1. Transfusion-Related Acute Lung Injury
Melanie F. Clemens, CRNA, MSN
Brooklyn VA Medical Center

2. Objectives Discuss the incidence of TRALI
Review the proposed pathophysiology of TRALI
Discuss the proposed risk factors associated with TRALI
Review the clinical presentation & diagnosis of TRALI
Review the treatment of TRALI
Discuss the clinical impact of TRALI

3. Disclosures

4. Clinical Relevance Bacterial Contamination Related Sepsis TRALI
Hepatitis C
1 in 5,000 units*
1 in 1,935,000 transfusions
1 in 625 patients*
Hepatitis B
Bacterial Contamination Related Sepsis
1 in 205,000 transfusions
HIV
1 in 25,000 platelets
1 in 250,000 PRBCs
1 in 2,135,000 transfusions
The incidence of TRALI is equal in males and females and has been identified in pts of all ages. It is estimated to occur in 1 in 5000 transfused units and 1 in 625 pts. It frequently goes unrecognized or misdiagnosed and thus is underreported.
In the past transfusion related infective processes accounted for the majority m&m. Due to the increased testing of donor pool, extensive donor interviewing, and having an entirely volunteer donor pool these have decreased significantly.

5. Clinical Relevance
This is a table from the FDA of reported transfusion associated deaths from TRALI accounted for 47% of all transfusion related deaths-making it the number one etiology. Of those who develop TRALI, 5%-20% die.
Other causes of transfusion related mortality are listed here. Hemolytic reactions are rare, but carry a high death rate when the do occur.

6. Presentation Within 6 hours of transfusion Symptoms Dyspnea Fever
Cyanosis
Chills
Hypoxemia
Cough
Pulmonary edema
Tachycardia
Hypotension
Frothy sputum
Decreased lung compliance
Absence of other clinical indicators of fluid overload
Can be difficult to recognize in the anesthetized pt.

7. Pathophysiology Antibody Hypothesis Biologic Response Modifiers
Human leukocyte antigen (HLA)
Class I & class II
Human neutrophil antigen (HNA)
Biologic Response Modifiers
Not antibody mediated
Two-Hit Hypothesis
2 events
Opportunistic
There are several hypotheses regarding the pathogenesis of TRALI. The exact mechanism is unknown, but probably incorporates factors from several theories.
The association of antibodies directed against white blood cells and TRALI was first recognized in the 1970s. HLA antigens are immune system proteins involved in immune system self recognition. HNA antigens are present on neutrophils and other select cells. Antibodies to these antigens form after exposure to foreign antigens. The figure at the right depicts 4 different ways in which antibody-antigen binding can occur and trigger TRALI. Neutrophils are involved in all of the scenarios and may be directly or indirectly triggered.
The biologic response modifiers theory has to do with accumulation of compounds in stored blood products.
The two-hit hypothesis incorporates ideas from the antibody theory, but accounts for instances where antibody positive products have been transfused to pts without resulting in TRALI.
Sachs 2011

8. Pathophysiology Antibody mediated lung injury 70% of TRALI cases
85%-90% component based
5%-10% recipient based
HLA & HNA antibody formation
Pregnancy
Transplantation
Transfusion
Antibodies target WBCs
Pulmonary microvascular infiltration & damage
Antibodies are identified in about 70% of cases of TRALI. In 85% to 90% of cases in which an antibody is identified, the antibody is present in the transfused blood component. In about 10% of cases, the antibody is present in the transfusion recipient.
In rare cases, an antibody present in one blood component corresponds to an antigen present in another blood component received by the patient-called interdonor TRALI.
Human leukocyte antigen and HNA antibodies can form after exposure to foreign antigens. The 3 potential means of exposure are transfusion, transplantation, and pregnancy. Since blood donors represent a very healthy population, the majority of blood donors with HLA antibodies are multiparous females.
The exact mechanism of lung injury in TRALI is not understood. Two mechanisms of antibody-mediated lung injury have been hypothesized. HLA & HNA antigens are present on WBCs. The antibodies target the WBCs and trigger a reaction. In the case of HNA and HLA class I antibodies, it is thought that antibody-coated neutrophils localize to the pulmonary microvasculature. The ensuing complement activation of the antibody coated neutrophils damages the endothelium of the pulmonary microvasculature. This damage leads to leakage of protein-rich fluid from the microvasculature into the pulmonary alveolar spaces.
As I stated before, the neutrophils may not be directly targeted, but may be indirectly activated. An alternate hypothesis is that the antibody directly interacts with antigens on the pulmonary endothelial cells or on monocytes, not the neutrophils, but then neutrophils are attracted by release of secondary mediators.
Dennison 2008

9. Pathophysiology Biologic Response Modifiers Independent of antibodies
Accumulate in stored blood
Activate & prime neutrophils
Independent of antibodies
Lower morbidity & mortality
Another theory for the etiology of TRALI is the biologic response modifier hypothesis.
Lysophosphatidylcholines accumulate in stored blood products. When transfused they activate neutrophils which then migrate to pulmonary vasculature and activate compliment systems.
Biologic response modifiers have also been identified in an autologous unit of red blood cells associated with a TRALI reaction The development of TRALI after transfusion of an autologous unit implies that an antibody to HLA or HNA antigens is not involved in the pathogenesis of all cases of TRALI since an autologous donor unit would not contain antibodies to the donor’s own antigens.
Transfusion-related acute lung injury associated with biologic response modifiers tends to be associated with a less severe clinical course than TRALI associated with antibodies.

10. Pathophysiology Two-Hit Theory First event Second event
System activation
Pulmonary endothelium
Primed neutrophils
Second event
Transfusion
Opportunistic
Threshold
Whether TRALI is associated with biologic response modifiers or with antibodies, there is a growing appreciation that 2 separate events may be needed to
initiate a clinical TRALI reaction. In the first event, biologically active compounds generated as a result of a stress event are thought to activate the pulmonary vascular endothelium and prime neutrophils. This can be an illness, trauma, surgery etc. It results in sequestration of neutrophils in the pulmonary microvasculature. The neutrophils are primed and ready for further activation.
The second event is the infusion of either biologic response modifiers or antibodies in a unit of a blood product. The second event triggers the response from the primed neutrophils and results in damage to the pulmonary vascular endothelium and leakage of protein-rich fluid into the pulmonary alveoli.
Look-back studies of patients who did not develop TRALI and received a unit of blood from a donor who was subsequently discovered to have antibodies support a 2-event model of TRALI.
Presence of the antibodies in donated products is relatively common, thus expected rates of TRALI would be higher every pt who received the antibody containing blood developed TRALI.
Maybe the intensity of the first hit dictates the severity of TRALI.
Sachs 2011

11. Risk Factors Product related risk factors
So what products carry the highest risk of TRALI?
Blood components containing 50mL or greater of plasma are the most commonly associated products with the development of TRALI. FFP & platelets are considered plasma rich. The overall incidence of TRALI is quoted 1:5000 products, but the true incidence is unknown. FFP is the most commonly implicated product. Single donor platelets are second. RBCs carry the lowest risk.
Additionally, as we mentioned earlier, the age of the products may impact the development of TRALI. The longer the product is stored, the more breakdown products are present which can lead to activation of the complement system upon transfusion.
Triulzi 2009

12. Risk Factors Recipient related risk factors
As I stated earlier-TRALI rates are equal among males and females and may occur at any age. Here are some of the pt specific risk factors for the development of TRALI.
Obviously the sicker pts are those most likely to receive more transfusions. Liver patients receive more plasma rich products-FFP & platelets.
Trauma pts may receive massive transfusion.
There have been case reports of ASA I pts developing TRALI.
Sachs 2011

13. Diagnosis Unrecognized TRALI vs. TACO
So now that we know what causes it, how do I diagnose that a pt is developing TRALI?
We mentioned the symptoms earlier. A big obstacle that we in the anesthesia field face is that many of our pts are under general anesthesia and many of the symptoms go unrecognized. The intubated and anesthetized pt cannot tell us that they feel dyspneic. There may only be subtle changes in SPO2 and lung compliance. You may notice deterioration of PaO2 and the pt may fail extubation criteria at the end of the case.
Additionally, we need to be able distinguish between TRALI and TACO.

14. Diagnosis Transfusion-Related Cardiac Overload (TACO)
Similar presentation to TRALI
Jugular venous distension
Hypertension
Elevated pulmonary artery occlusion or central venous pressures*
Prompt improvement of symptoms with diuresis
Pulmonary edema/plasma protein concentration ratio <0.65
≥50% increase in post transfusion BNP levels
So what is TACO? It is lung injury and pulmonary edema as a result of an inability of the heart to maintain sufficient cardiac output in the wake of volume administration. Its presentation is similar to that is TRALI and the two can be difficult to distinguish.
Pts who develop TACO frequently have previous diagnosis of cardiac m&m, but the presence of such a diagnosis does not rule in TACO and rule out TRALI. Pts with cardiac m&m can develop TRALI and those without cardiac m&m can develop TACO.
Pts with TACO will have symptoms of fluid overload. Changes in hemodynamic parameters are not necessarily specific as there can be individual pt anomalies and interprovider differences in monitoring technique.
TACO should improve with diuresis whereas the hypotension often associated with TRALI can be complicated with diuretics.
A study by Ware et. al. used tiny catheters to aspirate pulmonary fluids in order to measure protein content. They suggested that a ratio of pulmonary fluid protein content to plasma protein content of <0.65 was suggestive of a hydrostatic phenomenon. In other words, if the protein content of the pulmonary edema is similar to plasma protein content the pt is likely fluid overloaded. The problem with this is that it is not practical to aspirate pulmonary fluids and they must be measured as soon as the pt is intubated. So it’s not a practical distinguishing test.
Another lab test that has been suggested to distinguish TRALI from TACO is brain naturetic peptide levels. An greater than or equal to 50% increase of post transfusion BNP levels is suggestive of fluid overload.

15. Presentation Within 6 hours of transfusion Symptoms Dyspnea Fever
Cyanosis
Chills
Hypoxemia
Cough
Pulmonary edema
Tachycardia
Hypotension
Frothy sputum
Decreased lung compliance
Absence of other clinical indicators of fluid overload
Here are the symptoms again, just to review. Most of them are present in TRALI and TACO. Main distinguishing factors are blood pressure and s/sx of fluid overload.

16. Diagnosis
So does our pt meet criteria for TRALI? Here are consensus criteria. This is what CXR would look like.
Gilliss et al. 2011

17. Diagnosis
Here is a proposed algorithm to help distinguish between TRALI and TACO. Our medical and surgical colleagues are frequently quick to blame us for overloading the pt. It is important to distinguish between these as the treatments are different.
Gajic et al. 2006

18. Diagnosis Here’s a table comparing and contrasting symptoms.
Skeate et al. 2007

19. Treatment Differential diagnosis Stop the suspected product Supportive
Intubation & mechanical ventilation
Fluids
Vasopressors
5%-20% mortality rate
Retain the transfused products
So how do we manage the pt suspected of developing TRALI? First, you must arrive at the correct diagnosis-as the treatment for TRALI is different than TACO.
Stop any currently infusing products.
Treatment of TRALI is largely supportive as few interventions beyond respiratory and hemodynamic support have been shown to definitively speed recovery or improve outcome.
Somewhere around 70% of TRALI cases require intubation and mechanical ventilation. Lung compliance is decreased with TRALI-in fact in the anesthetized pt, stiff lungs are often appreciated following changes in SPO2. Small tidal volumes may limit barotrauma.
Administration of diuretics may be detrimental to pts with TRALI. They are frequently hypotensive and require hemodynamic support. Crystalloids and non-blood based colloids are recommended. Some pts require pressors. Steroids have not been shown to definitively improve healing times and outcome. Most patients recover fully, however TRALI is still the leading cause of transfusion related mortality and the actual mortality rate is somewhere between 5%-20%.
It is important to retain the products and report the reaction to the blood bank. The blood bank should take the products for testing.

20. Clinical Impact Prevention Limit unnecessary transfusions
Donor limitations
Leukocyte reduction
Washing cellular components
Pooled products
Product testing
Using freshest available products
The old adage and ounce of prevention is worth a pound of cure implies that investment is disease prevention will usually give a healthy return for pts.
First and foremost the best way to prevent TRALI is to limit transfusions. This means using evidence based criteria for transfusion and possibly adopting conservative guidelines for transfusion. This doesn’t mean withholding blood from pts who really need it, it means treat each pt individually and look at the clinical indications for transfusion. Is the pt symptomatic or are we transfusing just because theirs h&h is low? Are we transfusing based on EBL or actual lab values? Is the pt bleeding?
Other strategies employed include limiting the donor population to exclude plasma products from females. This is currently employed in Britain and several other European countries and since June 2007 the American Association of Blood Banks has recommended that the US take similar actions. While it has an impact on available supply, it hasn’t seemed to create such as shortage that pts who need products cannot get them.
Additionally, excluding donations from those who have received transplants or transfusions could limit TRALI, however this may have too great an impact of supply.
Leukocyte reduction has been shown to reduce neutrophil priming activity. It also significantly increases the cost of the products.
Washing components is costly and decreases the shelf life of platelets from 5 days to 4 hours and PRBCs from 42 days to 24 hours. It may only be practical for planned transfusions.
Pooling platelets and plasma from multiple donors theoretically dilutes the antibodies, however if a large number of the pooled donors have antibodies, this is moot.
Product testing for antibodies is not available at all blood banks and is time consuming and cost prohibitive.
Using the freshest products available is important to reduce compliment activation. It seems, however that the blood bank is always pushing the oldest products on us so they don’t expire. In a collaborative effort, work with the blood bank to educate them on the risks of transfusion of old products. The freshest products should be used on the sickest pts.

21. Clinical Impact Alternatives to transfusion Crystalloids Colloids
Conservative transfusion thresholds
Risk stratification
Concentrated fibrinogen/Factor VII
Vitamin K
There are no currently approved synthetic hemoglobin alternative for use in the US.
Use crystalloids and colloids to supplement volume loss.
Used evidenced based criteria for transfusion. The 10/30 rule is passé in most cases. Check labs. Is the pt symptomatic? You must carefully weigh the risks and benefits of transfusion for each individual pt.

22. Questions

23. References
Curtis, Brian. McFarland, Janice. (2006). Mechanisms of Transfusion-Related Acute Lung Injury. Critical Care Medicine, 34, S118-S123.
Dennison, Carol. (2008). Transfusion-Related Acute Lung Injury-A Clinical Challenge. Dimensions of Critical Care Nursing, 27, 1-7.
Gajic, Ognjen. Gropper, Michael. Hubmayr, Rolf. (2006). Pulmonary Edema After Transfusion: How to Differential Transfusion-Associated Circulatory Overload from Transfusion-Related Acute Lung Injury. Critical Care Medicine, 34, S109-S113.

24. References
Gillis, Brian. Looney, Mark. Gropper, Michael. (2011). Reducing Noninfectious Risks of Blood Transfusion. Anesthesiology, 115,
Kopko, Patricia. (2010). Transfusion-Related Acute Lung Injury. Journal of Infusion Nursing, 33,
Looney, Mark. Gillis, Brian. Matthay, Michael. (2010). Pathophysiology of Transfusion-Related Acute Lung Injury. Current Opinion in Hematology, 17,
Mair, D. Hirschler, Nora. Eastlund, Ted. (2006). Blood Donor and Component Management Strategies to Prevent Transfusion- Related Acute Lung Injury. Critical Care Medicine, 34, S137- S143.

25. References
Moore, S. (2006). Transfusion-Related Acute Lung Injury: Clinical Presentation, Treatment, and Prognosis. Critical Care Medicine, 34, S114-S117.
Sachs, Ulrich. (2011). Recent Insights into the Mechanic of Transfusion-Related Acute Lung Injury. Current Opinion in Hematology, 18,
Skeate, Robert. Eastlund, Ted. (2007). Distinguishing Between Transfusion-Related Acute Lung Injury and Transfusion- Associated Circulatory Overload. Current Opinion in Hematology, 14,

26. References
Triulzi, Darrell. (2009). Transfusion-Related Acute Lung Injury: Current Concepts for the Clinician. Anesthesia and Analgesia, 108,
Vlaar, Alexander. Binnekade, Jan. Prins, David. Van Stein, Danielle. Hofstra, Jorrit. Schultz, Marcus. Juffermans, Nicole. (2010). Risk Factors and Outcome of Transfusion- Related Acute Lung Injury in the Critically Ill: A Nested Case- Control Study. Critical Care Medicine, 38,
Federal Drug Administration (2010). Fatalities Reported to FDA Following Blood Collection and Transfusion. Annual Summary for Fiscal Year