VIOLET
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?
Background
- 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
Design
- 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
Setting
- 44 hospitals in the USA (as part of the PETAL trials network)
- Data collected and analysed from April 2017 to November 2019
Population
Inclusion:
- 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
Exclusion:
- 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)
Participants:
- 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
Intervention
- 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
Control
- 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
Outcome
- 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)
- Length of stay
- 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
- Hypercalcemia to day 7
- There was a significantly higher total calcium up to day 14 in the intervention group (p=0.004)
- There was no significant difference between groups with regards to:
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.
Strengths
- Prospective multi centre double blinded RCT
- Diverse population
- Impressive early recruitment and treatment
Weaknesses
- 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
- [article] Early High-Dose Vitamin D3 for Critically Ill, Vitamin D–Deficient Patients
- [further reading] LITFL: Vitamin D in Critical illness
- [further reading] VITdA-ICU – TBL Review
- [Study Protocol] VITDALIZE study
Metadata
Summary author: Joel Swindin @JSwindin
Summary date: 8th April 2020
Peer-review editor: David Slessor