EM Cases Classics: IV Iron for Anemia in the ED

Our latest collaboration will see the publication of classic episodes of Emergency Medicine Cases published on CanadiEM. Emergency Medicine Cases is an exceptional podcast developed by fellow Canadian emergency physician, Dr. Anton Helman. In the first episode of Emergency Medicine Cases Classics on CanadiEM, Anton discusses the role of IV Iron for Anemia in the ED. Sound crazy? Read below or listen to the episode and you may reconsider. -CanadiEM Editor Brent Thoma

For years we’ve been transfusing red cells in the ED to patients who don’t actually need them. A Canadian study looking at trends in transfusion practice in the ED found that about 1/2 of transfusions given were deemed unnecessary [1]. As we explained in previous EM Cases episodes, there have been a whole slew of articles in the literature over the years that have shown that morbidity and mortality outcomes with lower hemoglobin thresholds, like 70g/L for transfusing ICU patients (TRICC trial [2]), patients in septic shock (TRISS trial [3]), and patients with GI bleeds are similar to outcomes with traditional higher hemoglobin thresholds of 90 or 100g/L [4]. We’re simply transfusing blood way too much! The American Association of Blood Banks, in conjunction with the American Board of Internal Medicine’s Choosing Wisely campaign, called out this practice by selecting: “don’t transfuse iron deficiency without hemodynamic instability” as one of its 5 statements on overuse.

This episode of the Emergency Medicine Cases podcast discusses why it’s important to avoid red cell transfusions in certain situations, why IV iron is sometimes a better option in a significant subset of anemic patients in the ED, and the practicalities of exactly how to administer IV iron and features:

• Transfusion specialist, researcher and transfusion guidelines author Dr. Jeannie Callum,
• Transfusion specialist and researcher Dr. Yulia Lin
• The “walking encyclopedia of EM” Dr. Walter Himmel

The blog post outlines the key points from the podcast using three illustrative cases. For more on this topic download the podcast, download the PDF summary, or add Emergency Medicine Cases to your podcast app and listen to Episode 65.

Case 1: IV Iron for Anemia secondary to Menorrhagia

A 49 year old woman is sent in by her family physician with a note indicating “severe menorrhagia for several months and hemoglobin 57 g/L; please transfuse.” She has no past medical history but complains of decreased exercise tolerance and increasingly heavy periods. She denies dizziness or syncope. Her vitals and physical exam are within normal limits. How would you manage this patient’s anemia?

How can we determine if an anemic patient is iron deficient?

It was determined that this patient had iron-deficiency anemia.

Is severe anemia unsafe?

In a study of healthy subjects where hemoglobin concentration was reduced from 131 g/L to 50 g/L by replacing aliquots of blood (450-900 mL) with 5% human albumin and/or autologous plasma, there was no evidence of inadequate systemic oxygen delivery (as assessed by change of O2 and plasma lactate concentration) [5]. Holter readings suggested that in this resting healthy population, myocardial ischemia would occur infrequently.

Patients with chronic anemia can adjust physiologically to anemia even more readily than patients with acute anemia because of the shift in the oxygen dissociation curve. This is facilitated by a change in the 2,3-DPG level allowing the RBCs to be ‘less selfish’ so they can more easily offload oxygen to the tissues. As such, a hemoglobin of 50g/L can be considered as physiologically higher than it appears in patients with chronic anemia.

Another trial showed that young women can safely tolerate a hemoglobin as low as 50 g/L [6]! The WOMB trial was a multi-centered Dutch trial that enrolled 521 women with severe postpartum anemia (hemoglobin 48 to 79 g/L) who were randomized to transfusion or transfusion only if they developed severe symptoms. 517 units were transfused to the “transfused group” vs. 88 for the group for only severe symptoms. It found no differences in any important outcomes (recovery of hemoglobin, 6 week hemoglobin). There was, however, a non-clinically significant difference in fatigue scores at 7 days that was not persistent at later time point.

While this patient’s hemoglobin is very low, it is likely safe if she is not having ongoing bleeding.

Is transfusion unsafe?

Perhaps the most important and under-recognized risk of red cell transfusions is allo-immunization among women of childbearing age [7]. Allo-imunization, which has a rate of 8% per transfusion in young women, involves the development of antibodies against red blood cells, which in future pregnancies can cross the placenta and precipitate hemolytic disease of thenewborn in women who have received previous transfusion, can render the patient ineligible for an organ transplant if required and can make them unmatchable for future transfusions. Think of a blood transfusion as a blood transplant: When you give someone a blood transfusion, you are changing their immune system for life. Red cell transfusions should not be thought of as a delivery system for iron!

Other risks of packed red blood cell transfusions include a 1/700 risk of TACO (Transfusion Associated Circulatory Overload) a 1/10,000 risk of TRALI (Transfusion Related Lung Injury) and a 1/40,000 risk of an acute hemolytic transfusion reaction [8].

Can we use Iron for anemia in the ED? When?

The American Society of Anesthesiologists recommends against RBC transfusions in young, healthy patients without ongoing blood loss and a hemoglobin >60 g/L, unless they are symptomatic or hemodynamically unstable [9]. Symptoms to screen for include chest pain, SOB, pre-syncope, lightheadedness, hypotension and tachycardia. Fatigue, pallor and reduced exercise tolerance are NOT, in and of themselves, an indication for red cell transfusion. The trigger for transfusion related to “ongoing blood loss” will depend on acuity of blood loss, volume of ongoing bleeding and hemodynamic instability.

IV Iron is indicated when [10]:

1. Oral iron poorly tolerated or failure of oral trial
2. Poor oral absorption (ie. gastric bypass, celiac disease, gastritis)
3. Rate of bleeding is too brisk for oral iron
4. Severe anemia (Hb <90g/L) especially if ongoing bleeding
5. Time-sensitive pressures (OR etc.)

The main contraindications to IV Iron are active systemic infection (eg: suspected sepsis) since iron is a good microbial nutrient, and a known allergic or hypotensive reaction in the past. Risks of administration include hypotension (1-2%) and serious allergic reactions (< 1 in 1,000,000). In patients with chronic kidney disease IV iron may result in more infections and cardiovascular complications than oral iron [11]. More common adverse reactions which generally resolve spontaneously within 24hrs of administration of IV iron include joint aches, muscle cramps, headache, chest discomfort, nausea, vomiting and diarrhea.

IV Iron seems like it would be a reasonable treatment for this patient.

How can we administer IV Iron for anemia in the ED?

The product you choose will depend on the dose you want to give, how quickly you want to deliver it and the side-effect profile (a sample order is available [12]).

Patients with the following risk factors should receive slower infusions (e.g. Feraheme® [ferumoxytol] over 60 minutes or Venofer® [iron sucrose] 300mg over 2 hours)

• Age > 65 yrs
• Baseline systolic BP less than 100
• Severe asthma or eczema
• Severe respiratory or cardiac disease
• Treatment with beta-blockers, ACE inhibitors or 3 or more anti-hypertensive medications
• Nephrology patients

After IV Iron, and with ongoing oral supplementation, a patient’s hemoglobin will start to rise 3-7 days. You can expect a 1-2 point rise in the hemoglobin per day, and after 2-4 weeks the hemoglobin will have risen 20-30g/L. Ferrous sulfate 300mg contains 60mg of elemental iron and 1 tab can be taken each night on an empty stomach at least 2 hours after meals with Vitamin C 500mg. Patients should also avoid taking with calcium or magnesium supplements as these decrease absorption.

Case 2: IV Iron instead of recurrent red cell transfusions for anemia of chronic disease

A 85 year old male from nursing home sent in for his “usual red cell transfusion” which he receives on a monthly basis. He denies chest pain, shortness of breath, palpitations, dizziness, or melena but has a past history of congestive heart failure and chronic renal insufficiency. His hemoglobin is 65 g/L. Would you transfuse this patient with RBCs?

Elderly patients with anemia

Most of the patients in the ED found to be anemic are elderly. These patients generally fall into one of three categories: one third will have a simple nutritional deficiency (iron or B12), another third will have anemia secondary to a chronic disease, and the rest of the patients will have an undifferentiated cause of their anemia that will require further investigation.

For an elderly patient with multiple comorbidities it can be challenging to determine if their anemia is secondary to iron deficiency as well as anemia of chronic disease. To you help differentiate and decide whether a patient would benefit from IV iron and supplementation, our experts have suggested the following approach:

If their anemia is, in part, due to iron deficiency it may benefit from therapy with IV iron.

Case 3: The pre-operative patient

An 82 year old woman with a mechanical fall at home. She was unable to stand up and called EMS, who noted an externally rotated and shortened right leg. She has a past medical history of diabetes, hypothyroidism, hypertension, hypercholesterolemia, and B12 deficiency anemia (non compliant with treatment). She also notes chronic shortness of breath on exertion that has not changed for months but denies chest pain. Her vitals and physical exam are within normal limits and she has no orthostatic changes. While in the ED her hip fracture is confirmed and her hemoglobin is found to be 83 g/L. Orthopedic surgery requests that she be transfused with 2U of packed red blood cells prior to the OR. Do you order a pRBC transfusion for this patient?

Would IV Iron benefit an anemic pre-operative patient?

The FOCUS trial [13] sought to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for a hip fracture. They showed that even among elderly patients with known coronary artery disease or multiple coronary risk factors, there was less mortality post-operatively at 30 and 90 days among patients with a transfusion trigger of 80 g/L compared to those with a higher transfusion trigger. Other observational studies of the use IV iron pre-operatively for patients with anemia have shown a reduced rate of red cell transfusion required [14].

References

1. Ghali WA, Palepu A, Paterson WG. Evaluation of red blood cell transfusion practices with the use of preset criteria. CMAJ. 1994; 150(9): 1449-54. PMID: 8168009
2. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999; 340(6): 409-17. PMID: 9971864
3. Holst LB, Haase N, Wetterslev J, et al. Transfusion requirements in septic shock (TRISS) trial – comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial. Trials. 2013; 14: 150. PMID: 23702006
4. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11-21. PMID: 23281973
5. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998; 279(3): 217-21. PMID: 9438742
6. Prick BW, Steegers EA, Jansen AJ, et al. Well being of obstetric patients on minimal blood transfusions (WOMB trial). BMC Pregnancy Childbirth. 2010; 10: 83. PMID: 21162725
7. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ. 2013; 347: f4822. PMID: 23950195
8. Bloody Easy 3 – Blood Transfusions, Blood Alternatives & Transfusion Reactions: A Guide to Transfusion Medicine. 3rd edition. 2008. Ontario Regional Blood Coordinating Network. PDF
9. American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006; 105(1): 198-208. PMID: 16810012
10. Intravenous Iron Therapy: Indications & Criteria for use. Sunnybrook Hospital, revised November 4, 2013 and posted to Emergency Medicine Cases with permission. PDF
11. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int. 2015; 88(4): 905-14. PMID: 26083656
12. Intravenous Iron Outpatient Order Sheet. Sunnybrook Hospital, revised February 18, 2015 and posted to Emergency Medicine Cases with permission. PDF
13. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011; 365(26): 2453-62. PMID: 22168590
14. Muñoz M, Gómez-Ramírez S, Cuenca J, et al. Very-short-term perioperative intravenous iron administration and postoperative outcome in major orthopedic surgery: a pooled analysis of observational data from 2547 patients. Transfusion. 2014; 54(2): 289-99. PMID: 23581484

This blog post was written by Dr. Michael Kilian and edited by Dr. Anton Helman in May 2015. It was edited for the CanadiEM blog by Dr. Brent Thoma in February, 2016.

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Anton Helman

Anton is an emergency physician at North York General, an Assistant Professor at the University of Toronto, and the Education Innovation Lead at the Schwartz-Reisman Emergency Medicine Institute. He is also the founder and host of Emergency Medicine Cases.

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