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).

Shock Index - A Better Vital Sign in Trauma

The gist:  Don't rely on a trauma patient's normal vital signs to assume they're hemodynamically stable. Rather, use the shock index (HR/SBP) to predict a patient's need for massive transfusion.

The Shock Index (SI) is Heart Rate divided by Systolic Blood Pressure (HR/SBP)

• Heart rate and blood pressure are often poor predictors of a patient's perfusion status.  Patients notoriously crash, even if they never really become hypotensive or tachycardic (especially in the elderly!).  In trauma patients, a better assessment of a patient's vital signs is the SI.

Normal SI = 0.5-0.7

• SI > 0.9 then approach the patient as though they are actively bleeding 
• SI increases more than 0.3 at any point in care (prehospital to ED), then treat this as though the patient is actively exsanguinating 
• Don't rule out bleeding if SI is within normal limits
• Elderly patient multiply their age by the SI (Age x SI)

The Vandromme, et al paper in the Journal of Trauma in 2011 posited that the following holds true...

• SI > 0.9  predicts twice the risk of massive transfusion
• SI > 1.1 predicts four times the risk of massive transfusion
• SI > 1.3 predicts nine times the risk of massive transfusion!

So, in trauma patients who come in with normal appearing vital signs, calculate the SI (and hopefully get a lactate and base deficit) before determining the patient is stable. 

References:
Paladino L, Subramanian RA, Nabors S, Sinert R.  The utility of shock index in differentiating major from minor injury. Eur J Emerg Med. 2011 Apr;18(2):94-8.

Vandromme, Griffin, Kerby, McGwin, Rue, Weinber Identifying Risk for Massive Transfusion in the Relatively Normotensive Patient: Utility of the Prehospital Shock Index. J Trauma. 2011 Feb;70(2):384-8; discussion 388-90.