Role of vitamin D supplementation in modifying outcomes after surgery: a systematic review of randomised controlled trials

Introduction

Public Health England and Food Standards Agency data suggest that vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)-D) <30 nmol/L) is present in 23% of people aged 19–64 years and in 21% of people aged 65 years and over. From January to March, this increases to 40% of people aged 19–64 years and 30% of people aged 65 years and over.1 2 While vitamin D deficiency is clearly linked to impaired calcium homeostasis and bone metabolism, there has been growing interest in the possible impact of vitamin D on extraskeletal function.3 This includes effects on immune4 and vascular function5 that have potential implications for surgery and surgical outcomes.

Over 310 million major surgeries are performed globally per year, with varying rates of postoperative morbidity and mortality.6 7 There is a lack of consensus on the association between circulating vitamin D levels and postoperative outcomes in patients undergoing surgery. However, it has been suggested that hypovitaminosis D is associated with adverse outcomes in patients undergoing surgery.8 In selected surgical cohorts (cardiac, thoracic and gastrointestinal), there is a trend towards prolonged intensive care unit (ICU) stays and mechanical ventilation in vitamin D-deficient patients.9–11 The same group9 determined that there is an independent association between low levels of the active form of vitamin D, 1,25-dihydroxyvitamin D and the risk of postoperative infections in these patient groups.

There are also data supporting a link between vitamin D deficiency and cardiovascular disease10; however, despite experimental and observational studies demonstrating this association, randomised trials have not so far shown a beneficial effect of vitamin D supplementation on subclinical or clinical cardiovascular outcomes. Similarly, for all-cause mortality, meta-analytical evidence of level one randomised data has shown no association with vitamin D supplementation when compared with control in both surgical and non-surgical patients.12 This may be a result of the heterogeneity of the study populations included within the analysis, the baseline vitamin D status and the dose, mode of administration and duration of vitamin D supplementation. This heterogeneity is further compounded in surgical cohorts by the added physiological insult of surgery, which may differ according to the access routes of surgery,13 14 which in itself is an evolving field.

With a greater number of randomised controlled trials (RCTs) being conducted evaluating the impact of vitamin D supplementation in surgical patients, it is an opportune time to perform a systematic review of the literature in this area. As such, the primary aim of this study was to assess the association between vitamin D supplementation and overall postoperative survival by combining data from RCTs of patients undergoing any form of surgery. The secondary aim was to assess other clinical outcomes, including postoperative complications and the length of hospital stay.

Methods

Discussion

Several retrospective and observational studies have reported low perioperative vitamin D levels to be associated with a range of adverse outcomes in the postoperative patient.8 In light of these findings, it is tempting to extrapolate that vitamin D supplementation could potentially improve postoperative outcomes. However, studies correlating vitamin D levels with outcomes are often subject to considerable confounding and selection bias, given that several risk factors for hypovitaminosis D are also associated with patient outcomes (eg, obesity and frailty). As such, observational associations between vitamin D levels and postoperative outcomes do not necessarily imply that vitamin D supplementation will result in improved outcomes. Consequently, there has recently been interest in the potential benefits of vitamin D supplementation in for critically ill patients. A recent meta-analysis by Shen et al32 assessed the impact of vitamin D supplementation in critically ill patients and found no evidence of a significant survival benefit, but did find a significant reduction in the length of hospital stay. Additionally, a large-scale clinical trial in clinically ill, vitamin D-deficient patients found no significant benefit of vitamin D supplementation for any clinical outcomes assessed.33

In light of these findings, we felt that a similar investigation into the effect of vitamin D supplementation on the population of patients undergoing surgery was warranted. This was particularly pertinent due to the lack of consensus across the increasing number of studies in this area. The resulting systematic review highlights the need for robust experimental design, standardisation in the timing and dosing of supplementation intervention groups and explicit outcome reporting. In addition, a lack of studies with longer-term follow-up was identified, which is exemplified by the fact that only a single study reporting long-term overall survival was identified. Short-term postoperative survival was more commonly reported, with data being available from four studies.23 28–30 However, the postoperative mortality rate in these studies was generally low, with a total of only 12 deaths in 631 patients. As such, all four studies were considerably underpowered to be able to detect a clinically meaningful difference in this outcome, leading to an inflated false-negative rate. Consequently, there were insufficient data to draw any reliable conclusions on the association between vitamin D supplementation and postoperative mortality. A meta-analysis of this outcome was not performed on account of the variability in the time at which postoperative mortality was assessed. Surgical mortality has traditionally been assessed at arbitrary intervals out to 1 year without an agreed optimum time point, as evidenced by the fact that all four studies reporting this outcome measured it at different time points. It has been suggested that surgery has the greatest impact on the risk of death when assessed closest to the time of the operation.34 Parametric hazard function modelling by Sergeant et al34 has shed more light on understanding time-varying trends of mortality after coronary artery bypass graft (CABG) surgery and found that the instantaneous hazard of death remains elevated well past 90 days and stabilises around 180 days (6 months) postoperatively. It was deduced that a combination of early in-hospital mortality and 180-day mortality are the optimum time points at which to capture the early phase of the hazard of death post-CABG. This may well be relevant to major surgery on the whole, but without robust data capture, this is a large assumption, and further work would be required to identify the optimum timing of postoperative assessment of mortality rates for future studies.

Length of hospital stay was a commonly reported outcome, being included in eight studies. However, considerable heterogeneity was observed, with the wide range of different surgeries being assessed likely being a major contributor to this. Two studies reported a significant reduction in the vitamin D supplementation arm relative to controls. However, this was in contrast to the remaining studies, which generally reported similar averages in the two arms, generally with a negligible trend towards longer lengths of hospital stay in the vitamin D supplementation arm. Five studies19 21 24 27 30 assumed a normal distribution when summarising the length of hospital stay and ICU stay24 30 data, reporting these as means with SDs. However, in many cases, these statistics indicated that the underlying data likely followed a skewed distribution. For example, some SD values were of a similar magnitude to the mean, implying that some patients would be expected to have a negative length of hospital stay if the underlying distribution were actually normal. This is also supported by the fact that the other studies reported medians and IQRs, which are commonly used in the absence of a normal distribution. As such, pooling these studies would likely have given unreliable results, particularly since most standard meta-analysis models make the assumption of underlying normality.

The two studies reporting a significant difference in the length of hospital stay additionally found significant differences in the length of ICU stay. However, these were again inconsistent with the remaining studies, both of which showed a non-significant tendency for a longer length of stay in the vitamin D supplementation arm. As such, while a reliable formal meta-analysis was not possible for the reasons described previously, the considerable heterogeneity and inconsistency of the direction of any effect do not imply a consistent benefit of vitamin D supplementation for this outcome.

Of the other outcomes considered, quality of life was only reported in two studies, which found no significant difference between arms across a range of different measures. Naguib et al reported a significantly lower rate of hospital-acquired infection in the vitamin D supplementation arm, compared with controls, which also coincided with significantly shorter lengths of hospital and ICU stays in this arm. However, no other study reported data for this outcome, with no significant differences being detected for other complication-related outcomes that were reported. As such, the potential effect of vitamin D on infection-related outcomes is an area that may warrant further research.

It has been suggested that vitamin D status at the time of surgery is the most relevant predictor of long-term outcomes, compared with vitamin D status in the days to weeks after surgery and that minimal benefits can be gained by supplementation at the time of surgery.8 This may go some way to explain the lack of significance in the majority of the studies included in this systematic review since most studies commenced vitamin D supplementation either shortly before or after the index surgery. As such, it is possible that this would have given insufficient time for the supplemental vitamin D to be absorbed and to have positive effects before the physiological insult of surgery. Consequently, in future studies, the commencement of vitamin D supplementation earlier in the preoperative period may result in greater benefit. However, this will only be applicable to elective non-urgent surgeries, which take a sufficiently long period from diagnosis to surgery.

Vitamin D supplementation has shown benefits in low vitamin D groups in terms of reduced postoperative infection and hospital and ICU stays in cardiac surgery30and reduced postoperative atrial fibrillation rates following CABG19 and improved survival following digestive tract cancer resection.29 Meta-analytical data hypothesised that vitamin D supplementation would be of benefit to vitamin D-deficient patients with lung cancer with respect to survival.29 The benefit of vitamin D in deficient patients may vary across different cancer types. It is worth noting that the perceived benefit of vitamin D supplementation in low-baseline subgroups must be interpreted with caution, particularly when the primary outcome measures in the overall cohort are null, along with the potential for type I error owing to multiple comparison testing. Future trial designs where vitamin D status is manipulated in the perioperative period must measure baseline levels preoperatively and seek to either titrate vitamin D therapy according to a specific circulating concentration or aim for fixed dosing only if there is adequately powered subgroup stratification according to the baseline level. Moreover, normalising individual vitamin D concentrations and determining a vitamin D response index to quantify perceived responses to treatment based on genomic susceptibility are also likely to be of importance.35

Vitamin D supplementation has not been shown to result in a lower incidence of cancer or cardiovascular events when compared with control.36 The dose of vitamin D used in the included trials varied between studies, such that it was difficult to compare equivalent daily doses owing to different treatment regimens and dosing intervals. A similar review has found this to be a reason behind the difficulty in determining an effective daily dose of vitamin D supplementation.12 The authors asserted that long-term vitamin D status is expected to be a much more accurate, reliable and important clinical parameter compared with a daily dose of vitamin D supplementation. Allied to this, the whole premise of vitamin D dosing is meaningless unless it can be shown to have a proven effect on serum vitamin D levels at long-term follow-up. In order to elevate serum 25(OH)-D, patients would need daily supplementation for at least 3 months prior to an operation. The earliest preoperative dosing time was 5 weeks,22 with other studies dosing in the postoperative period,18 20 25 27 29 which is unlikely to have an impact on serum 25(OH)-D levels. Single high-dose bolus supplementation, as performed in some of the included trials,19 23 28 may well raise serum 25(OH)-D levels rapidly but will also trigger catabolic feedback enzymes that negate the likely beneficial effects of vitamin D.4 5 So, while bolus dosing is tempting in surgical settings due to short inpatient stays, it is less likely to be effective. A meaningful trial in this area should account for all these factors.

Numerous studies have reported several benefits of vitamin D supplementation in different surgical settings without any consistency, which warrants the supposition that a biological effect may not exist. The observed improvement in outcomes in the low vitamin D groups may be attributable to chance. Focusing on a specific question with a specific outcome that has biological rationale should be the aim of future randomised trials in this area, taking into account all design factors highlighted above.