 250,000 IU and the 500,000 IU Vitamin D3 groups, compared to the placebo group (25 ± 14 and 18 ± 11 days compared to 36 ± 19 days, respectively; P = 0.03). From the above pilot study, they concluded by stating that high-dose Vitamin D3 safely increased plasma 25(OH) D concentrations into the sufficient range and was associated with decreased hospital length of stay without altering other clinical outcomes. The need for inotropic support during ICU stay in Group 1 was 65.4% versus 34.6% in Group 2. We noticed statistically significant difference in need for inotropic support in between the two groups with P = 0.037. In support of our study result, we did not get any study. Few studies mentioned in a review of literature got insignificant results for need for inotropic support between Vitamin D supplementation and placebo group. To support or refute our study results, further studies are needed in large sample size. The mean duration of mechanical ventilation in Group 1 and Group 2 was 18.77 ± 9.61 days and 15.03 ± 9.62 days, respectively. However, the mean decrease in the duration of mechanical ventilation in Group 2 was not statistically significant (P = 0.138). Verceles et al., 2015, conducted a study on 183 patients and no association was found between 25(OH) D concentration and weaning from mechanical ventilation. Increased comorbidity was associated with decreased odds of weaning (odds ratio of 0.50, 95% CI: 0.25–0.99, P = 0.05).[11] The 28-day ICU mortality in Group 1 and Group 2 was 20% and 23.3%, respectively. More percentage of people in Group 2 showed mortality though it was statistically not significant (P = 0.284). Moraes et al., 2015, found in their cohort analysis that the 28-day mortality percentage in patients having Vitamin D <12 ng.mL-1 was 32.2% versus 13.2% in patients having Vitamin D >12 ng.mL-1 and the difference was statistically significant (P = 0.014).[12] The limitation of our study was that we have admissions of heterogeneous patient group, that is, patients of various diagnoses were included in this study. They were also under the care of different treating physicians and so the mode of treatment may be varied. The impact of the various frequently administered drugs being received by the patient on serum electrolyte and Vitamin D levels has been well documented. This however was not assessed in our study group and therefore its impact on our results is unclear.

This change in lifestyle has led to decrease in serum Vitamin D level in almost all healthy patients. In critically ill patients, this deficiency is exaggerated.

CONCLUSION

In view of previous studies and our study results, we are in support of supplementation of Vitamin D in critically ill patients to get better clinical outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.