Table 1.
Characteristics of included studies (n = 5)
| Study | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Garrido-Martin et al. (2012) [19] | Madi-Jebara et al. (2004) [21] | Pieracci et al. (2009) [22] | Pieracci et al. (2014) [23] | van Iperen et al. (2000) [24] | ||||||
| Iron | No iron | Iron | No iron | Iron | No iron | Iron | No iron | Iron | No iron | |
| Randomised, n | iv 71, oral 73 | 66 | 40 | 40 | 97 | 103 | 75 | 76 | 12 | 12 |
| Analysed n | iv 54, oral 53 | 52 | 40 | 40 | 97 | 103 | 75 | 75 | 12 | 12 |
| Age, mean (SD/range) | iv 65 (11) oral 65 (10) |
65 (12) | 59.1 (9.1) | 55.3 (9.5) | 55.7 (1.9) | 58.2 (1.7) | 41.6 (18–83) | 40.4 (18–87) | 67 (49–89) | 69 (45–80) |
| Male, %: | iv 70.3 % oral 71.7 % |
76.9 % | 90 % | 90 % | 50.5 % | 46.6 % | 77.3 % | 60.5 % | 66.6 % | 66.6 % |
| ICU setting | Cardiothoracic | Cardiothoracic | General surgical, burns, neurosurgical | Trauma | Mixed (surgical, medical, neurological, trauma) | |||||
| Inclusion criteria | Age >18 years old, elective cardiac surgery under extracorporeal circulation, no previous anaemia, susceptible to treatment, no preoperative blood transfusion, able to complete all study visits as per protocol, able to provide written consent | Elective cardiac surgery with CPB, post-pump Hb 7 –10 g.dL-1 | General surgical, burn, neurosurgical ICUs, age >18 years, Hb <13 g.dL-1 prior to enrollment, <72 hours from hospital admission, current tolerance of enteral medication, expected ICU LOS >5 days | Admitted to ICU with trauma, Hb <12 g.dL-1, Age >18 years, <72 hours from ICU admission, expected ICU LOS >5 days | Hb <11.2 g.dL-1, <12.1 g.dL-1 if cardiac disease, age >18 years, expected ICU LOS >7 days, informed consent from patient or relative | |||||
| Exclusion criteria | Elective cardiac surgery without exclusion criteria, fibrinolytic therapy 48 hours prior to CPB, impaired renal function (CrCl <50 mls.min-1), previous surgery for IE, repeat surgery, pregnant or lactating, active gastrointestinal bleeding, B12 deficit, ferropenic anaemia, asthma or allergy, active infection, included in another study, hepatic disease, history of allergy to iron, unlikely to adhere to protocol follow up | Intra-operative blood transfusion, post-operative haemodynamic instability, ejection fraction <40 %, chronic kidney disease, hypothermic bypass, hypersensitivity to iron | Active bleeding, chronic inflammatory conditions, end-stage renal disease, haematologic disorders, macrocytic anaemia, current use of EPO, pregnancy, prohibition of RBC transfusion, imminent death, co-enrollment in another trial | Active haemorrhage, iron overload (serum ferritin >1000 ng.mL-1), conditions associated with iron overload e.g. haemachromatosis, active infection, chronic inflammatory conditions, pre-existing haematological disorders, macrocytic anaemia, current/recent (within 30 days) use of immunosuppression, use of EPO within 30 days, pregnancy or lactation, prohibition of RBCs, imminent death, history of allergy to iron | Pregnancy, iron deficiency anaemia (ferritin <50 ug.L-1), vitamin B12 deficiency (<160 pmol.L-1), recent use of cytostatics or recent radiotherapy, life expectancy <7 days, chronic renal failure, prior use of EPO | |||||
| Intervention(s) | (1) Iron-hydroxide sucrose complex, iv (Venofer; Uriach Laboratory) 3 doses of 100 mg/24 hours during pre- and post-hospitalisation, and 1 pill/24 hours of oral placebo during the same period and during 1 month after discharge (2) Ferrous fumarate (105 mg of iron) 1 pill/24 hours orally pre- and postoperatively and during 1 month after discharge, and intravenous placebo while hospitalised |
i) Iron, iv (Venofer; Luitpold Pharmaceuticals) 200 mg/day to reach total iron deficit + s/c placebo (a) | Enteral ferrous sulphate 325 mg (oral solution or capsule) (Rockwell Compounding Inc.) thrice daily until hospital discharge. Co-intervention: ascorbic acid 500 mg thrice daily, cyanocobalamin 1 mg, folic acid 1 mg | Iron sucrose, iv (Venofer; Luitpold Pharmaceuticals) 100 mg thrice weekly for up to 6 doses or until ICU discharge | Iron saccharate, iv (Venofer; Vifor) 20 mg and iv folic acid 1 mg daily from day 1–14 (b). Co-intervention: folic acid 1 mg daily |
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| Comparator | Oral and iv placebo pre-operatively and postoperatively following same protocol. | Placebo - s/c and iv (0.9 % saline). | Oral placebo, same schedule as intervention protocol. Co-intervention: ascorbic acid 500 mg thrice daily, cyanocobalamin 1 mg, folic acid 1 mg |
Placebo, iv (100 mL of 0.9 % saline) similar dosing schedule to intervention | No iron. Co-intervention: folic acid 1 mg daily | |||||
| Reported outcomes (follow-up time points, days) | • Hb concentration (baseline, operating room entry (day 7), exit operating room, ICU admission, ICU discharge, postoperative day10 and day 30 post-hospital hospital discharge) • Immature reticulocyte fraction, reticulocyte count, serum ferritin (day 1, postoperative day 10 and day 30 post-hospital discharge) • RBC transfusion (number of patients transfused, location of transfusion, mean number of units) |
• Hb concentration (day 0, day 1–5, day 15, day 30) • Reticulocyte counts (day 1, day 5, day 15, day 30) • Serum ferritin (day 0, ay 5, day 15) • RBC transfusion • Mortality |
• Difference in Hct (baseline, days 7, 14, 21 and 28) (primary outcome) • Serum iron, serum ferritin, eZPP (baseline, day 7, day 14, day 21, day 28) • RBC transfusion • Estimated blood loss per study day • Nosocomial infection • Antibiotic days • Adverse outcomes - gastrointestinal upset • ICU and hospital LOS • Mortality |
• Number of total doses of study drug received • Hb concentration (daily) • Serum iron, serum ferritin, serum Tsat, eZPP (baseline, day 7, day 14) • RBC transfusions • Transfusion-free days • Nosocomial infection and type • Antibiotic exposure • ICU and hospital LOS • Mortality |
• Hb concentration (days 0, 7, 14, 21) • Reticulocyte count, sTfR (days 0, 7, 14, 21) • Serum EPO (days 0, 2, 6, 10, 21) • Serum iron, transferrin, Tsat, ferritin, eZPP, CRP (days 0, 10, 21) • Mean blood loss (day 0–21) • RBC transfusion (mean number of units) (day 0–21) • ICU LOS • Mortality |
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aIn a second intervention arm, patients received intravenous iron and recombinant-human erythropoietin (EPO) (300 IU/kg) subcutaneously (s/c) on day 1; this treatment arm was not included in this review because the co-intervention was not matched in the control group. bIn a second intervention arm, patients received intravenous iron and EPO alfa (300 IU/kg) s/c on days 1, 3, 5, 7, 9; this treatment arm was not included in this review because the co-intervention was not matched in the control group. ICU intensive care unit, Hb haemoglobin, Hct haematocrit, Tsat transferrin saturation, sTfR soluble transferrin receptor, eZPP erythrocyte zinc protoporphyrin, LOS length of stay, CBP cardiopulmonary bypass, RBC red blood cell, CrCl creatinine clearance, IE infective endocarditis