Vitamin D Status in Patients With Severe Sepsis

Sepsis is a clinical entity that complicates infections [1]. Without early recognition and
timely management, it can rapidly progress to severe sepsis, septic shock, and culminate in
multiple organ dysfunction syndrome. The incidence of severe sepsis is between 300 to 1000
cases per 100,000 persons [2] and is projected to increase annually due to an aging
population, increasing burden of chronic disease, and greater use of invasive procedures,
chemotherapy, and immunosuppressive agents [3]. Severe sepsis is the leading cause of
mortality in critically ill patients, with healthcare costs exceeding $16 billion annually
[4]. Despite evolving clinical guidelines for sepsis [5-7], and intense research, only a
modest reduction in case fatality rates has been documented over the last two decades [8].
Aside from early administration of antibiotics, there is no effective stand-alone or
adjuvant pharmacological intervention to improve survival in patients with severe sepsis.

The degree of immune dysfunction precipitated by an inciting infection is thought to
correlate with the severity of sepsis. Recently, key cells of the immune system were shown
to express the vitamin D receptor (VDR) [9]. Additionally, macrophages and neutrophils
activated through VDR up-regulate expression of endogenous antimicrobial peptides (AMPs)
that are active against a broad spectrum of infectious agents [10]. AMPs, influenced by
vitamin D status, likely represent an important first-line of defense against microbial
invasion. While circulating 25-hydroxyvitamin D (25OHD) is the most abundant vitamin D
metabolite [11], under normal circumstances, 85-90% of 25OHD is tightly bound to vitamin D
binding protein (DBP) and is unavailable to activate innate immune responses during acute
stress [12]. The remaining 10-15% is more readily bioavailable (b25OHD), and is composed of
the free and albumin-bound components of 25OHD. Fluid loading, albumin wasting, and
increased DBP expression during critical illness may affect 25OHD homeostasis [13].

Low vitamin D status (25OHD <20ng/mL) is associated with increased mortality in critical
illness [14]. Forty to 70% of septic patients have low vitamin D status [15-17], yet little
is known about the impact of vitamin D3 (vitD3) supplementation in this patient population.
As such, the investigators propose a randomized, double-blinded, placebo-controlled trial to
test the hypothesis that early, rapid correction of low vitamin D status, as an adjunct to
established treatment guidelines, will improve clinical outcomes and measurably alter immune
profile in patients with severe sepsis. Patients will be assigned to a single dose of vitD3
(400,000 IU) or placebo (n=300/arm) within 24 hours of new-onset severe sepsis, followed by
weekly doses of vitD3 (25,000 IU) or placebo, respectively, up to 90 days to assess clinical
outcomes and key biomarkers.

AIM 1: To determine if early administration of vitD3 (vs placebo) improves clinical outcomes
in patients with low vitamin D status and severe sepsis. Hypothesis 1a: Early vitD3
decreases 90-day mortality after onset of severe sepsis (Primary Outcome). Hypothesis 1b:
Early vitD3 decreases sequential organ failure assessment scores in the first 5 days after
onset of severe sepsis. Hypothesis 1c: Early vitD3 decreases non-home discharge rate in
those who survive severe sepsis.

AIM 2: To determine if early administration of vitD3 (vs placebo) modulates b25OHD, AMPs,
and key cytokines in patients with low vitamin D status and severe sepsis. Hypothesis 2a:
Early vitD3 increases b25OHD in the first 5 days after the onset of severe sepsis.
Hypothesis 2b: Early vitD3 increases expression of AMPs, cathelicidin (LL-37) and β-defensin
(hBD-2). Hypothesis 2c: Early vitD3 decreases pro-inflammatory cytokine (IL-1β, IL-6) and
increases anti-immunoparalytic cytokine (IL-10, IFN-γ) expression.

Severe sepsis is a significant public health problem with limited treatment options. A 2010
NIH workshop on sepsis identified deep gaps in understanding innate host immune responses in
sepsis and emphasized the need for novel therapies [18]. The proposed trial is well powered
to investigate whether immunomodulation with vitD3 improves survival after severe sepsis. By
optimizing endogenous host responses to infection, the investigators anticipate that vitD3
supplementation will augment the life-saving impact of current therapies for severe sepsis.
Moreover, the investigators will investigate several vitamin D-related biomarkers, which may
identify future therapeutic targets. The trial will be performed by a highly-experienced
team that includes experts in vitamin D, sepsis, critical care, and clinical trials; they
have successfully carried out several clinical studies of vitamin D in critically ill
patients.

Inclusion Criteria:

- Age ≥18 to <80 years

- Admitted to 1 of 4 participating ICUs

- Meet criteria for new-onset severe sepsis* within past 12 hours

Exclusion Criteria:

- Age ≥80 years

- Not anticipated to survive ≥48 hours

- Inability to obtain informed consent from patient/suitable proxy within 22 hours of
new-onset severe sepsis

- Comfort measures, hospice, or palliative care status

- Documented adverse reaction to vitamin D supplementation

- Inability to tolerate enteral feeds/medications

- Renal stones within past year

- Hypercalcemia within past year

- Baseline serum calcium ≥10.5 mg/dL

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