TRIMming Transfusions

The Gist:  Transfusions aren't benign and Transfusion Related Immunomodulation (TRIM) may play a role in complications associated with transfusions.  Data suggest that allogenic blood transfusions (ABTs) may have immunosuppressive properties [1-6]. Yet, TRIM is a vague controversial entity without easily identifiable clinical markers or pathogenesis and is predominantly based on observational and animal data [3,8].   Keep this entity in mind, not withholding blood products when indicated, but when contemplating the risks and benefits for those patients with borderline indications.  Give the patient all the blood they need, but not one drop more.

Free Open Access Medical education (FOAM) sources have increasingly mentioned this entity, TRIM, over the past few years, including this recent Maryland Critical Care Project podcast.  On a recent FOAMcast, we reviewed the core content associated with adverse effects of transfusions; yet, we did not encounter TRIM overtly in the review of Rosen's and Tintinalli.  Thus, I needed to find out more about this entity I had only learned about through podcasts.

TRIM has not made its way into many classrooms, likely secondary to the lack of understanding of the clinical significance and etiology of TRIM.  The development of pneumonia in the weeks following a transfusion is more difficult to attribute to a single etiology than a hemolytic reaction occurring during the transfusion.  Furthermore, much of the data are observational are observational and animal based with uncertain clinical implications.  As we see transfusion triggers decrease with equivalent or superior outcomes, it may be helpful to keep an eye on TRIM and, when we are tempted to transfuse individuals who are just above the transfusion threshold or give 2 units of red cells empirically, recall that blood product transfusions are actually transplants.  Perhaps we should have the same obsession with transfusions as we do fluid responsiveness summed up eloquently in the words of Dr. Paul Marik, "give that patient all the fluid they need, but not one drop more."

Clinical effects attributed to TRIM

Increased risk of infection

• Contamination of blood products with infectious particles is not common and ranges from 1 in 1-3 million for HIV and hepatitis C, to 1 in 2000 for bacteria in platelets [11].  Studies, including the recent JAMA meta-analysis by Rhode et al, demonstrate more infections in individuals with higher transfusion targets.  Thus, some postulate that the increase in infections is a result of the immunomodulatory effects of transfusions. 

Tumor growth/Cancer - The roots of this notion, particularly an association with lymphoma, lie in retrospective and observational studies [6]

• Randomized controlled trials (RCTs) looking at leukoreduced blood products did not demonstrate an increase in cancer  [1,2,6]

Multi-organ failure - this is one of the effects we care about most clinically and studies of various quality demonstrate an association between multi-organ failure/short-term mortality and transfusion [1].

• Studies confounded by the underlying severity of illness of the patients, which itself predisposes the patients to multiorgan failure. 
• The most consistent effects of TRIM are in RCTs involving cardiac surgery patients [1]

Improved survival in renal transplants - In the 1970's, patients awaiting renal transplants were given one or more ABT, leading to increased graft survival [1].

• Immunosuppressive pharmaceuticals such as cyclosporine have replaced this practice.

Decreased spontaneous abortions [2]

Pathophysiology of TRIM -   These are postulated theories and associations since the exact etiology isn't clear.  Texts tend to agree that TRIM is the result of a complex inflammatory and immunosuppressive happenings that may result from downregulation of cellular immunity, induction of humoral immunity, and altered inflammatory responses. TRIM may depend on:

Degree of contamination of transfused blood with leukocytes - this is one of the reasons the FDA recommends leukoreduction of all blood [12].  Transfusions with leukoreduced blood have demonstrated varying results.

• The beneficial effects of TRIM have been attributed to donor dendritic cells (or Allogeneic Mononuclear Cells - AMCs), which may invoke a tolerance among recipient cells and downregulate T cells.
• Leukocytes release reactive oxygen species and proteolytic chemicals that may cause an inflammatory cascade and tissue injury [1].
• Not the the sole culprit as trials in which one group received leukoreduced blood do not consistently demonstrate a difference [2].

Soluble components or "mediators" - This includes things like histamine, cytokines, and proteins in the plasma or released from the white cell membranes and granules are released upon degradation.  Also, there's some thought that plasma contains soluble class I HLA molecules, which may be partially responsible.

• These "soluble mediators" may inhibit proper T cell function and ability of neutrophils to work properly [1].  
• Higher levels of cytokines such as IL-10 have been demonstrated in patients receiving more blood in the peri-operative period.  It's theorized that these cytokines, whether they're generated by the recipient in response to a stimulus or from the donor, play an immunosuppressive effect [7].
• However, filtration of these products before storage has not demonstrate a difference in "TRIM effects" (OR 1.06 (0.91-1.24)p>0.05), indicating that these are not the sole mediator of TRIM [2]. 

Storage time - This is not an exact etiology but may amplify the effects of the above proposed mediators.  This is purported secondary to the release of soluble mediators during storage of blood products.  Some studies have found increased infection, morbidity, or mortality with older red blood cells (RBCs) but the totality of the literature is inconclusive. Most of the studies have small numbers, have differing definitions of "old" RBCs, and are retrospective or observational in nature; however, results from the RCTs ABLE and RECESS may clarify [13].

• Leukocytes degrade during the first two weeks of storage and release chemicals called soluble mediators.  RCTs that filtered leukoreduced and non-leukoreduced blood still demonstrated an increased incidence of infection in the non-leukoreduced blood (OR 2.25 (1.12-4.25) p<0.05) [2]
• Free Iron - blood undergoes a degree of hemolysis during prolonged storage, freeing iron which is biologically reactive.   

So, we're not sure precisely what TRIM is, whether TRIM is clinically significant, or what may cause TRIM.  The bottom line is that transfusions likely have effects beyond what we currently understand, so it is prudent to treat this type of transplant with respect.

References:
1. Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev. 2007;21(6):327–48. 
2. Blajchman MA, Vamvakas EC.  (2009).  Transfusion-related immunomodulation In Pamphilon DH (ed). Practical Transfusion Medicine (pp. 98-106).  Blackwell Publishing
3. Zimring JC, Nester T.  (2013). Transfusion Related Immunomodulation In Shaz BH (ed.) Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects, Elsevier Science, Chapter 69.
4.  Chen W, Lee S, Colby J, et al.The impact of pre-transplant red blood cell transfusions in renal allograft rejection. Rockville, MD, USA: Agency for Healthcare Research and Quality. Technology Assessment Report; Project ID RENT0610; 2012.
5. Scornik JC, Bromberg JS, Norman DJ et al. An update on the impact of pre-transplant transfusions and allosensitization on time to renal transplant and on allograft survivalBMC Nephrology 2013, 14:217 
6. Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood transfusion. Anesthesiology. 2011;115(3):635–49. 
7. Theodoraki K, Markatou M, Rizos D, et al. The impact of two different transfusion strategies on patient immune response during major abdominal surgery: a preliminary report. J Immunol Res. 2014;2014:945829. 
8.  Geiger T. Transfusion-associated immune modulation: a reason to TRIM platelet transfusions? Transfusion. 2008 Sep;48(9):1772-3.  doi: 10.1111/j.1537-2995.2008.01860.x.
9. Rohde JM, Dimcheff DE, Blumberg N et al. Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014 Apr 2;311(13):1317-26. 
10. Sparrow RL. Red blood cell storage and transfusion-related immunomodulation. Blood Transfus. 2010;8 Suppl 3:s26–30.
11.Hillyer CD, Josephson CD, Blajchman CJ et al.  Bacterial Contamination of Blood Components: Risks, Strategies, and Regulation.  ASH Education Book January 1, 2003 vol. 2003 no. 1 575-589
12. Food and Drug Administration.   Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion. U.S. Department of Health and Human Services, Center for Biologics Evaluation and Research.  September 2012
13.Aubron et al. Age of red blood cells and transfusion in critically ill patients.  Annals of Intensive Care 2013, 3:2

Special (Medical) Transfusion Situations

The Gist:  There are myths and uncertainty surrounding transfusion of packed red blood cells (PRBCs) in certain circumstances.  It appears that old blood isn't necessarily bad blood. Also, lactated ringer may be ok with transfusion. We've moved to restrictive transfusion strategies (hb <7.0) in many of the critically ill medical patients.  This philosophy is now creeping into other realms such as upper GI bleed and ACS, where dogma has traditionally demanded a higher trigger for transfusion. 

Lactated Ringer (LR) running during transfusion?  Probably fine.  On an exam, PRBCs shouldn't run with anything but normal saline and a few select medications.  Most hospitals and blood banks also state that LR and PRBCs are not compatibile.  Studies are popping up, however, that indicate that the idea of clot formation (from the amount of calcium in LR compared with the citrate in PRBCs) with this infusion may not be a major risk.  Check out this editorial that evaluates these recommendations.

• Albert et al 
• Simulation of intraoperative blood transfusion using units of PRBCs and either NS or LR, as well as filters to analyze clots. LR did not lead to visible or molecular evidence of activation of the clotting cascade
• Cull et al

• PRBCs diluted with LR or normal saline (NS) in ratios between 5:1 to 1:20 (PRBC to crystalloid) and examined for clot formation at intervals up to two hours at body temperature. Although clotting occurred at dilutions of 1:1 (PRBC to LR) and greater, no clot formation occurred in the clinically relevant dilutions between 5:1 and 2:1
• No difference in flow rates between PRBC diluted with LR or NS
• Lorenzo et al
• PRBC or whole blood (WB) (n=51) mixed with NS, lactate solution and LR solutions
• No significant differences in infusion time or filter weight using WB or PRBC with NS or LR  
• No significant difference in clot formation between NS and LR with WB or PRBC

Is old blood bad blood? Tintinalli says old blood is associated with poorer outcomes, using a study by Zallen et al (Ch 26). This is based on the following premises:

• Microcirculatory changes - laboratory studies have shown that older RBCs may be more fragile and less pliable, resulting in vasoocclusion (ref).
• Fitzgerald et al, Dietrich et al, and Tsai et al proposed that RBCs a few weeks old may not have the same oxygen carrying capacity.
• It's proposed that this is secondary to decreased 2,3 DPG, which helps facilitate the unloading of O2 into tissues. 

 

(Wikimedia commons)

• A study by Walsh et al demonstrated no difference in measurements of oxygen carrying capacity.
• A blinded trial in septic patients by Lebiedz et al (2012) found that PRBCs >1 week old were associated with a poorer outcome. 

However, this data is sketchy, as described in this counterpoint (Flegel 2012). Lelubre et al did a review and basically couldn't find a solid difference between old blood and fresh blood. Newer studies have not found measurable patient centered harms associated with older PRBCs.

• RECESS 
• Prospective, multicenter trial of n=1098 adult patients undergoing cardiac surgery randomized to "fresh" PRBCS (<8 days) or "old" PRBCs (>21 days)
• No difference in the primary outcome of change in the Multi-Organ Dysfunction Score (MODS) or in other endpoints such as 7 or 28 day mortality.
• ABLE
• Multicenter trial of n=2430 adult intensive care unit patients randomized to receive fresh PRBCs (<8 days) or standard PRBCs (oldest compatible units)
• Powered to detect a 5% 90 day mortality reduction but found no difference with a 90 day mortality of 37.0% in the fresh PRBC group compared with 35.3% in the standard-blood group.
• Exclusion criteria made most screened ineligible, predominantly because of receiving PRBCs previously in the hospital stay.  Further, most of these patients were transfused by a restrictive strategy. 

Liberal Transfusion in Upper GI Bleed? Villanueva et al demonstrated a mortality benefit in a restrictive transfusion strategy in UGIB (<7g/dL) in carefully selected patients receiving early endoscopy (may not be applicable everywhere). 

• Excellent review by BroomeDocs 
• Now@NEJM has a great review
• EMdose has a short summary

How About Cardiac Disease? Traditional teaching recommends a higher hemoglobin as a "transfusion trigger" than in other patient populations, which is plausible given ischemia and potential pump problems. Recently, some literature has come out that these patients probably don't need automatic transfusions with a hb of 9-10 g/dL, but there is insufficient data to recommend a good trigger point.

Yang et al (2005)

• n = 85,111 with NSTE ACS, observational study, mean transfusion nadir HCT 26%(8.6 g/dL).  
• LOS- higher in transfused group 7 days (5.0-11.0) vs. 4 days (2.0-5.0). 
• Absolute rate of death higher in transfused group (11.5% vs. 3.8%)
• Death or MI combined higher in transfused group (13.4% vs. 5.8%)
• Adjustment for patient and hospital characteristics - transfused patients remained 67% more likely to die and 44% more likely to experience either death or MI than those who did not undergo transfusion.
• Limitations:  observational study, statistical adjustments, records review (data dredge).

Meta-analysis by Chatterjee et all (2012)

• Included 10 studies, n=203,665
• Mortality in transfused vs non-transfused 18.2% vs 10.2% (weighted absolute risk increase of 12% or a number needed to harm of 8)
• No mortality difference in studies that included patients with STEMI (RR, 2.89; 95% CI, 0.54-15.58; P = .22) 
• No mortality difference in patients with a baseline hematocrit of less than 30% (RR, 1.72; 95% CI, 0.39-7.63;P = .47). Note: few studies satisfied this.
• Blood transfusion was also significantly associated with a higher risk for subsequent myocardial infarction (RR, 2.04; 95% CI, 1.06-3.93; P = .03
• Limitations: almost all were observational studies, only 1 was an RCT. Few reported baseline hemoglobin levels and those that did varied widely (8-11 g/dL).

Sickle Cell? These patients live with low hb so a 7 g/dL transfusion trigger may not really apply to this population. Patients with sickle cell typically receive many transfusions throughout their life. This increases their risks of adverse effects from transfusions (and can make it more difficult to find usable blood).  These are the recommendations from the NIH and this literature review. There are controversial indications (complicated pregnancy, limb ulcers, refractory priapism), but these are generally outside the realm of EM.

Transfuse:

• The bad stuff we see in the ED:
• Acute Stroke/TIA
• Acute Chest Syndrome/Cardiopulmonary compromise
• Acute Splenic Sequestration
• Severe infection with symptomatic anemia
• Aplastic crisis
• Acute multiorgan system failure - often liver/lungs/kidneys
• Before surgery requiring general anesthesia 

Don't need to transfuse: 

• Clinically stable patients with high reticulocyte count 
• Typical pain crises (there's some data, scant as it is, that transfusions could exacerbate a pain crisis)

Brain Injury  A recent review in Current Opinion in Critical Care  suggests that the restrictive transfusion strategy does not benefit patients with acute brain injury (perhaps may be harmful) but states that there is insufficient data to recommend a specific transfusion strategy in these situations.  LeRoux makes the following statements in the article

• SAH - theoretical benefit and a study shows improved oxygenation but some studies show increased vasospasm.
• TBI - Limited data suggest transfusion only with symptomatic anemia.
• Acute ischemic stroke - no sign that  PRBCs help

Updated 4/14/15

What's Your Trigger?

The Gist: "Permissive _____" is becoming increasing popular in medicine-blood glucose, blood pressure, and oxygen saturation. Hemoglobin is similar, but common refrains may be heard "well, he looks puny, let's give him a couple of units." Currently, the best evidence suggests that transfusion of packed red blood cells (PRBCs) should be considered in most critically ill medical patients, in the absence of massive hemorrhage, at a hemoglobin (hb) <7 g/dL. The data show that liberal transfusions don't benefit the patient and may harm them. However, there are limitations to the data and it and should be interpreted within the context of the individual patient. Treat the patient, not the lab value! Prevent iatrogenic anemia, resulting in more transfusions.  Excellent review article from Annals of Intensive Care

The case(s): In the ED, transfusion of PRBCs is often clear-cut. Massive hemorrhage with high TASH score? Activate the protocol. Patient with melena, as white as the sheets, with a hemoglobin of 4.0 g/dL? Hang the blood. What about the 60 year old patient with suspected sepsis, resting comfortably without complaints, who has a hemoglobin of 7.8 g/dL (baseline ~8-8.5 g/dL)? What if we know he is undergoing fluid resuscitation due to the sepsis, borderline hypotension, and tachycardia, which will likely cause a dilutional drop in hemoglobin?
I recently encountered similar cases and found the art of medicine plays a large role when patients. Tintinalli recommends transfusion at 7.0-9.0 g/dL, but our patient, like many, falls within that grey area so any course of action is justified (Ch 146). Can the literature help sort this out?

What did the FOAM say?

• The NNT review (2010)- 100% saw no benefit, 1 in 18 harmed by pulmonary edema by liberal transfusion.
• Yasser Sakr's talk offers some skepticism to this practice (note: second author on the SOAP study paper).  

How About the Society Guidelines?
Society of Critical Care Medicine.  Suviving Sepsis 2012 Guidelines

• RBCs when the hemoglobin concentration decreases to < 7.0 g/dL (target a hb 7.0-9.0 g/dL)

AABB (American Association of Blood Banks) Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB (full text)

• Consider transfusion at hb of 7 g/dL or less. 
• Postoperative surgical patients, consider RBCs at hb of 8 g/dL or less or for symptoms (chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or CHF)

American College of Critical Care Medicine Clinical practice guideline - Pulm CCM review

• Transfuse RBCs as single units in the absence of hemorrhage (Level 2 evidence)
• Cognitive changes seem to occur at <5 g/dL so some asymptomatic, hemodynamically stable patients may not need transfusion with hb 5-7 g/dL. 

What do we mean by symptoms?  

• Cognitive changes, syncope, dyspnea, chest pain, etc

Transfusion Problems.. FOAM resources, FOAMcast, LITFL review and Gould et al)

• Febrile nonhemolytic reactions (most common)
• Hemolytic transfusion reaction (type 2 hypersensitivity)
• Transmission of pathogens (Viral, Bacterial)
• TRALI (transfusion-associated lung injury), Pulmonary Edema, ARDS
• Transfusion Associated Circulatory Overload (new respiratory distress and hydrostatic pulmonary edema within 6 hours after RBCs) - associated with renal failure and number of units (ref)
• TRIM (Transfusion Related Immunomodulation)
• Biochemical - may lead to vasoconstriction, GFR changes, hyperkalemia (older cells)
• Hypothermia, coagulopathy (dilutional), thrombocytopenia with massive transfusion.
• Human error
• Expensive -Cost to transfuse 1 unit PRBCs to patient $1600-2400 (ref)
 

Prevention:

•  Avoid Iatrogenic Anemia.  Spahn et al address this artfully.

Literature base for society recommendations: 

• Based on a single RCT (TRICC), and a few observational studies
• These all look at a hemoglobin level as a transfusion trigger, not symptoms.
• Observational studies have large potential for bias due to variation in a physician's decision to transfuse as well as individual patient factors (despite statistical models to account for this).

Cochrane review 2012

• 19 trials (Diverse: 8 surgical, 5 in setting of acute hemorrhage, 1 oncologic, 3 critical care, 1 pediatric), n=6264 patients
• 30 day mortality - no significant difference (RR 0.85, 95% CI 0.70-1.03)
• In hospital mortality - lower in restrictive group (RR 0.77, 95% CI 0.62-0.95) 
• Risk of receiving RBCs - average absolute risk reduction of 34% (95% CI 24%-45%). The volume of RBCs transfused was reduced on average by 1.19 units (95% CI 0.53-1.85 units).
• Restrictive transfusion strategies did not appear to impact on the rate of cardiac events, myocardial infarction, stroke, and thromboembolism (i.e. appeared as safe from a hemodynamic standpoint).
• Infection - no significant difference (6 trials)
• Limitations - Lots of heterogeneity, TRICC study contributed the majority to the review.

Trial of Transfusion Requirements in Critical Care (TRICC trial) Hebert et al

• Multicenter RCT, n=838, ICU setting.  Restrictive: transfuse <7.0g/dL; Liberal transfuse <10.0 g/dL
• 30 day Mortality - no statistical difference between groups: 18.7% vs 23.3% in the restrictive vs. liberal-strategy group (95% CI –0.84-10.2%)
• Subgroup analysis showed that younger patients (<55 years old) and less sick patients (APACHE II <20) who received transfusion had increased mortality.
• Mortality rates during hospitalization- lower in the restrictive group 22.2% vs. 28.% (P=0.05)
• ICU mortality- lower in restrictive group, but not significant 13.9% vs. 16.2% (P=0.29) 
• 60-day mortality- lower in restrictive group, but not significant 22.7% vs. 26.5% (P=0.23)
• Limitations:  
• Study stopped early due to poor enrollment. Physicians hesitant to enroll patients, possibly due to fear of restrictive transfusion.
• Excluded: chronic anemia, surgical patients, active bleeding.
• Subgroup analyses: underpowered.

Anemia and blood transfusion in critically ill patients (ABC study) Vincent et al (2002)

• Observational study, European ICUs n=3534 patients
• ICU  mortality =18.5% vs 10.1%, (transfused vs not transfused); P<.001
• Overall mortality rates =29.0% vs 14.9%, P<.001 (transfused vs not transfused)
• For similar degrees of organ dysfunction, patients who had a transfusion had a higher 28-day mortality rate 22.7% vs 17.1% (p =.02) in a matched patients in the propensity analysis
• Higher mortality in ICU patients receiving PRBC transfusion (OR of death of 1.37).
• Limitation: observational, although analysis accounted for degree of organ dysfunction, provider discretion played a role in decision to transfuse; thus, the sicker patients likely received more transfusions.

The CRIT study Corwin et al (2004)

• Prospective, multi-center, observational study in US ICUs with n = 4,892
• Upon mulivariate analysis, the number of PRBCs a patient received was independently associated with longer ICU and hospital LOS and an increase in mortality 1.65; 95%CI 1.35–2.03, p <.001). Note: one model showed increased mortality in patients with hb nadir <9.0.
• Patients who received transfusions also had more total complications.
• Most common reason for transfusion - low hemoglobin (mean transfusion hb = 8.6 g/dL) not symptoms
• Excluded: cardiac/burn/neuro/pediatric ICUs, renal failure. Limited by statistical analysis instead of direct comparison.

SOAP study Vincent et al (2008)

• Prospective, multi-center, observational. n=3,147 patients
• Transfused patients had higher ICU LOS (5.9 vs. 2.5 days; P <0.001)
• Transfused patients had higher ICU mortality rate (23.0 vs. 16.3%; P<0.001)
• Lower 30-day hazard of death in the transfused group when adjusted (HR 0.73; 95% CI 0.59–0.90; P <0.004)
• Why the difference from the very similar ABC study?  
• Used more leukodepleted blood than the ABC study. This is now standard practice.
• More knowledge about potential harms of transfusions by this time (ABC, TRICC studies already published) so more likely that sicker patients received the transfusions.

The evidence is basically non-inferior from a morbidity and mortality standpoint for the use of 7.0 g/dL and presence of symptoms as a transfusion trigger in medical patients without acute hemorrhage.

Update 2014:  Holst et al performed a randomized, multicenter, parallel-group study (TRISS) in which patients with sepsis were randomized to transfusion triggers <9 g/dL or <7g/dL.  In another demonstration that transfusion at a hemoglobin <7 g/dL in patients without active ischemia does not incur excess harm, the study found that 90 day mortality was not significantly different between the groups (43% <7 g/dL and 45% <9 g/dL).