Intravenous iron for severe iron deficiency anaemia
2018; Elsevier BV; Volume: 121; Issue: 2 Linguagem: Inglês
10.1016/j.bja.2018.05.055
ISSN1471-6771
AutoresAryeh Shander, Manuel Múñoz, Donat R. Spahn,
Tópico(s)Iron Metabolism and Disorders
ResumoAccording to WHO, iron deficiency is the most common nutritional deficiency across the globe and the only such condition that is significantly prevalent in both the developing and industrialised nations. This leaves roughly one-third of the world population anaemic, with an unimaginable burden of disease1Kassebaum N.J. The global burden of anemia.Hematol Oncol Clin North Am. 2016; 30: 247-308Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar and far-reaching negative consequences on health, economy, quality of life, and mortality everywhere.2WHO The global prevalence of anaemia in 2011. World Health Organization, Geneva2015Google Scholar Although often ignored and accepted as a bystander (observed in multiple haemoglobin plots in various transfusion trials that show patients remaining anaemic until discharged with no apparent treatment),3Mazer C.D. Whitlock R.P. Fergusson D.A. et al.Restrictive or liberal red-cell transfusion for cardiac surgery.N Engl J Med. 2017; 377: 2133-2144Crossref PubMed Scopus (389) Google Scholar ample evidence places anaemia (even mild anaemia) as an independent risk factor for various negative outcomes.4Shander A. Goodnough L.T. Javidroozi M. et al.Iron deficiency anemia—bridging the knowledge and practice gap.Transfus Med Rev. 2014; 28: 156-166Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Perhaps the part that distresses the most is that it is a modifiable risk factor, mostly treatable and often quite easily curable. In this issue of the British Journal of Anaesthesia, Füllenbach and colleagues5Füllenbach C. Triphaus C. Glaser P. et al.Iron supplementation in a case of severe iron deficiency anaemia.Br J Anaesth. 2018; 121: 502-504Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar report on the management of a patient with chronic severe iron deficiency anaemia in an outpatient setting. Despite a haemoglobin concentration of 4.5 g dl−1 at presentation, the patient was largely asymptomatic except for fatigue and general weakness. Severe anaemia had been previously diagnosed in this patient with a haemoglobin concentration of 6.2 g dl−1, and clinicians had recommended admission for diagnostic work-up and blood transfusion, which was rejected by the patient for unknown reasons. There is no mention of iron supplementation during those past episodes of care. This time, the patient was managed in an outpatient setting and had a remarkable (nonetheless anticipated) response to a single 1 g dose of i.v. iron, with haemoglobin increase to 8.7 g dl−1 and improvements in iron profile and overall health status in 3 weeks.5Füllenbach C. Triphaus C. Glaser P. et al.Iron supplementation in a case of severe iron deficiency anaemia.Br J Anaesth. 2018; 121: 502-504Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar This case report serves to remind us all that iron deficiency anaemia is omnipresent, it can lower haemoglobin concentration (often single-handedly as seems to be the case here) to strikingly low concentrations, affecting quality of life. As demonstrated in this case, despite the low haemoglobin concentration, his anaemia was well managed without a single unit of blood, and blood transfusion does not need to be the default treatment, even in severe chronic cases. Indeed, we ought to be asking ourselves, when anaemia is so commonly caused or exacerbated by iron deficiency, why are we still hesitating so often to address the core underlying cause by simply giving iron, following that with a diagnostic work-up to determine the cause of iron deficnecy?6Muñoz M. Gómez-Ramírez S. Kozek-Langeneker S. et al.‘Fit to fly’: overcoming barriers to preoperative haemoglobin optimization in surgical patients.Br J Anaesth. 2015; 115: 15-24Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar As pointed out by Muñoz and colleagues,6Muñoz M. Gómez-Ramírez S. Kozek-Langeneker S. et al.‘Fit to fly’: overcoming barriers to preoperative haemoglobin optimization in surgical patients.Br J Anaesth. 2015; 115: 15-24Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 7Muñoz M. Gómez-Ramírez S. Besser M. et al.Current misconceptions in diagnosis and management of iron deficiency.Blood Transfus. 2017; 15: 422-437PubMed Google Scholar the barriers against effective treatment of iron deficiency anaemia are multifaceted: underestimation of the prevalence of anaemia, over-reliance on WHO definition of anaemia (which is derived from epidemiological studies, ‘accepting’ a lower haemoglobin concentration for women as ‘normal’), dismissing the risks of anaemia to patients, relying on ferritin as the sole or main laboratory measurement to rule out iron deficiency, assumption that iron deficiency without anaemia does not merit attention, concerns over the cost-effectiveness of management of anaemia, general preference of oral iron over i.v. iron formulations, and a belief that i.v. iron should be reserved for most severe cases only, assumption that all i.v. iron formulations are created equal and all pose similar risks (including a widespread and unjustified fear of ‘anaphylaxis’), concerns over risk of infection and oxidative stress, and overlooking the need to reassess iron stores after iron repletion.6Muñoz M. Gómez-Ramírez S. Kozek-Langeneker S. et al.‘Fit to fly’: overcoming barriers to preoperative haemoglobin optimization in surgical patients.Br J Anaesth. 2015; 115: 15-24Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 7Muñoz M. Gómez-Ramírez S. Besser M. et al.Current misconceptions in diagnosis and management of iron deficiency.Blood Transfus. 2017; 15: 422-437PubMed Google Scholar Correction of each of these misconceptions offers opportunities to improve clinical practices and eventually help with better and more effective management of anaemia. Returning to our severely anaemic patient, what role does allogeneic blood transfusion play in his management? Thanks to declining trends in haemoglobin-based transfusion thresholds in the last decade, most transfusion guidelines suggest a haemoglobin concentration of around 6 g dl−1 in non-bleeding, asymptomatic patients without major comorbidities in most clinical settings as the concentration below which blood transfusion should be considered.8Shander A. Gross I. Hill S. Javidroozi M. Sledge S. A new perspective on best transfusion practices.Blood Transfus. 2013; 11: 193-202PubMed Google Scholar While each transfusion decision should be made based on the individual patient's condition and preferences, the goal should always remain to treat the patient and not a laboratory value, and even when the decision to transfuse is made, one should not forget that allogeneic blood is a temporary symptomatic relief and should not be viewed as a treatment for anaemia or iron deficiency.9Shander A. Javidroozi M. The patient with anemia.Curr Opin Anaesthesiol. 2016; 29: 438-445Crossref PubMed Scopus (13) Google Scholar Blood transfusion is not a decision to be taken lightly in any patient but the stakes here are potentially higher. In patients with chronic severe anaemia (such as this case), several compensatory mechanisms are activated to improve tolerance of anaemia. Transfused blood is not saturated with oxygen as it enters the circulation and might not confer an immediate positive effect on oxygen delivery (as its oxygen downloading capacity is limited by low 2,3-bisphosphoglyceric acid concentrations in transfused red blood cells),10Li Y. Xiong Y. Wang R. Tang F. Wang X. Blood banking-induced alteration of red blood cell oxygen release ability.Blood Transfus. 2016; 14: 238-244PubMed Google Scholar while it has an immediate impact on circulatory volume, viscosity, and rheological characteristics of the recipient's blood. This can lead to various positive and negative changes in macro- and microcirculation (e.g. transfusion-associated circulatory overload, reduced cardiac output, or improved microcirculation).11Agrawal A.K. Hsu E. Quirolo K. Neumayr L.D. Flori H.R. Red blood cell transfusion in pediatric patients with severe chronic anemia: how slow is necessary?.Pediatr Blood Cancer. 2012; 58: 466-468Crossref PubMed Scopus (11) Google Scholar, 12Zimmerman R. Tsai A.G. Salazar Vazquez B.Y. et al.Posttransfusion increase of hematocrit per se does not improve circulatory oxygen delivery due to increased blood viscosity.Anesth Analg. 2017; 12: 1547-1554Crossref Scopus (28) Google Scholar Another issue is the change in left ventricular geometry seen in chronic anaemia (such as ventricular hypertrophy) that might even be aggravated with complete correction of anaemia.13Eckardt K.U. Scherhag A. Macdougall I.C. et al.Left ventricular geometry predicts cardiovascular outcomes associated with anemia correction in CKD.J Am Soc Nephrol. 2009; 20: 2651-2660Crossref PubMed Scopus (95) Google Scholar In severe anaemia, allogeneic blood transfusion is often the first treatment option that comes to mind. While it might be hard to argue against transfusion in acute, actively bleeding, or unstable cases with very low haemoglobin concentrations, other treatment modalities should not be overlooked. The American Association of Blood Banks (AABB) recommendations for the Choosing Wisely campaign call against red blood cell transfusion for chronic iron deficiency anaemia even with low haemoglobin concentrations in absence of haemodynamic instability.14Callum J.L. Waters J.H. Shaz B.H. Sloan S.R. Murphy M.F. The AABB recommendations for the choosing wisely campaign of the American board of internal medicine.Transfusion. 2014; 54: 2344-2352Crossref PubMed Scopus (116) Google Scholar Transfusion for anaemia may not be associated with reduced postoperative mortality.15Feng S. Machina M. Beattie W.S. Influence of anaemia and red blood cell transfusion on mortality in high cardiac risk patients undergoing major non-cardiac surgery: a retrospective cohort study.Br J Anaesth. 2017; 118: 843-851Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Haematinic agents are effective options in compensated chronic cases of severe anaemia—even as the main treatment as shown in this case report—and acute cases as the adjuvant treatment after emergency transfusion to ensure a sustained and lasting increase in haemoglobin concentration. In a patient with severe anaemia, iron deficiency should be searched, with assessment of iron stores and calculation of total iron deficit if present. I.V. iron formulations that allow delivery of a large doses of iron in one or a few injections to replenish iron stores are preferred in patients with severe anaemia.16Baird-Gunning J. Bromley J. Correcting iron deficiency.Aust Prescr. 2016; 39: 193-199Crossref PubMed Scopus (30) Google Scholar, 17Auerbach M. Adamson J.W. How we diagnose and treat iron deficiency anemia.Am J Hematol. 2016; 91: 31-38Crossref PubMed Scopus (154) Google Scholar I.V. iron formulations that allow rapid restoration of iron deficiency in fewer infusions are generally associated with reduced overall resource utilisation and costs compared with formulations that require multiple infusions.18Pollock R.F. Muduma G. A budget impact analysis of parenteral iron treatments for iron deficiency anemia in the UK: reduced resource utilization with iron isomaltoside 1000.Clinicoecon Outcomes Res. 2017; 9: 475-483Crossref PubMed Scopus (9) Google Scholar Interestingly, the overall cost of treatment with rapid-infusion i.v. iron formulations can often be even less than the overall cost of treatment with oral iron supplementation despite the higher cost of i.v. medication per se, simply because patients require fewer visits to health care facilities and can enjoy a faster and more effective restoration of iron deposits and correction of anaemia.19Calvet X. Gene E. AngelRuiz M. et al.Cost-minimization analysis favours intravenous ferric carboxymaltose over ferric sucrose or oral iron as preoperative treatment in patients with colon cancer and iron deficiency anaemia.Technol Health Care. 2016; 24: 111-120Crossref PubMed Scopus (25) Google Scholar Clinical and laboratory responses are typically seen within 2–3 weeks after treatment with i.v. iron and improvements are expected to continue. Subsequent evaluation is often indicated 6–8 weeks later to ensure that body iron stores are restored. As iron supplementation is provided, potential causes of blood loss, iron deficiency (e.g. on-going blood loss from gastrointestinal tract or restricted dietary iron intake), or both, should be investigated and any such underlying causes should be addressed.9Shander A. Javidroozi M. The patient with anemia.Curr Opin Anaesthesiol. 2016; 29: 438-445Crossref PubMed Scopus (13) Google Scholar It should be remembered that, while replenishing the iron stores is often the central step in these cases, other haematinic agents, namely vitamin B12 and folate, are also needed to support accelerated erythropoeisis.20Muñoz M. Gómez-Ramírez S. Martín-Montañez E. Auerbach M. Perioperative anemia management in colorectal cancer patients: a pragmatic approach.World J Gastroenterol. 2014; 20: 1972-1985Crossref PubMed Scopus (79) Google Scholar Proper management of anaemic patients requires on-going care and subsequent follow-ups to make sure patients do not end up with severe anaemia again in a few months. This is aligned with the general approach in medicine in which the underlying condition is diagnosed and proper treatment administered, as opposed to the more passive and traditional approach to anaemia that involves temporary symptomatic treatment from time to time as haemoglobin concentration gets too low. In the former approach, the focus remains on the patient, the diagnosis, and the proper treatment—which often includes i.v. iron. In the latter approach, we remain preoccupied with hot debates over giving or not giving blood at arbitrary haemoglobin concentrations.21Shander A. Kim T.Y. Goodnough L.T. Thresholds, triggers or requirements-time to look beyond the transfusion trials.J Thorac Dis. 2018; 10: 1152-1157Crossref PubMed Scopus (7) Google Scholar Contributed to the entirety of the manuscript and reviewed and approved it in its final form before submission: all authors. A.S. has been a founding member of Society for Advancement of Bloodless Medicine and a paid speaker for CSL Behring, Masimo, Merck and Portola Pharmaceuticals, consultant for AMAG, CSL Behring, Gauss Surgical, Instrumentation Laboratory, Masimo, Portola Pharmaceuticals, and Vifor Pharma and a research grant recipient from CSL Behring, Gauss Surgical, HbO2 Therapeutics, LLC, Instrumentation Laboratories, and Masimo. D.S.’s academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland, the Ministry of Health (Gesundheitsdirektion) of the Canton of Zurich, Switzerland for Highly Specialized Medicine, the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland, the Swiss Foundation for Anesthesia Research, Zurich, Switzerland, CSL Behring, Berne, Switzerland, Vifor SA, Villars-sur-Glâne, Switzerland. D.S. is co-chair of the ABC-Trauma Faculty, sponsored by unrestricted educational grants from Novo Nordisk Health Care AG, Zurich, Switzerland, CSL Behring GmbH, Marburg, Germany, LFB Biomédicaments, Courtaboeuf Cedex, France and Octapharma AG, Lachen, Switzerland. D.S. has received honoraria or travel support for consulting or lecturing from: Danube University of Krems, Austria, US Department of Defense, Washington, USA, European Society of Anesthesiology, Brussels, BE, Korea, Korean Society for Patient Blood Management, Seoul, Korea, Korean Society of Anesthesiologists, Seoul, Baxter AG, Volketswil, Switzerland, Baxter S.p.A., Roma, Italy, Bayer AG, Zürich, Switzerland, Bayer Pharma AG, Berlin, Germany, B. Braun Melsungen AG, Melsungen, Germany, BoehringerIngelheim GmbH, Basel, Switzerland, Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France and Baar, Switzerland, CSL Behring GmbH, Hattersheim am Main, Germany and Berne, Switzerland, Celgene International II Sàrl, Couvet, Switzerland, Curacyte AG, Munich, Germany, Daiichi Sankyo AG, Thalwil, Switzerland, GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany, Haemonetics, Braintree, MA, USA, Instrumentation Laboratory (Werfen), Bedford, MA, USA, LFB Biomédicaments, Courtaboeuf Cedex, France, Merck Sharp & Dohme, Kenilworth, New Jersey, USA, Octapharma AG, Lachen, Switzerland, Organon AG, Pfäffikon/SZ, Switzerland, PAION Deutschland GmbH, Aachen, Germany, Pharmacosmos A/S, Holbaek, Denmark, Photonics Healthcare B.V., Utrecht, The Netherlands, Roche Diagnostics International Ltd, Reinach, Switzerland, Roche Pharma AG, Reinach, Switzerland, Sarstedt AG & Co., Sevelen, Switzerland and Nümbrecht, Germany Schering-Plough International, Inc., Kenilworth, New Jersey, USA, Tem International GmbH, Munich, Germany, VerumDiagnostica GmbH, Munich, Germany, Vifor Pharma, Munich, Germany, Vienna, Austria and Villars-sur-Glâne, Switzerland, Vifor (International) AG, St. Gallen. M.M. declares no relevant conflicts of interest. Iron supplementation in a case of severe iron deficiency anaemiaBritish Journal of AnaesthesiaVol. 121Issue 2PreviewAnaemia is associated with a reduced blood oxygen carrying capacity; it is defined by the WHO as a haemoglobin (Hb) concentration of <12 and <13 g dl−1 for women and men, respectively. Recent data highlight anaemia as an independent risk factor for morbidity and mortality.1 Despite potential risks, transfusion with allogeneic blood products has been considered the mainstay to correct severe anaemia.2 Patient blood management (PBM) evolved from the urgent need for adeqaute anaemia management and encompasses more than 100 measures to date. Full-Text PDF Open Archive
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