Perioperative iron deficiency anaemia

Learning objectivesBy reading this article, you should be able to:•Describe iron physiology in health and disease states relevant to perioperative medicine.•Interpret laboratory tests, particular markers of status, the diagnostic work-up anaemia.•Outline prevalence deficiency anaemia various groups surgical patients.•Discuss benefits risks treatments for including therapy, erythropoiesis-stimulating agents blood transfusion.•Explain recent guidelines clinical trials on management anaemia.Key points•Iron is most common cause anaemia, affecting at least 1.2 billion people worldwide.•Iron essential haemoglobin synthesis, cell growth differentiation, oxygen sensing, muscle energetics cellular immunity.•Systemic homeostasis finely regulated by hepcidin.•Pre- postoperative affects nearly all patients an independent risk factor poor outcomes after both elective non-elective surgery.•Perioperative commonly treated with oral or i.v. some evidence improved outcomes. Ongoing research will provide further use agents. By anaemia. •Iron Iron ∼2 worldwide.1Camaschella C. Nai A. Silvestri L. metabolism disorders revisited hepcidin era.Haematologica. 2020; 105: 260-272Crossref PubMed Scopus (257) Google Scholar It commonest becomes more important when we consider functional sequestration secondary inflammation. This review provides update epidemiology, underlying mechanisms, implications undergoing emergency surgery. The detection one three key pillars patient management, along minimising loss bleeding, optimising patient's physiological reserve latter two are beyond scope article detailed elsewhere.2Thakrar S.V. Clevenger B. Mallett S. Patient anaemia.BJA Educ. 2016; 17: 28-34Abstract Full Text PDF (23) aetiology multifactorial can to: (i) pre-existing nutritional deficiency, comorbidities (e.g. cancer), both; (ii) inflammation; (iii) from procedure itself. Many these factors coexist practice. Other causes summarised as being attributable to:•Reduced absorption—bariatric surgery, coeliac disease, gastritis, drugs proton pump inhibitors)•Reduced intake—eating disorders, vegetarians/vegans•Increased requirements—infants, adolescents, athletes, pregnancy, donors•Chronic loss—gastrointestinal tumours, hookworm infestation, abnormal uterine bleeding.1Camaschella Scholar,3McNally S.A. Perioperative anaemia: a new guideline.Br J Hosp Med (Lond). 2023; 84: 1-4Crossref (0) (Hb) synthesis. Humans normally synthesise 2 million erythrocytes per second. Each mature red (RBC) contains 280 molecules Hb each four globin subunits atom haem, resulting total flux required maintain erythropoiesis 2–3 × 1015 atoms second adult human.4Drakesmith H. Nemeth E. Ganz T. Ironing out ferroportin.Cell Metab. 2015; 22: 777-787Abstract (374) Total body content ∼3–4 g, which 1–2 mg lost every day, 1 approximately monthly during menstruation. unable excrete actively have therefore developed tuned regulatory mechanisms control amount dietary intake, uptake, bodily distribution export.5Ganz Systemic homeostasis.Physiol Rev. 2013; 93: 1721-1741Crossref (720) Dietary must pass through absorptive enterocytes enter circulation. Haem effectively absorbed. Inorganic non-haem ferric reduced soluble ferrous (Fe2+) brush border ferrireductase before it (Fig. 1) hepcidin, predominantly produced liver.5Ganz Hepcidin expression results degradation ferroportin, only known mammalian exporter iron, blocks release macrophages duodenal subsequently reduces availability.5Ganz upregulated presence inflammation high circulating concentrations transferrin-bound labile both. Conversely, decreased hypoxia, increased erythropoietic activity (via erythroferrone).5Ganz Genetic leads overload such haemochromatosis, thalassaemia syndromes (α β) congenital dyserythropoietic anaemia.1Camaschella Stressors acute illness, infection stress response trigger host immune inflammatory profound changes trafficking. proinflammatory cytokine, interleukin (IL)-6, seems play role developing anaemia.6Weiss G. Goodnough L.T. Anemia inflammation.Blood. 2019; 133: 40-50Crossref (442) IL-6 upregulates turn absorption retention (‘hepcidin block’) leading state iron-restricted erythropoiesis. also considered part evolutionary (‘nutritional immunity’) limit free (or non-transferrin-bound iron) invading pathogens, particularly iron-dependent extracellular bacteria Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia) that could otherwise overwhelming infection.7Drakesmith Prentice A.M. iron-infection axis.Science. 2012; 338: 768-772Crossref (502) cytokines IL-1, IL-6, IL-10 tumour necrosis (TNF)-α promote into via transferrin receptor-mediated endocytosis. Inflammation production erythropoietin its efficacy IL-1 IL-6.6Weiss Recovery has been shown lower levels, many other processes neurotransmission, defence cardiopulmonary function.7Drakesmith Scholar, 8Litton Lim J. metabolism: emerging therapeutic target critical illness.Crit Care. 23: 81Crossref (28) 9Frost J.N. Tan T.K. Abbas M. et al.Hepcidin-mediated hypoferremia disrupts responses vaccination infection.Med. 2021; 2: 164-179.e12Abstract proteins require function. Examples include components mitochondrial electron transport chain. Enzymes involved DNA metabolism, ribonucleotide reductase, primase helicase bind iron.5Ganz ATPase ABCE1, needed messenger RNA translation, binds iron. plays sensing hypoxia inducible (HIF) pathway. HIFs, especially HIF-2α prolyl hydroxylases, dependent oxygen, studies healthy volunteers demonstrated depletion augments pulmonary hypertensive whilst loading attenuates response.10Frise M.C. Robbins P.A. Iron, circulation.J Appl Physiol (1985). 119: 1421-1431Crossref immunity. Both associated infection.11Swenson E.R. Porcher R. Piagnerelli infection: another pathway explore critically ill patients.Intensive Care Med. 2018; 44: 2260-2262Crossref (8) Recent work hypoferraemia impairs adaptive (T B cells) vaccination.9Frost Assessment necessitates careful history, examination analysis ‘battery’ tests. Current consensus threshold <130 g L−1 define sexes.12Munoz Acheson A.G. Auerbach al.International statement peri-operative deficiency.Anaesthesia. 2017; 72: 233-247Crossref (463) A summary different types expected findings potential treatment strategies displayed Table 1.Table 1Definitions, characteristics stages deficiency. CHr, reticulocyte content; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Hb, haemoglobin; i.v., intravenous; Tsat, saturation.Iron statusDefinitionLaboratory findingsIron therapy strategiesTrue/absolute deficiencyDepletion stores, inadequate erythropoiesisFerritin <30 μg Tsat <20% and/or CHr<30 pg, >130 L−1, low hepcidinOral if poorly toleratedIron-deficiency anaemiaReduced because insufficient vailabilityHb ferritin CHr tolerated rapid correction requiredIron sequestration/iron-restricted erythropoiesisInsufficient mobilisation stores demands, despite adequate storesFerritin >100 <20%, ≥30 bothPossibly CRPVariable hepcidinErythropoietin alone normalIron inflammationReduced supply (functional) availability (absolute) meet requirementsFerritin 30–100 CRP >5 GFR <60 ml min−1Increased hepcidinI.V. Open table tab indicators status found elsewhere but brief, serum currently used indicator deficiency.3McNally However, phase reactant may surgery), so normal values do not exclude Measurement protein recommended aid interpretation concentrations. useful tests saturation (Tsat)—a marker bound (CHr)—a measure available bone marrow. newer erythroferrone, area active research. Preoperative 30–60% varies according type surgery.13Musallam K.M. Tamim H.M. Richards al.Preoperative non-cardiac surgery: retrospective cohort study.Lancet. 2011; 378: 1396-1407Abstract (813) Scholar,14Munoz Laso-Morales M.J. Gomez-Ramirez Cadellas Nunez-Matas Garcia-Erce J.A. Pre-operative levels large multicentre major surgery.Anaesthesia. 826-834Crossref (114) highest reported gynaecological surgery (64%) colorectal cancer resection (58%), women disproportionately affected 68.9%.14Munoz was absolute Among two-thirds 10–15% <10% B12 folate deficiency.14Munoz transfusion, in-hospital complications, delayed hospital discharge recovery.13Musallam More who undergone abdominal death disability up 90 days unplanned ICU admission longer stays.15Boyd-Carson Shah Sugavanam Reid Stanworth S.J. Oliver C.M. association pre-operative morbidity mortality laparotomy.Anaesthesia. 75: 904-912Crossref ability perform normovolaemic haemodilution. cardiac 40% patients. independently stays.16Klein A.A. Collier T.J. Brar M.S. al.The incidence importance UK – first Association Cardiothoracic Anaesthetists national audit.Anaesthesia. 71: 627-635Crossref (118) Nearly deficient relevant, impaired left ventricular function, treating congestive failure improve reduce cardiovascular-related readmissions mortality.17Ponikowski P. Kirwan B.A. Anker S.D. al.Ferric carboxymaltose heart failure: multicentre, double-blind, randomised, controlled trial.Lancet. 396: 1895-1904Abstract (306) Anaemia around time very common.18Partridge Harari D. Gossage Dhesi older patient: prevalence, causes, management.J R Soc 106: 269-277Crossref In contrast planned procedures, there period preoperative optimisation, view guidance advocating expedited fixation fractured neck femur). laparotomy, than half increasing 60–80% period. Even ‘mild’ (Hb 110–126 L−1) mortality, prolonged hospitalisation reoperation.15Boyd-Carson Similar trends observed hip fracture where multifactorial, arising either chronic injury surgery.18Partridge negative impact recovery, length stays readmission rates.18Partridge One study linear between higher inability walk third day.18Partridge usually imbalance demand. Approximately 45% begin pregnancy stores.19Benson C.S. effect women’s health.Anaesthesia. 76: 84-95Crossref (19) maternal 50% low- middle-income countries, largely combination infectious diseases variant disorder. ranges 24% 46% booking 28-week check UK. Maternal adverse peripartum perinatal preterm labour, small-for-gestational age babies, birth weight, fetal neonatal obstetric haemorrhage.19Benson Data beginning emerge neurocognitive children born utero (defined cord <75 ng ml−1) memory, altered interactions caregivers neurological reflexes infants.19Benson Children aged <5 yrs susceptible long-term effects untreated series observational stay need transfusion children, neonates, surgery.20Charuvila Davidson S.E. Thachil Lakhoo K. Surgical decision making paediatric low-income countries.Lancet Child Adolesc Health. 3: 814-821Abstract (2) remains unclear what best way identifying Comprehensive identification recently published Centre (CPOC).3McNally Treatment dedicated clinics improvements requirements. correlated greater increase until months Hb.21Guinn N. Fuller Murray al.Treatment clinic reduction orthopedic gynecologic surgery.Transfusion. 2022; 62: 809-816Crossref Oral form sulphate fumarate, cheap successful absorbed duodenum jejunum bioavailability. often gastrointestinal side-effects, principally constipation. Correcting whole store requires course enteral taken over several months. mechanistic kinetics once day alternate dosing better compared traditional doses. single dose rise remain 48 h. Any doses ineffective ‘hepcidin block’ exposing effects. As result, ∼40–60 daily 80–100 now guidelines: equates sulphate/ferrous fumarate 200 400 days.12Munoz Sucrosomial promising iron-containing carrier. Ferric pyrophosphate protected phospholipid bilayer membrane (sucrosome) creating complex transported mucosa.22Hawkins Agarwal Evans C.R. guideline: anaesthesia.Br Anaesth. 130: 115-119Abstract protects acidic environment stomach hepcidin–ferroportin pathways. Early studies, mostly show larger required.22Hawkins For procedures appropriate window prescribe Enteral likely absence pathologies causing ongoing malignancy, menorrhagia) Certain patients, those cancer, combined loss, direct chemotherapy), erythropoiesis, nutrition concomitant rendering ineffective. Prescribing early unlikely replenish treat I.V. bypass caused intracellular stores. After treatment, increases quickly evident 3 days, 75% weeks maximal 4 true anaemia; report accompanying well-being.12Munoz Scholar,23Neef V. Baumgarten Noone timing intravenous supplementation scheduled surgery.Blood Transfus. 20: 188-197PubMed formulations, (FCM) derisomaltose (FDM; previously isomaltoside), enable delivery reticuloendothelial system manner, thus limiting toxic iron.19Benson concentration, performance quality life, requirements conditions bowel kidney failure). recommend undergo within 4–6 weeks, cannot tolerate both.12Munoz shorter frame preclude treatment. Clinical placebo, reducing inconsistent (Table 2).24Khalafallah Yan Al-Badri al.Intravenous versus standard care prospective, open-label, randomised trial.Lancet Haematol. e415-e425Abstract 25Kim Y.W. Bae J.M. Park Y.K. al.Effect hemoglobin among isovolemic anemia following gastrectomy: FAIRY randomized trial.JAMA. 317: 2097-2104Crossref (51) 26Richards Baikady R.R. open PREVENTT RCT.Health Technol Assess. 25: 1-58Crossref 27Talboom Borstlap W.A.A. Roodbeen S.X. infusion (FIT): 10: e250-e260Abstract 28Lasocki S, Capdevila X, Vielle al. Efficacy injection plus topical administration tranexamic acid (the HiFIT Trial): 2x2 factorial, randomized, double-blind trial. Available from: https://ssrn.com/abstract=4277521 https://doi.org/10.2139/ssrn.4277521 [accessed 10 May 2023].Google 29Spahn D.R. Schoenrath F. Spahn G.H. ultra-short-