VITDAL-ICU

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Amrein et al. "Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial". JAMA. 2014. 312(15):1520-1530.
PubMedFull textClinicalTrials.gov

Clinical Question

In adult patients admitted in an ICU with a lower serum Vitamin D level, does supplementation with Vitamin D3 540 000 IU load followed by 90 000 IU for 5 months decrease length of stay

Bottom Line

Supplementation of vitamin D did not affect length of stay but in a subgroup of severe deficiency, a subgroup showed a decrease in mortality. More study is needed.

Major Points

Hypovitaminemia was first observed in the critically ill decades ago but the affect on outcomes was unclear. Given the cutaneous synthesis step of vitamin D activation, patients whom are admitted for any extended period may use up their fat-soluble vitamin D stores quickly. This insufficiency may affect a patient in any number of ways.

The VITdAL@ICU trial included 492 patients, admitted to one of 5 ICUs in a single centre in Austria. Randomized to receive either a loading dose of 540 000 units of Vitamin D3 followed by 5 monthly doses of 90 000 units or matched placebo, their primary outcome of hospital length of stay showed no difference of 20 vs. 19 days, respectively. They also found no difference in their secondary outcomes of mortality, in ICU, hospital, at 28 days, and 6 months. In a per-specified subgroup analysis, in patients with severe deficiency (defined as 25-hydroxyvitamin D level ≤30 nmol/L) they observed no difference in hospital length of stay nor ICU mortality. With in hospital mortality and severe deficiency, there was an absolute risk reduction of 17, translating to a NNT of 6. 26 Day mortality also demonstrated a NNT of 6 and 6 month mortality was a NNT 7.

There are a number of limitations in this trial, the first is the narrow population included (caucasian adults) and it was conducted at a single centre. There is also the possibility of bias introduced with the sponsor providing the drug. Overall this is hypothesis generating and further studies likely need to be completed.

Guidelines

As of September 2019, no guidelines have been published that reflect the results of this trial.

Design

  • randomized double-blind, placebo-controlled, single-centre trial
  • N=492
    • Vitamin D3 (n=237)
    • Placebo (n=238)
  • Setting: 5 ICUs including both medical and surgical patients
  • Enrollment: May 2010 - September 2012
  • Mean follow-up: 6 months
  • Analysis: Intention-to-treat
  • Primary Outcome: hospital length of stay

Population

Inclusion Criteria

  • ≥18 years old
  • expected ICU stay >48 hours
  • 25-hydroxyvitamin D ≤50 nmol/L [≤20 ng/mL]

Exclusion Criteria

  • severely impaired gastrointestinal function
  • other trial participation (including pilot trial)
  • pregnant or lactating
  • hypercalcemia (total calcium > 2.7 mmol/L [>10.6 mg/dL] or ionized serum calcium >1.4 mol/L [>5.4 mg/dL])
  • tuberculosis
  • sarcoidosis
  • nephrolithiasis within the prior year
  • patients not deemed suitable for study participation (ie, psychiatric disease, living remotely from the clinic, or prisoner status)

Baseline Characteristics

Vitamin D3 Group displayed

  • Demographics: mean 63.9 years old, 35% female, 100% caucasian
  • Physiologic parameters: Chalson comorbidity index 3.0, mean SAPSII 32.4, mean TISS-28 37.7,
  • Anthropomorphics: mean BMI 27.2,
  • Labs: mean eGFR 63.7, Mechanical ventilation 63.7%, Norepinepherine use 55.3%, mean baseline 25-hydroxyvitamin D 32.7 nmol/L [13.1 ng/mL]
  • Admission diagnosis: Sepsis 8%, Cardiovascular 11.8%, Neurologic 22.8%, other nonsurgical 16.9%, Cardiosurgical 19%, Trauma 9.7%, other surgical 11.8%

Interventions

  • 540 000 IU of vitamin D3 dissolved in 45 mL of oleum arachidis load then monthly 90 000 IU maintenance doses for 5 months.
  • Placebo of 45mL of oleum arachidis and placebo maintenance doses

Outcomes

Comparisons are Vitamin D3 vs. Placebo.

Primary Outcomes

Hospital Length of Stay
20.1 days vs. 19.3 days (P = 0.98)

Secondary Outcomes

ICU Length of Stay
9.6 days vs. 10.7 days (P = 0.38)
Hospital Mortality
28.3% vs. 35.3% {HR 0.81; 95% CI 0.58-1.11) P = 0.18
ICU Mortality
22.8% vs. 26.5% (HR 0.97; 95% CI 0.67-1.39) P = 0.86
28 day Mortality
21.9% vs. 28.6% (HR 0.76; 95% CI 0.53-1.09) P = 0.14
6 month Mortality
35.0% vs. 42.9% (HR 0.78; 95% CI 0.58-1.04) P = 0.09

Subgroup Analysis

Severe deficiency (25-hydroxyvitamin D level ≤30 nmol/L [≤12 ng/mL]) n=200

Hospital Mortality with Severe Deficiency
28.6% vs. 46.1% (ARR 17, HR 0.56; 95% CI 0.35-0.90) P = 0.01; NNT 6
28 Day Mortality with Severe Deficiency
20.4% vs. 36.3% (ARR 15.9, HR 0.52; 95% CI 0.30-0.89) P = 0.02; NNT 6
6 month mortality with Severe Deficiency
34.7% vs. 50.0% (ARR 15.3, HR 0.60; 95% CI 0.39-0.93) P = 0.02; NNT 7

Criticisms

  • challenges against external validity
    • narrow population included (caucasian adults)
    • single centre
  • no adverse events reported despite supra-therapeutic doses of vitamin D administered

Funding

  • European Society for Clinical Nutrition and Metabolism (ESPEN)
  • research grant including provision of study medication from Fresenius Kabi (Germany)
  • Austrian National Bank (Jubiläumsfonds, Project Nr. 14143)

Further Reading