Download - Iron: Is it Fool’s Gold? By Litton
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?