Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-deficient Patients

Petal Trials Network. NEJM December 2019; doi:10.1056/NEJMoa1911124

Clinical Question

  • In critically ill patients with Vitamin D deficiency and a high risk of death, does early enteral replacement of Vitamin D3 compared with placebo improve survival at 90 days?


  • Vitamin D has been suggested to be a potent immunomodulatory agent that is essential for lung development and function and may attenuate lung injury
  • Observational data suggests that vitamin D deficiency is common in critically ill patients and represents a potentially modifiable risk factor
  • Vitamin D deficiency is associated with prolonged length of stay, organ failure, prolonged mechanical ventilation and death
  • Vitamin D is also associated with a number of chronic conditions and frailty, and the above findings may be more a reflection of these factors rather than vitamin deficiency alone
  • In a previous phase 2 trial (VITdAL-ICU) of 475 patients, vitamin D replacement in vitamin D deficient patients was associated with a non-significant reduction in mortality at 28 days compared to placebo. This larger phase 3 trial was designed to further test the hypothesis


  • Double blinded, multi-centre, randomized control trial
  • Randomized in 1:1 ratio stratified by site using a central electronic system and permuted blocks
  • A p value of 0.05 was used as the cut-off for significance. The statistical analysis assumed that the mortality would be 20% and 15% in the control and intervention groups respectively. The trial was calculated to have 87% power if 3000 patients were randomized
  • Intention to treat analysis
  • Trial stopped after 1st interim analysis on basis of futility


  • 44 hospitals in the USA (as part of the PETAL trials network)
  • Data collected and analysed from April 2017 to November 2019



  • Age ≥ 18 years
  • Within 12 hours after decision to admit to ICU
  • At least 1 acute risk factors for lung injury or mortality contributing directly to the need for ICU admission:
    • Pneumonia
    • Aspiration
    • Smoke Inhalation/Lung contusion
    • Mechanical ventilation for acute respiratory failure
    • Shock
    • Sepsis
    • Pancreatitis
  • Vitamin D deficiency – 25OHD level <20 ng/mL
    • randomized on basis of screening test: either point of care test or test conducted by laboratory at enrolling hospital
    • included in primary analysis on basis of confirmatory test: liquid chromatography-tandem mass spectrometry tested at reference laboratory


  • Unable to take enteral medication
  • Baseline hypercalcaemia (serum calcium >10.2 mg/dL (2.54 mmol/L) or ionized calcium >5.2 mg/dL (1.30 mmol/L))
  • Known kidney stone in past year or history of multiple (>1) prior kidney stone episodes
  • Decision to withhold or withdraw life-sustaining treatment (patients were still eligible if they are committed to full support except cardiopulmonary resuscitation if a cardiac arrest occurs)
  • Expected <48 hour survival
  • If no other risk factors present, a) mechanical ventilation primarily for airway protection, pain/agitation control, or procedure; or b) elective surgical patients with routine postoperative mechanical ventilation; or c) anticipated mechanical ventilation duration <24 hours; or d) chronic/home mechanical ventilation for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion)


  • 15924 were assessed for eligibility, 1360 randomized after screened positive for vitamin D deficiency and met eligibility criteria
  • 1078 patients confirmed to have vitamin D deficiency
  • 1059 patients included in primary analysis (lost to follow up, n=19)
  • Randomisation took place within the 12 hours (mean 6.7+-3.5) following decision to admit to ICU.
  • Comparing baseline characteristics of intervention vs. placebo group
    • Age : 57 vs. 55
    • Female: 43% vs. 44%
    • Race or ethnic group
      • Non-hispanic white: 52% vs. 53%
      • Black: 24% vs. 23%
    • Acute risk factor for death
      • Pneumonia: 38% vs. 34%
      • Shock: 36% vs. 37%
      • Sepsis: 34% vs. 32%
      • Mechanical ventilation for acute respiratory failure: 22% vs. 22%
    • Total SOFA score: 5.6 vs. 5.4
    • 25-hydroxyvitamin D level: 11.2 vs. 11.0ng/ml


  • Vitamin D (n=690)
    • Single dose of 540,000 international units of vitamin D3 given enterally
    • Average time to administration from randomization was 1.2 hours
    • 14 patients did not receive vitamin D


  • Placebo (n=668)
    • 17 patients did not receive placebo

Management common to both groups

  • No other care was specified in each group, but the treating clinicians were strongly encouraged to not check a vitamin D level or prescribe any vitamin supplementation for a month following enrolment


  • Primary outcome: All cause  mortality at 90 days – no significant difference
    • 23.5% in Vitamin D group vs. 20.6% in control group
    • difference 2.9%, 95% C.I. -2.1 to 7.9, P = 0.26
  • Secondary outcomes:There was no significant difference between intervention vs. control groups with regards to:
    • Length of stay
      • 9.1 vs. 10.4 days (difference-1.4, 95% C.I. -2.7 to 0.0)
    • Ventilator Free days to day 28
      • 21.3 vs. 22.1 (difference -0.8, 95% C.I. -2.1 to 0.5)
    • New ARDS to day 7
      • 4.9% vs. 4.1% (difference 0.7, 95% C.I. -2.1 to 3.6)
    • Severity of respiratory failure
    • Acute kidney injury
    • New renal replacement therapy to day 7
      • 4.1 vs. 3.6% (difference 0.5, 95% C.I. -1.9 to 2.9)
  • Secondary safety outcomes:
    • There was no significant difference between groups with regards to:
      • Hypercalcemia to day 7
        • 2.7% vs. 2.1%
      • Renal stones to day 90
      • Falls to day 90
      • Fall-related fractures to day 90
    • There was a significantly higher total calcium up to day 14 in the intervention group (p=0.004)

Authors Conclusions

  • In this phase three trial early administration of high dose Vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other measures of non-fatal outcomes among critically ill patients with vitamin D deficiency.


  • Prospective multi centre double blinded RCT
  • Diverse population
  • Impressive early recruitment and treatment


  • This trial was made up of predominately medical patients whereas the previous phase 2 trial had a greater proportion of neurosurgical and surgical patients
  • The trial did measure response to treatment, and although this was impressive 24.8% of the intervention group still had a low vitamin D level (<30ng/ml) at day 3 (compared to 100% in control arm)
  • This trial did not examine patients who were vitamin D deficient at the later stages of their critical illness

The Bottom Line

  • This trial does not provide evidence to support screening all critically ill patients for vitamin D deficiency, or that early replacement in those with vitamin D deficiency changes outcome
  • There may be sub-groups for which Vitamin D replacement may have a positive effect, but none were identified in this trial
  • I will not routinely screen Critically ill patients for Vitamin D deficiency


External Links


Summary author: Joel Swindin @JSwindin
Summary date: 8th April 2020
Peer-review editor: David Slessor

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