Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality?
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- Lee, P., Nair, P., Eisman, J.A. et al. Intensive Care Med (2009) 35: 2028. doi:10.1007/s00134-009-1642-x
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The association between vitamin D deficiency and chronic illness is well-known. Vitamin D deficiency has been associated with increased mortality in the general population. Despite this knowledge, vitamin D insufficiency is seldom considered and rarely replaced adequately, if at all, in critically ill patients in intensive care. We present a hypothetic model demonstrating how vitamin D deficiency may be an unrecognized contributor to adverse outcome in intensive care patients.
KeywordsEndocrine disordersElectrolyte disordersMultiple organ failureNutritionSystemic diseasesCardiovascular issues in the ICUVitamin D deficiencyHypocalcaemia
Critically ill patients in the intensive care unit have a high mortality. Modern critical care provides comprehensive life support for patients with multi-organ failure. The association between vitamin D deficiency and chronic illness, and its likely progressive decline with intensive care unit stay due to sunlight and dietary depletion is well-known. Despite this knowledge, vitamin D deficiency is seldom considered and rarely replaced adequately, if at all, in critically ill patients. We present a hypothetic model discussing how vitamin D deficiency may be an unrecognized contributor to adverse outcome in intensive care patients.
Contrary to the view that vitamin D deficiency is a mild chronic condition, recent reports associating vitamin D deficiency with severe hypocalcaemia in intensive care [1, 2] highlight how vitamin D deficiency may contribute to acute complications. In a recent observational study, the prevalence of vitamin D insufficiency (serum 25-hydroxyvitamin D (25-OH D) between 30 to 60 nmol/L) and deficiency (serum 25-OH D <30 nmol/L) was estimated to be as high as 50% in critically ill patients, with undetectable vitamin D levels in 17% of patients . Mortality rate predicted by the simplified acute physiologic scores was close to 3 times higher in vitamin D deficient patients compared to those who were sufficient (25-OH D >60 nmol/L). While the study was small (N = 42) and could be subject to a referral selection bias, it raised the question of whether vitamin D deficiency is a potentially important contributor to worse outcomes and replacement could be beneficial in critically ill patients.
The classic role of vitamin D relates to its maintenance of calcium homeostasis. Hypocalcaemia, even after adjustment for protein and pH (i.e. ionized calcium), is common in critically ill patients and has been found in 15–88% in adults in intensive care units [4–7]. Risk factors include sepsis, burns, pancreatitis and rhabdomyolysis [5, 7]. As calcium is important in many physiological processes, it is not surprising that hypocalcaemia may be associated with disease severity  and mortality . However, parenteral calcium supplementation has not been shown to improve the outcome of intensive care patients, as noted in a recent Cochrane review . The reasons for this lack of benefit are unclear but hypocalcaemia may be a sign of disease severity rather than a causal factor per se. Indeed, in one study hypocalcaemia was not an independent predictor of day-30 all cause mortality . In addition, although various mechanisms have been proposed to explain how hypocalcaemia occurs in critical illness, including intracellular sequestration of calcium and relative hypoparathyroidism, it is unclear why hypocalcaemia occurs.
Severe hypocalcaemia is an uncommon finding in non-critically ill patients, due to the presence of multiple compensatory mechanisms to maintain normocalcaemia. The ability to maintain calcium homeostasis is dependent on a sufficient and responsive parathyroid hormone (PTH)-vitamin D axis. Calcium-sensing receptors in the parathyroid glands are exquisitely sensitive to changes in serum calcium concentration. Hypocalcaemia is prevented by increase in intestinal calcium absorption, renal calcium re-absorption and release of calcium from the skeleton through bone resorption, mediated by 1,25-(OH)2-vitamin D (1,25-(OH)2D). The skeleton is an important reservoir for calcium. Hypocalcaemia therefore does not occur unless PTH action is insufficient, as in hypoparathyroidism or PTH resistance (e.g. hypomagnesaemia, renal failure resulting in inadequate renal 1α-hydroxylation), or if vitamin D is severely deficient not allowing adequate formation of 1,25-(OH)2D despite maximal PTH stimulation [1, 2].
For example, the critical role of vitamin D in glucose and calcium homeostasis may explain the association between vitamin D deficiency and diabetes and osteomalacia or osteoporosis in the general population; in critically ill patients, however, vitamin D deficiency may lead to hyperglycaemia and hypocalcaemia. At an organ level, vitamin D deficiency is associated with cardiac failure and chronic airway diseases  in ambulatory patients, but may result in the cardiac dysfunction and acute lung injury seen in some critically ill patients. On a whole body level, vitamin D deficiency leads to immune dysfunction  and has been implicated in the pathogenesis of systemic infection such as tuberculosis and autoimmune diseases. In critically ill patients, such immunopathy may manifest as increased susceptibility to nosocomial infections such as ventilator associated pneumonia and central line infections, sepsis and the systemic inflammatory response syndrome. Indeed a recent study demonstrated a strong positive correlation between 25-OH D concentrations and levels of cathelicidin (LL-37), an endogenous antimicrobial peptide produced by macrophages, suggesting defense against infection in septic critically ill patients may be regulated by vitamin D status .
While vitamin D insufficiency does not pose immediate health hazards in otherwise well individuals, deficient states may prove detrimental during critical illnesses, if the circulating vitamin D pool functions as an important reservoir for conversion to their active metabolites at a tissue level during stress. We therefore hypothesize that vitamin D deficient/insufficient states may worsen existing organ dysfunctions in critically ill patients, leading to worse outcomes. In other words, the observed association between increased mortality and vitamin D deficiency in the general population may be magnified during critical illnesses, translating into excess morbidity and mortality [12, 13]. While at this stage, the role of vitamin D deficiency in adverse outcomes in the critically ill is speculative, the concepts discussed above as well as preliminary work lead us to believe that causation between vitamin D deficiency and adverse outcomes is more likely than purely an association. We propose performing further studies in this area to gain further understanding into the effect of adequate supplementation of vitamin D in the intensive care unit.
Vitamin D replacement is seldom considered in intensive care medicine. Standard enteral as well as parenteral nutrition (TPN) regimes provide between 1,000 and 2,000 Units of vitamin D per week [26, 28–30]. However, in one study in which the nutritional efficacy of a TPN regimen, designed to provide 2,100 Units of vitamin D per week, was evaluated in a group of cancer patients, the mean serum 25-OH D concentration 4 weeks after initiation of TPN was 36% lower than baseline level, implying inadequate replacement and possibly increased demand during active illness, in support of our hypothesis  (Fig. 2). In another study, daily administration of 500 IU of vitamin D failed to normalise vitamin D status during the course of admission in 22 critically ill patients in intensive care . In addition, obesity is associated with hypovitaminosis D and there is recent evidence that obese individuals may require larger replacement dosage .
Our concept of intensive care vitamin D insufficiency explains why hypocalcaemia and hyperparathyroidism relate to disease severity but why calcium replacement would not improve outcome. Both hypocalcaemia and hyperparathyroidism are markers of vitamin D insufficiency, but it is vitamin D insufficiency, the cause of hypocalcaemia, which leads to wide spread tissue dysfunction. In addition, vitamin D has benefits on bone health. Vitamin D supplementation may reduce bone loss, which is common in immobile intensive care patients frequently treated with high dose steroids .
Although the current model is hypothetical, improved understanding of the PTH-vitamin D axis and its relationship to morbidities in intensive care patients may shed light on therapeutic possibilities for vitamin D metabolites. Many single laboratory variables have been shown to predict disease severity in intensive care patients, including C-reactive protein, leucocyte and platelet counts, procalcitonin, d-dimer, interleukin-6 and thromboplastin time [35–37]. However, deficient vitamin D levels may not only predict disease severity and outcomes but due also, to its pleotropism, may contribute to intensive care co-morbidities. The potential for vitamin D therapy is important as, unlike other modern therapeutics used in critical care medicine, vitamin D is inexpensive and safe with a wide therapeutic window; thus it is critical that its potential role in this situation is clarified. This model aims to improve the care of critically ill patients, and may finally bring “light” into intensive care units.