Cholecalciferol Supplementation for Sepsis in the ICU

Sepsis is a clinical syndrome that complicates severe infections. It is characterized by the
cardinal signs of inflammation (e.g. vasodilation, leukocytosis, increased microvascular
permeability) occurring in tissues that are remote from the site of an infection. Current
theories about the onset and progression of the sepsis syndrome focus on dysregulation of
inflammatory responses, including the possibility that a massive and uncontrolled release of
pro-inflammatory mediators initiates a chain of events that lead to widespread tissue
injury. The degree of immune dysfunction is thought to correlate with the severity of the
sepsis syndrome. Sepsis syndrome can range from sepsis, to severe sepsis, septic shock, and
multiple organ dysfunction syndrome (MODS). The mortality associated with each of these is
estimated to be 16%, 20%, 46%, >80%, respectively. The annual incidence of sepsis syndrome
exceeds 1.6 million cases in the United States alone.

Recently, cells of the innate and adaptive immune system have been shown to express the
vitamin D receptor. Vitamin D appears to be necessary for interferon-γ dependent T cell
responses to infection. In low vitamin D states, dysfunctional macrophage activity becomes
evident. Vitamin D is also an important link between Toll Like Receptor (TLR) activation and
antibacterial response. Human macrophages stimulated by TLR induce: 1) vitamin D receptor
expression; 2) conversion of 25(OH)D to its most biologically active form of
1,25-dihydroxyvitamin D; and 3) production of cathelicidin (LL-37), an endogenous
antimicrobial peptide with potent activity against bacteria, viruses, fungi, and
mycobacteria. LL-37 is highly expressed in both the plasma and at natural barrier sites
(e.g. skin, gut, lungs) and may represent an important first-line of defense for the innate
immune system.

In humans, cholecalciferol (vitamin D3) is either obtained through the diet or synthesized
by skin upon exposure to ultraviolet B (UVB) radiation. Cholecalciferol is converted to
25(OH)D in the liver or by cells of the immune system. Serum 25(OH)D can be measured with
relative ease and is the most abundant vitamin D metabolite. It is therefore, often used as
a proxy for total body vitamin D status and 25(OH)D levels <30 ng/mL characterize an
insufficient state. A growing body of evidence suggests that a significant proportion
(50-90%) of critically ill patients may have insufficient 25(OH)D levels during admission to
the intensive care unit (ICU). 25(OH)D insufficiency, in turn, appears to be associated with
a higher risk of mortality in critically ill patients. However, randomized,
placebo-controlled trials (RCTs) aimed at studying the effect of vitamin D supplementation
in critical illness are limited and have largely focused on superficial assessments of
vitamin D status. While it is known that septic patients have nearly universally low 25(OH)D
levels and that the vitamin D levels are inversely correlated with the severity of sepsis,
little is known regarding the effects of vitamin supplementation in this patient cohort.
Therefore, our goal is to determine whether vitamin D supplementation in patients highly
suspected of sepsis syndrome may be effective in optimizing 25(OH)D levels and in improving
host production of the antimicrobial polypeptide LL-37.

Inclusion Criteria:

- English or Spanish speaking

- Within 24 hours of a suspected diagnosis of sepsis

- Meeting criteria for sepsis (defined as suspected or confirmed infection AND at least
one diagnostic criteria in each of the following groupings):

1. Vital signs:

1. Temperature: >38.3C or <36C

2. HR: >90/min, or >2 standard deviation above normal

3. Tachypnea (>20 breaths per minute)

4. Altered mental status

5. Positive fluid balance (>20 mL/Kg over 24 hrs)

6. Glucose >140 mg/dL in the absence of diabetes mellitus

2. Inflammatory markers:

1. WBC: >12,000 or <4,000

2. Normal WBC count with >10% immature forms

3. CRP >2 standard deviation above normal value

4. Pro‐ calcitonin >2 standard deviation above normal value

3. Hemodynamic

1. SBP <90mmHg, MAP <70mmHg or SBP decrease >40mmHg

2. Vasopressor therapy to maintain MAP >65mmHg

4. Organ dysfunction

1. Arterial hypoxemia (PaO2/FiO2 <300)

2. Acute Oliguria (UoP <0.5 mL/Kg/hr for at least 2 hours)

3. Cr increase >0.5 mg/dL

4. Coagulopathy: INR >1.5 or aPTT >60 sec

5. Thrombocytopenia: PLT <100K

6. Hyperbilirubinemia: TBili >4 mg/dL

5. Tissue perfusion

1. Lactate >2 mmol/L

2. Decrease cap refill or mottling

Exclusion Criteria:

- Pregnant females or immediate post-partum status

- "Comfort measures only" status

- Inability to provide informed consent or have a surrogate consent

- History of renal stones within the past year

- History of hypercalcemia within the past year

- Baseline serum total calcium >10 mg/dL

- Established diagnosis associated with increased risk of hypercalcemia (e.g.
metastatic cancer, sarcoidosis, multiple myeloma, primary hyperparathyroidism)

- History of severe anemia (Hematocrit <25%)

- Medications that affect vitamin D metabolism (e.g. antiepileptics, tuberculosis
medication

- Already enrolled or planning to enroll in a research study that would conflict with
full participation in the current study or confound the observation or interpretation
of the study findings