Iron in Critical Illness

Fool’s Gold, Or The End Of The Rainbow? 20 March 2014

SMACC Gold – Qld.

Ed LittonIntensivist, Royal Perth Hospital, Western Australia

Clinical Senior Lecturer, University of Western Australia

Disclaimers…• Study drug supplied by Vifor Pharma

• 1. Blood…we’ve got a problem on our hands

• 2. Patient Blood Management…an evolving story

• 3. Iron…metabolism and role in the critically ill

Scale of RBC Transfusion

• RBC units collected per annum:– ≅100 million worldwide– 17 million USA1

– 6.5 million India2

1 National Blood Collection and Utilisation Survey Report 2011, 2 Maharashtra State Blood Transfusion Council 2013, 3 Australian Red Cross Annual Report 2011

Critically ill ≅ 20% of all RBC units3

Rationale for Reducing RBC Transfusion

- Scarcity1

– Donor pool versus recipient pool

–Costs1,2 – Complexities

–Harm– Mechanisms & associations

1 Hofmann et al Strategies to preempt and reduce the use of blood products: An Australian Perspective. Current Opinion in Anaesthesiology 2012; 25(1):66-732 Australian Red Cross Annual Report 2011

RBC Scarcity

• In next 15 years…– Over 65’s will increase by 146%– Under 65’s will increase by only 38%1

1 WA Tomorrow – Population projections for regional planning 2004 to 2031 http://www.planning.wa.gov.au/Publications/723.aspx

RBC Cost• Australian Transfusion Service:

– Total cost $1 billion1

– RBC $500 million (… so critical care $100 million)

• Product cost versus Total cost:– Australia: $370 versus $875– US: $210 versus $3433

• Costs escalating rapidly3

1 Australian Red Cross Annual Report 2011, 2 Shander et al, Estimating the Cost of Blood: Best Pract Res Clin Anaesth 2007;21(2):271-89, 3 Toner et al Costs to hospitals of acquiring and processing blood in the US Appl Health Econ Health Policy 2011; 9(1)29-37

Harm - Anaemia

• 227,425 non-cardiac major surgery participants: – 30% preoperative anaemia1

– independently associated increased risk of 30-day mortality OR 1.4 (95%CI 1.3-1.5)

• Anaemia after critical illness:– Common – Associated with adverse HRQoL2

1 Musallam et al Lancet 2011;378:1396-407, 2 Bateman et al Critical Care Medicine 2009; 37(6):1906-1912

Harm – RBC TransfusionStorage Lesion

• Depletion of 2,3-DPG and ATP• Accumulation of pro-inflammatory

cytokines, RBC membrane microparticles

• Loss of normal RBC-mediated vasoregulation (NO)

• Immunosuppression • Free iron• ABLE (Canada), RECESS (CTS US), TRANSFUSE

(Aus)

Leukoreduction• Decreased transmission of

viruses, febrile non-haemolytic reactions, HLA alloimmunisation, immunosuppression

• Hebert, decrease in mortality in Canada following leukoreduction, RCTs no effect

RBC Harm - Evidence• 1999 TRICC1

– Similar findings in elderly & with cardiac disease or risk factors2

• 2004 ABC and Crit observational studies3:– transfusion associated with increased mortality

• 2008 SOAP: – no association with increased mortality

1 Hebert et al TRICC New England Journal of Medicine 1999 340(6), 2 Carson et al. Liberal or restrictive transfusion in high-risk patients after hip surgery NEJM 2011;365(26):2453-62 , 3 Corwin HL, et al: The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States. CCM 2004, 32(1):39-52

RBC Harm - Evidence

• Systematic review of 45 observational studies with 272,596 participants • Transfusion in critically ill associated with increased:

– Odds ratio for mortality 1.7 (95%CI 1.4-1.9)– Odds ratio for nosocomial infection 1.8 (95%CI 1.5-2.2)– Odds ratio for ARDS 2.5 (95%CI 1.6-3.3)

Marik et al. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Critical care medicine 2008, 36(9):2667-2674

RBC Harm – Evidence

• RCT of old versus fresh RBC transfusion in septic beagles1

1 Solomon et al Blood 2013 121:1663-1672

Patient Blood Management

Patient Blood Management

3 Pillars

Assess Physiological Threshold

Minimising Blood LossOptimising Patient Blood Elements

Assessing Thresholds…

• Hb 50g/l tolerated without problems

• Already few RBC transfusions outside of current guidelines

Westbrook et al: Transfusion practice and guidelines in Australian and New Zealand intensive care units . Intensive Care Med 2010, 36(7):1138-1146.

Assessing Thresholds…

• Majority of RBC units transfused for anaemia1

• Restrictive transfusion threshold beneficial even in acute bleeding:– GI bleeding survival benefit HR 0.55,

p=0.02

1 Westbrook et al. Transfusion practice and guidelines in Australian and New Zealand intensive care units. Intensive Care Medicine 2010; 36(7):1138-46, 2 Corwin et al The Crit Study Critical Care Medicine 2004 32(1) 39-52, 3 Villanueva et al. Transfusion Strategies for Acute Upper Gastrointestinal Bleeding. The New England Journal of Medicine 2013; 368(1): 11-21

Minimising Blood Loss…• Prevention and treatment of major

bleeding:– Prophylaxis e.g. Stress ulcer prophylaxis– Treatment e.g. source control

• Prevention and treatment of minor bleeding:– Mean decrease in Hb 5g/l/day in ICU

patients with Length of Stay >3 days– Approximately 40ml phlebotomy/day– Small volume tubes, non-invasive

testing, reinfusion of sample, elimination of unnecessary blood tests, removal of arterial line

Nguyen et al Time course of haemaglobin concentration in non-bleeding intensive care unit patients CCM 2003 31(2):406-10

Optimising Blood Elements…

Erythropoiesis

Erythropoiesis

Erythropoiesis

Erythropoiesis

Epoetin & Other Blood Elements

• Epoetin in ICU:– No decrease in RBC

transfusion– Trend to mortality

reduction– Significant increase in

thromboembolism

• Relationship to iron?

Corwin et al. Efficacy and safety of epoetin alfa in critically ill patients. New England Journal of Medicine 2007; 357(10): 965-76

IV Iron - Rationale in Critical Illness

• Most common nutritional deficiency worldwide1

• Enteral iron ineffective in the setting of inflammation

1 Pasricha et al. Diagnosis and management of iron deficiency anaemia: a clinical update. MJA 2010; 193(9) 525-32, 2 Coyne et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: Results of the DRIVE Study. Journal of the American Society of Nephrology 2007. 18: 975-984

Iron Metabolism

Iron Metabolism

Iron Metabolism

Hepcidin

Hepcidin

IV Iron - Pharmacology

• Pharmacokinetics:– Size & composition of carbohydrate

shell– Size of Fe3+ core

• Non-dextran iron hypersensitivity rare

• Theoretical risk of infection

Danielson. Structure, chemistry and pharmacokinetics of intravenous iron agents. Journal of the American Society of Nephrology. 2004; 15: s93-S98

Safety & Efficacy of IV Iron

• Systematic Review1:– 75 RCTs– 10,605 participants

• Risk ratio transfusion 0.74 (95% CI 0.62-0.88)

• Risk ratio infection 1.33 (95% CI 1.1-1.6)

1 Litton et al BMJ 2013;347:f4822 (Published 15 August 2013)

Intravenous iRon or placebO for aNaeMiA in iNtensive care: The IRONMAN Study

• Question:– Does the administration of IV iron to patients

admitted to an ICU who are anaemic:• 1. Reduce RBC transfusion• 2. Improve clinical outcomes including mortality at

hospital discharge

Australian New Zealand Clinical Trials Registry ref: ACTRN12612001249842

Summary• Strong grounds to reduce RBC transfusion on the basis of cost and scarcity, irrespective of

(mounting) strength of evidence for harm

• IV iron reduces transfusion requirement in non-critically ill

• Patient-centered outcomes and role in ICU promising but require further investigation

Questions?