Intravenous iron supplementation treats

anemia and reduces blood transfusion

requirements in patients undergoing
coronary artery bypass grafting—A
prospective randomized trial
Presented by:
Dr Faizan Ahmad Ali
Resident Anaesthesiology
 Introduction

 Coronary artery diseases are associated with

morbidity and mortality all over the world.

 Patients undergoing cardiac surgery along with CPB

may have excessive perioperative blood loss requiring
red blood cell transfusions.[1]

1. Ozolina A, Strike E, Harlamovs V, Porite N. Excessive bleeding after cardiac surgery in adults: Reasons and
management. Acta Chir Latviensis 2009;9:86–91.
 Introduction

 The severity of preoperative anemia is considered an

important predictor for perioperative blood
transfusions, and it is associated with higher
incidence of postoperative morbidity[1] and 30‑day
mortality.[2,3]

1. Jans O, Jorgensen C, Kehlet H, Johansson PI, Lundbeck Foundation Centre for Fast‑track Hip and Knee Replacement Collaborative
Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast‑track hip and knee arthroplasty.
Transfusion 2014;54:717–26.
2. Wu WC, Schifftner TL, Henderson WG, Eaton CB, Poses RM, Uttley G, et al. Preoperative hematocrit levels and postoperative
outcomes in older patients undergoing noncardiac surgery. JAMA 2007;297:2481–8.
3. Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al. Preoperative anaemia and postoperative
outcomes in non‑cardiac surgery: A retrospective cohort study. Lancet 2011;378:1396–407.
 Introduction

 In many studies, it was assumed that 30% of anemic

patients scheduled for cardiac surgery received more
allogeneic blood transfusions than those with normal
hemoglobin (Hb) levels.[1]
 Preoperative anemia results in two‑ to sixfold
increased incidence of perioperative blood
transfusion and low postoperative Hb levels.[2]

1. Basora M, Deulofeu R, Salazar F, Quinto L, Gomar C. Improved preoperative iron status assessment by soluble transferrin receptor
in elderly patients undergoing knee and hip replacement. Clin Lab Haematol 2006;28:370–5.
2. Carson JL, Brooks MM, Abbott JD, Chaitman B, Kelsey SF, Triulzi DJ, et al. Liberal versus restrictive transfusion thresholds for
patients with symptomatic coronary artery disease. Am Heart J 2013;165:964–71.
 Introduction

 Preoperative anemia is associated with complications,

such as:[1,2]
 Stroke
 Postoperative myocardial infarction
 Prolonged hospital or (ICU) stay
 Increased 30‑day mortality
 Kidney injury
 Transfusion induced lung injury.
1. Nelson M, Green J, Spiess B, Kasirajan V, Nicolato P, Liu H, et al. Measurement of blood loss in cardiac surgery: Still too much. Ann
Thorac Surg 2018;105:1176–81.
2. Tzatzairis T, Vogiatzaki T, Kazakos K, Drosos G. Perioperative blood management strategies for patients undergoing total knee
replacement: Where do we stand now? World J Orthop 2017;8:441–54.
 Introduction

 Perioperative blood Hb adjustment has been adopted

to maximize Hb levels and reduce the risk of blood
transfusion.[1]
 Preoperative administration of intravenous iron is a
promising and feasible alternative to blood
transfusion for controlling preoperative anemia,
which affects one in four patients scheduled for
surgical procedures.[2]
1. Beghé C, Wilson A, Ershler WB. Prevalence and outcomes of anemia in geriatrics: A systematic review of the literature. Am J Med
2004;116:3S–10S.
2. Beris P, Muñoz M, Garcia‑Erce JA, Thomas D, Maniatis A, Van der Linden P. Perioperative anaemia management: Consensus
statement on the role of intravenous iron. Br J Anaesth 2008;100:599–604.
 Introduction

 This prospective study was designed to investigate

the effect of preoperative intravenous infusion of iron
on incidence of anemia, Hb levels, red blood cell
transfusion requirements, and incidence of
postoperative adverse in patients undergoing elective
CABG.
 Methods

Study Design:
 Prospective, randomized, double‑blind, parallel‑group
study.
 Carried out in the Cardiothoracic Academy of Ain
Shams University, Egypt from September 2019 to
January 2020.
 Preoperative check‑up was completed 3–4 weeks in
advance.
 Methods

 Inclusion Criteria:
 Aged 52–67 years
 Elective CABG scheduled
 Eligibility to receive the study medication
 Clopidogrel interruption 10 days before surgery
 Anemia defined as Hb less than:
 13 g/dL for men
 12 g/dL for women
 Methods

Exclusion Criteria:
 Hypersensitivity to iron  Pregnancy or nursing
 Folate or vitamin B12 deficiency  Anemia from intestinal
 Hb <8 g/dL bleeding
 History of Hep B or C or HIV  Active severe infection
 Hx of stroke in the last 6mo  Unstable angina
 Suspicion of acquired iron  Impaired renal function
overload (ferritin >300 μg/L) (s‑creatinine >1.7mg/dL,
 Autologous blood transfusion hemochromatosis or
in the previous month hemosiderosis)
 Methods

 Patients of the iron group (n = 40) received a single

intravenous dose of ferric carboxymaltose (1000 mg
in 100 mL saline) infused for 15 min 7 days before
surgery.
 Patients of the placebo group (n = 40) received a
single‑dose infusion of 100 mL saline for 15 min 7 days
before surgery.
 Methods

 The anesthesia procedure was standardized, and

surgeries were performed by the same surgical team.
 Premedication with midazolam was limited to a
maximum of 0.05 mg/kg.
 Anaesthesia was induced with 12 μg/kg fentanyl, 5–7
mg/kg sodium thiopental, and 0.15 mg/kg
pancuronium and was maintained with 1–2.0%
isoflurane.
 Methods

Monitoring during surgery:

 Invasive arterial blood pressure
 Pulse oximetry
 Central venous catheter
 Arterial blood gases
 Nasopharyngeal temperature
 Methods

 Heart rate and blood pressure were maintained

within 20% of baseline.

 For anticoagulation treatment, heparin 300 U/kg was

administered into the right atrium to achieve an
activated clotting time above 480 s.
 Methods

 CPB was initially handled with nonocclusive roller pumps, membrane

oxygenators, arterial line filtration, and cold blood‑enriched hyperkalemic arrest.
 Next, the CPB circuit was primed with 1.8 L lactated Ringer’s solution and 50 mL
20% mannitol.
 CPB included systemic hypothermia (esophageal temperature 28°C) during
aortic cross‑clamping, perfusion pressure between 60 and 80 mmHg, and pump
flow rates of 2.2 L/min/m2.
 Myocardial protection was accomplished with antegrade cold blood
cardioplegia.
 A 32‑μm filter (Avecor Affinity, Minneapolis, MN, USA) was used in the arterial
perfusion line.
 Toward the end of the operation, patients were warmed to 36–37°C.
 Methods

 Following separation from the CPB, heparin was

neutralized with protamine sulfate (1 mg protamine
sulfate/100 U heparin) to achieve activated clotting
time within 10% of baseline.

 Finally, all patients were transferred to the ICU after

surgery.
 Methods

Primary endpoint:
 Effect of iron therapy on the incidence of anemia in each
group 4 weeks after discharge.
 Methods

Secondary end points:

 Measurement of the Hb level on admission, preoperatively,
postoperatively, 1 week and 4 weeks after discharge
 Number of pRBCs units
 Percentage of reticulocytes preoperatively, postoperatively
and 1 week later
 Hospital stay length
 Length of ICU stay
 Methods

Secondary end points:

 Incidence of postoperative complications including:
 Stroke
 Prolonged ventilation
 Heart failure
 Cardiac tamponade
 Hospital mortality
 Infection (sepsis and pneumonia)
 Myocardial infarction
 Pericardial effusion
 Results

 There was no significant difference in terms of

demographic data, American Association of
Anesthesiologists (ASA) status, comorbidities, and
surgical data between the two study groups;

 Aortic cross‑clamp time was significantly shorter in

iron group compared with placebo group, P<0.001.
Results
 Results

 The intention‑to‑treat analysis of the primary

outcome revealed an incidence of anemia 4 weeks
after discharge of (13/40) 32% in patients receiving
iron and (32/40) 80% in those receiving placebo
(P<0.001).
 Hb level was significantly higher in the iron group
compared to the placebo group preoperatively and
postoperatively and 4 weeks after discharge
(P<0.001).
 Results

 In contrast, Hb level was comparable between study

groups on admission and 1 week after discharge
(P=0.397).
 The amount of postoperative blood loss was similar
between the study groups (P=0.843).
 The number of pRBCs taken was significantly higher in
the placebo group than in the iron group given
postoperatively (P<0.001).
Results
 Results

 There was no statistically significant difference regarding the

incidence of adverse cardiovascular events such as atrial
fibrillations (P=0.531) and also the incidence of infection
(P=0.456).
 There was no significant difference between the study groups in
terms of prolonged ventilation (P=0.136), mortality rate (P=0.644),
heart failure (P=0.305), and the incidence of stroke (P = 0.314).
 The incidence of pericardial effusion and cardiac tamponade were
similar between the two groups (P=0.556 and P=1.00,
respectively).
Results
 Results

 Percentage of reticulocytes was comparable between

the two study groups preoperatively (P=0.293).
However, percentage of reticulocytes was
significantly higher in placebo group than in iron
group postoperatively and 1 week after discharge
(P<0.001)
Results
 Discussion

 The results of this study showed that the preoperative

management of anemia with intravenous iron therapy in
patients undergoing CABG was associated with less
incidence of postoperative anemia 4 weeks after discharge,
increased Hb level preoperatively, postoperatively and 4
weeks after discharge, significant decrease in the
postoperative packed RBC requirements, shorter hospital
and ICU stay length, shorter aortic cross‑clamp time, and
insignificant difference as regard the incidence
postoperative complications between the study groups.
 Discussion

 A variety of blood conservation programs have been

carried out to address the problem of preoperative
anemia aiming to limit RBC transfusions.[1]

1. Nissenson AR, Goodnough LT, Dubois RW. Anemia: Not just an innocent bystander? Arch Intern Med 2003;163:1400–4.
 Discussion

 A systematic review showed that anti‑fibrinolytic

drugs decreased blood loss during surgery and
consequently the need for RBC transfusions,[1,2]
although the drugs used to reduce blood loss may
provoke hypercoagulation.[3]

1. Perel P, Ker K, Morales Uribe CH, Roberts I. Tranexamic acid for reducing mortality in emergency and urgent surgery. Cochrane
Database Syst Rev 2013;CD010245. doi: 10.1002/14651858. CD010245.pub2.
2. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, et al. Anti‑fibrinolytic use for minimising perioperative
allogeneic blood transfusion. Cochrane Database Syst Rev 2011;CD001886. doi: 10.1002/14651858.CD001886.pub3.
3. Zufferey PJ, Miquet M, Quenet S, Martin P, Adam P, Albaladejo P, et al. Tranexamic acid in hip fracture surgery: A randomized
controlled trial. Br J Anaesth 2010;104:23–30.
 Discussion

 It was reported that erythropoiesis‑stimulating

agents are associated with thrombotic events.[1]
 Intravenous iron treatment is an effective
intervention for preoperative anemia. However,
definitive evidence is lacking.[2,3]

1. Glaspy J. Thrombosis during therapy with erythropoiesis stimulating agents in cancer. In: Nowrousian M.R. (eds) Recombinant
Human Erythropoietin (rhEPO) in Clinical Oncology 2008. https://doi.org 10.1007/978-3-211-69459-6_30.
2. Garrido‑Martin P, Nassar‑Mansur MI, de la Llana‑Ducrós R, Virgos‑Aller TM, Rodriguez Fortunez PM, Ávalos‑Pinto R, et al. The effect
of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective
cardiac surgery: A randomized clinical trial. Interact Cardiovasc Thorac Surg 2012;15:1013–8.
3. Edwards TJ, Noble EJ, Durran A, Mellor N, Hosie KB. Randomized clinical trial of preoperative intravenous iron sucrose to reduce
blood transfusion in anaemic patients after colorectal cancer surgery. Br J Surg 2009;96:1122–8.
 Discussion

 In a previous randomized controlled trial, Johansson et

al. compared iron isomaltoside to placebo regarding the
ability to change Hb from baseline to 4 weeks in patients
undergoing elective CABG or valve replacement. The
incidence of anemia was significantly less in the iron
isomaltoside group compared to the placebo group (P =
0.012), and the percentage of nonanemic patients at
week 4 was significantly more pronounced in the iron
isomaltoside group (38.5% vs. 8%; P < 0.05). [1]
1. Johansson PI, Rasmussen AS, Thomsen LL. Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in
preoperatively non‑anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a
combination thereof: A randomized double‑blind placebo‑controlled clinical trial (the PROTECT trial). Vox Sang 2015;109:257–66.
 Discussion

 IV iron therapy is more effective compared to oral

iron and it has many advantages such as higher and
prompt increase in Hb levels and rebuilding of body
iron stores.[1]

1. Lindgren S, Wikman O, Befrits R, Blom H, Eriksson A, Granno C, et al. Intravenous iron sucrose is superior to oral iron sulphate for
correcting anaemia and restoring iron stores in IBD patients: A randomized, controlled, evaluator‑blind, multicentre study. Scand J
Gastroenterol 2009;44:838‑45.
 Discussion

 A meta‑analysis by Schack and colleagues[1] investigated the effect

of preoperative iron therapy on allogenic blood transfusion,
postoperative Hb levels, length of hospital stay, mortality rate, and
postoperative infections in acute major non-cardiac surgeries.
 They found that there was risk reduction of transfusion
(P=0.0004) in seven studies.
 Postoperative mortality was reduced in the iron therapy group in a
meta‑analysis of four observational studies (P=0.04); postoperative
infection reduction was also detected in four studies.[1]

1. Schack A, Berkfors AA, Ekeloef S, Gögenur I, Burcharth J. The effect of perioperative iron therapy in acute major non‑cardiac
surgery on allogenic blood transfusion and postoperative haemoglobin levels: A systematic review and meta‑analysis. World J Surg
2019;43:1677‑91.
 Discussion

 In a recent study including 22,785 consecutive

patients, the research team found that transfusion of
1 or 2 units of RBCs resulted in increased morbidity
and mortality after cardiac surgery.[1]

1. Paone G, Likosky DS, Brewer R, Theurer PF, Bell GF, Cogan CM, et al. Transfusion of 1 and 2 units of red blood cells is associated
with increased morbidity and mortality. Ann Thorac Surg 2014;97:87–94.
 Discussion

 Zindrou and his colleagues[1] stated that

preoperative anemia was associated with a fourfold
increase of the odds of postoperative complications,
especially in valvular surgery and fivefold increase in
the mortality rate in patients undergoing cardiac
surgery.

29. Zindrou D, Taylor KM, Bagger JP. Preoperative haemoglobin concentration and mortality rate after coronary artery bypass
surgery. Lancet 2002;359:1747–8.
 Discussion

 In contrast, an earlier study by Garrido et al.,[1] found

that iron supplementation was ineffective.
 A possible cause may be insufficient dose of iron
therapy received or ineffective type of iron treatment
given (3 doses of 100 mg IV iron (III)– hydroxide
sucrose complex every 24 h pre–postoperatively).

1. Garrido‑Martin P, Nassar‑Mansur MI, de la Llana‑Ducros R, Virgos‑Aller TM, Rodriguez Fortunez PM, Avalos‑Pinto R, et al. The effect
of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective
cardiac surgery: A randomized clinical trial. Interact Cardiovasc Thorac Surg 2012;15:1013–8.
 Discussion

 Richards et al.[1] too, studied the efficacy of iron

therapy use for patients undergoing major abdominal
surgery.
 Showed that iron treatment raised Hb level but it did
not reduce the need for postoperative blood
transfusion or hospital stay length.
 This controversy may be due to the difference in the
nature of the surgical procedure.

1. Richards T, Baikady RR, Clevenger D, Butcher A, Abeysiri S, Chau M. Preoperative intravenous iron to treat anaemia before major
abdominal surgery (PREVENTT): A randomized, double blinded controlled trial. Lancet 2020;396:1353‑61.
 Discussion

 According to the International treatment guidelines,

patients scheduled for elective surgery associated
with an expected blood loss of 500 mL or more must
be screened for anemia 2 weeks prior to surgery and
anemia should be treated with intravenous iron
therapy.[1]

1. Mueller MM, Van Remoortel H, Meybohm P. Patient blood management: Recommendations from the 2018 Frankfurt Consensus
Conference. JAMA 2019;321:983‑97.
 Limitations

 Relatively small sample size.

 Further studies of a larger scale would be beneficial to
support the findings.

 The adverse events have not been classified as

serious or non-serious, recovering or non-recovering.
 Conclusion

 Preoperative IV iron infusion:

 safe and feasible way to manage preoperative anemia.
 higher preoperative and postoperative Hb levels.
 reduced the need for perioperative RBC transfusions.
 significantly shorter ICU and hospital stay length.
 Insignificant difference regarding the incidence of
postoperative complications between the study
groups.