IRONMAN

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Litton E, et al. "Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial". Intensive Care Med. 2016. 42:1715-1722.
PubMedFull text

Clinical Question

In patients requiring admission to critical care and are experiencing anemia, does early intravenous iron compared to placebo reduce the need for blood transfusion

Bottom Line

Inconclusive, in this trial intravenous iron supplementation to critically ill patients did not decrease the amount of blood transfused but patients were discharged from hospital with higher hemoglobin levels but was likely underpowered.

Major Points

Transfusion of blood products carry some level of risk for the patient. Giving a patient, outside of immediately increasing the hemoglobin level, also induces an immunogenic response leading ultimately destruction of these non-native cells and suppression of erythropoietin. Use of supplemental iron to utilize the patient’s own internal processes to replenish blood in times of anemia is an attractive option.

This randomized, placebo controlled trial conducted in 4 Intensive Care Units in Western Australia explored if the supplementation with 500mg of intravenous ferric carboxymaltose as compared to placebo, would decrease the number of units of packed red blood cells were transfused in each group. Intravenous iron did not significantly decrease the median number of units transfused per patient, with roughly half of each cohort receiving transfusions. The ICU mortality and length of stay were also similar between groups but the hemoglobin at hospital discharge was statistically different, with 107 g/L vs. 100 g/L, P = 0.02.

This trial is unfortunately likely underpowered and therefore inconclusive. The mean number of units transfused was less than half of the number used in the power calculation. Even though it did not find a statistically significant difference, the point estimates favoured the use of intravenous iron supplementation and further study is required to inform is iron is a safe choice.

Guidelines

As of June 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=140
    • Intravenous Iron (n=70)
    • Placebo (n=70)
  • Setting: four ICU in Western Australia
  • Enrollment: June 2013 to June 2015
  • Mean follow-up:
  • Analysis: intention-to-treat
  • Primary Outcome: reduction in units of pRBCs transfused

Population

Inclusion Criteria

  • ≥ 18 years
  • admission within last 48 hours
  • anticipated to require critical care beyond the next day
  • Hg < 100 g/L within preceding 24 hours

Exclusion Criteria

  • Suspected or confirmed sepsis
  • Ferritin > 1200 ng/mL
  • Transferrin saturation > 50%

Baseline Characteristics

‘’IV Iron Group shown, groups were similar

  • Demographics: mean age 58 years, 37% female
  • Physiologic parameters: mean APACHE II Score 12.2, mean SOFA 6.1
  • Admission source: Emergency Department 20%, Ward 7%, Operating theatre 71%, other hospital 1%
  • ICU type: General Surgical 13%, Cardiothoracic 43%, Trauma 29%, Neurosurgical 3%, Medical 13%
  • Anthropomorphics: Weight
  • Labs: mean Hemoglobin 89 g/L, Ferritin 317 ng/mL, Transferritin saturation 13%, C-reactive protein 111 mg/L
  • Interventions: Mechanical ventilation 64%, Vasoactive infusion 73%, Renal replacement therapy 4%

Interventions

  • 500mg ferric carboxymaltose in 0.9% Saline as two consecutive 50mL syringes
  • placebo
  • interventions repeated every 4 days while admitted to ICU, to a maximum of 4 doses

Outcomes

Comparisons are IV Iron therapy vs. Placebo.

Primary Outcomes

Total RBC units transfused
97 vs. 136
Median RBC units transfused (IQR)
1 (0-2) vs. 1 (0-3) (RR 0.71, 95% CI 0.43-1.18) P = 0.53

Secondary Outcomes

Proportion of patients receiving transfusion
54% vs. 56% (RR 0.97, 95% CI 0.72-1.31) P = 0.87
median Hemoglobin at hospital discharge
107 g/L vs. 100 g/L (Difference 7, 95% CI 1.89-12.11) P = 0.02
ICU length of stay
6 days vs. 6 days (Difference 0, 95% CI -1.07to 1.07) P = 0.70
Hospital length of stay
15 days vs. 18 days (Difference -3, 95% CI -7.95 to 1.95) P = 0.75

Adverse Events

ICU Mortality
7% vs. 4% (RR 1.67, 95% CI 0.41-6.71) P = 0.47
Hospital Mortality
1-% vs. 9% (RR 1.17, 95% CI 0.41-3.30) P = 0.77
Nosocomial Infection
28.6% vs. 22.9% (RR 1.25, 95% CI 0.71–2.21) P = 0.44
Clinically confirmed Venous Thromboembolism
6% vs. 6% (RR 1.0, 95% CI 0.26–3.84) P = 1.0

Criticisms

  • Medical patients made up only small portion of the population (14%)
  • Possibly underpowered: mean units transfused (1.9) was less than half of the estimate used in the power calculation (4.0)
  • Primary outcome was not normal and analysis had to be changed pot-hoc
  • Iron product may not be available world-wide and full class-effect may not be expected
  • no hemoglobin threshold was set trigger transfusion and could have led to bias

Funding

  • Not clearly reported

Further Reading