Knowing Transfusion-Related Acute Lung Injury
Submitted by Marina E. Bitanga BSN, RN, CCRN
Acute hemorrhage is the leading cause of acute life-threatening intravascular volume loss requiring aggressive fluid resuscitation to maintain tissue perfusion until the underlying cause can be corrected (1). Blood loss can occur secondary to gastrointestinal disorders, cirrhosis from alcohol abuse and esophageal varices, post-operative bleeding, post-partum hemorrhage, and trauma patients (1).
Tissue hypoperfusion leads to lactate production and metabolic acidosis (1), depressed myocardial contractility (1), loss of peripheral vasoconstriction (1), release of inflammatory mediators (1), and activation of cellular apoptotic pathways, leading to death (1).
Patients that are hemodynamically unstable, in shock, or in case of patients with massive hemorrhage, blood transfusion must be instituted immediately instead of fluid resuscitation (1). Blood transfusions are complicated by post-transfusion reactions like dyspnea which is considered as major cause of morbidity and death after blood transfusion (1), with transfusion related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO) as the most dangerous (1). TRALI is a life-threatening intervention that develops within six hours of transfusion of one or more units of blood (2). Two mechanisms lead to the development of this syndrome: immune-mediated and no immune-mediated TRALI (2). There is central importance of neutrophils in mediating early immune response and lung vascular injury (2). Central clinical symptoms include dyspnea, tachypnea, tachycardia, cyanosis, pulmonary secretions, hypotension, and fever (2).
TRALI remains a clinical problem and any complication suspected of TRALI should immediately be reported (2).
TRALI defined as new acute lung injury (ALI) which develops within six hours of transfusion of one or more units, not attributable to another ALI risk factors like sepsis, acute cardiogenic edema, and acute respiratory distress syndrome (2). It is currently regarded as the first cause of severe morbidity and mortality related to blood transfusion therapy (2) with the incidence of 1:1200 to 1:5000 transfused products (11). Plasma components and apheresis platelet concentrates conferred the highest risk of TRALI per component (4) prior to the institution of TRALI risk mitigation strategies. Currently, due to transfusion of a much larger number of red cell units compared with plasma and platelet, the largest number of TRALI-related deaths in the United States and other developed countries occur with red blood cell transfusion (4).
Transfusion of red blood cells or another blood product is common in the Intensive Care Unit (ICU) (5). It has been estimated that greater than 40 percent of patients received one or more blood cell transfusions while in the ICU, of which approximately 90 percent are provided in the context of stable anemia (5). The potential risks and benefits of appropriate use of blood products must be carefully weighed for each patient (5).
TRALI was introduced in 1983 to describe a clinical syndrome seen within six hours of a plasma-containing blood products transfusion (6). It is a potentially fatal blood-product transfusion complication that presents as acute hypoxemia and noncardiogenic pulmonary edema (6). The first case of TRALI was reported in the 1950s (6). Although TRALI has been termed a pulmonary hypersensitivity reaction (6), pulmonary infiltrate associated with transfusion reaction (6), and fulminating noncardiogenic pulmonary edema (6), the diagnostic term TRALI was first suggested by Popovsky et al. in 1983 (6).
TRALI is underdiagnosed and underreported as many clinicians are not familiar with the syndrome (18). For severe cases of TRALI, transfusion may not be considered as a possible cause and maybe regarded as acute respiratory distress syndrome (18). The exact mechanism of TRALI is still not fully understood (18). The common denominator known at present is the end of the pathway which presents with increased pulmonary permeability (18) and results in movement of plasma into the alveolar space causing pulmonary edema (18).
This article will explore the meaning of TRALI, causes, risk factors, signs and symptoms, pathophysiology, incidence, prevention, treatment and management, and education.
PATHOPHYSIOLOGY:The two mechanisms which lead to the development of TRALI are:
1. Immune-mediated TRALI – caused by anti-HLA ( human leucocyte antigen ) antibodies class I, II, and/or less frequent antibodies directed against specific antigens of granulocytes – ( human neutrophil antigen ), which can be present in the serum of the recipient or donors, and react with the donor’s or recipient’s leucocytes (2).
The immune-mediated TRALI is estimated at 65-85% of all reported TRALI cases (2). Of antibody with specifity known, those directed against HNA-1a, HNA -2a, HNA- 3a (5b) and HLA-2A are the most frequent documented (2). The presence of antibodies directed against HLA class II has been associated with TRALI (2).
2. Non-immune mediated TRALI – attributed to transfusion of biologically active compounds which are accumulated in stored blood components such as bioactive lipids, proinflammatory cytokines or platelet microparticles with high procoagulant activity (2). No antibodies detected despite the clinical symptoms (2).
Silliman et al. 1955 populated hypothesis of a “two-hit” model which assumes that TRALI depends on the coexistence of a factor that predisposes a recipient’s reaction, as well as on the presence of leucocyte-activating compounds in transfused blood (2).
First hit is mediated by an proinflammatory condition (2), an aggression that activate the pulmonary endothelium and promotes the recruitment and adhesion of neutrophils to the capillary endothelium (2) and causes disarray of lung alveolar-capillary permeability barrier (2).
Second hit is induced by transfusion of blood components (2). Neutrophils are activated and cytotoxic factors causing endothelial damage and capillary injury are released (2). Reactive neutrophils secrete proinflammatory mediators such as cytokines (1L-1, 1L-6, 1L-8, TNF-alpha) (2), release proteolytic enzymes (elastase, azurocidin) (2), and produce active oxygen species (2). The cascade of immune reactions with vascular endothelium damage are initiated by these events (2), with production of pulmonary capillary fluid leakage into the alveolar space causing edema (2).
The damage of the alveolar-capillary membrane where the neutrophil has been postulated as the protagonist cell for all reactions and subsequent trigger is the common pathway in the pathophysiology of TRALI (2). Antibodies present in the transfused blood agglutinate to the first found neutrophils after transfusion, which are trapped in the microvasculature (2). Neutrophils associated by leucocyte antibodies or biologically active lipids, liberate oxygen radicals which damage endothelial cells of the lung capillaries (2), leading to increased vascular permeability (2), and then the passage of fluid and proteins into the alveoli (2).
Recipient- related risk factors include:
• End – stage liver disease (6)
• Coronary artery bypass graft (6)
• Hematological malignancies (6)
• Massive transfusion (6) including platelets or plasma (6) and incidence increases as the number of units transfused increases (6).
• Sepsis (6)
• Heavy alcohol consumption (6) – secondary to reduced levels of the antioxidant glutathione in the lung, reduced phagocytosis of apoptic cells, and the resulting enhanced pulmonary inflammatory response (17).
• Shock (18) – results in tissue injury (17), perhaps predisposing to TRALI through priming of the recipient’s neutrophils (17).
• Elderly female Caucasians 65-79 years old with six months history of post-inflammatory pulmonary fibrosis and tobacco use (6)
• Positive fluid balance (18) – more likely to manifest clinical pulmonary edema when there is acute lung injury (ALI).
• Higher IL-8 (18)
• Peak airway pressures greater than 30 cm H2O (17)
• Critical illnesses (12)
Transfusion-related risk factors:
• Immunoglobin and stem cell preparation (6)
• Blood products including high-plasma volume (platelet concentrates, whole blood, and FFP) (6)
• High loading anti-human neutrophil antigen antibody (6)
• Plasma from female donors (6)
• Age of blood products (6) – storing red blood cells results in number of morphological and biochemical alterations known as RBC storage lesions (17)
• Mortality 5-10% (6)
• 90-day mortality associated with TRALI can reach 47 % in critically ill populations
Signs and Symptoms:
• Hypoxemia – increase for oxygen requirements in intubated patients (4)
• Pulmonary infiltrates on chest radiography – normal cardiac silhouette (4)
• Pink frothy airway secretions from the endotracheal tube for intubated patients (56%) (4)
• Fever (33%) (3,4)
• Hypotension (32%) (3,4)
• Cyanosis (25%) (4)
• Tachycardia (3)
• Tachypnea (4)
• Elevated peak and plateau airway pressures in intubated patients (4)
• Acute, transient drop in the peripheral neutrophil count (consistent with sequestration of large numbers of neutrophils in the lungs) (4)
1. Prompt reporting of suspected cases of TRALI to the blood bank (6). Blood bank should investigate all associated donors for presence of anti-HLA and anti-HNA antibodies to identify donors with these antibodies and prevent them from future donations (6).
2. Adhere to current guidelines for utilizing blood components (6), particularly those for plasma, is mandatory to decrease exposure risk for patients (6).
3. Clinicians should consider many factors when deciding to transfuse anemic patients, rather than basing the decision solely on a specified laboratory level (6).
4. Decision to transfusion should incorporate the patient’s clinical condition, co-morbidities, and the individual wishes of the patient (6).
5. Donors with little chance to be alloimmunized to leucocytes should receive high plasma volume components (e.g., FFP, plasma frozen within 24 hours of phlebotomy (FP-24), plasma, cryo-reduced plasma, apheresis platelets, or whole blood (6).
6. Use pooled solvent detergent-treated plasma as an alternative to FFP (6).
7. Test for anti-HLA antibodies in pregnant donors before apheresis of platelets or plasma (6).
8. Deferral of multiparous female donors to reduce incidence of TRALI (6).
9. Education and enforcement of the appropriate use of blood products (19).
10. Restrictive transfusion strategy (19).
11. Washing cellular components to remove the biologically active mediators including antibodies associated with TRALI (19). This strategy could be deployed for patients prior to major surgical procedures and those with predicted need for ongoing blood transfusion like patients with gastrointestinal bleed, thermal injuries, and septic shock (19).
TREATMENT AND MANAGEMENT:
1. Decrease transfusion from female donors (17).
2. Screen donors for strong human neutrophil antigen (HNA) class II antibodies (17).
3. Support lung functions – oxygen therapy, endotracheal intubation, and mechanical ventilation (2).
4. Conservative administration of fluids in presence of hemodynamic impairment (2).
5. Inotropes in case of response to fluids (2).
6. Avoid corticosteroids – there is no evidence of their use (2).
7. Supportive care including optimization of mechanical ventilator parameters to avoid further injuring the lung while making sure the patient does not become intravascularly fluid overloaded ( Wheeler and Bernard 2007) (19).
8. Discontinue blood products immediately if still being transfused (20) and blood bank should be notified (21).
9. For mechanically vented patients, tidal volume must be restricted to avoid worsening of lung injury (20).
10. Complete blood count should be obtained as transient leukopenia can be seen in TRALI (20).
11. Diuretics should be avoided because pulmonary edema in TRALI is not due to volume overload (20).
12. Echocardiogram and/ or pulmonary catheterization maybe helpful in distinguishing TRALI and TACO (20).
13. Extracorporeal Membrane Oxygenation (ECMO) is increasingly being used as supportive therapy for refractory cardiopulmonary failure (21). TRALI can cause severe, but self-limited, acute hypoxemic respiratory failure, making ECMO an attractive supportive therapy (21). Published literatures support positive results for use of ECMO to treat TRALI (21).
14. Prone positioning – associated with improvements in patient oxygenation and reduction of ventilator-induced lung injury. Multiple studies have shown proning leads to improved oxygenation due to number of mechanisms, including improved recruitment, V/Q mismatch and decreased lung compression by adjacent tissues (22).
15. Daily awakenings from sedation timed with a breathing trial to assess for extubation decreases time on mechanical ventilation and improve outcomes (Girard, et al 2008) (19).
16. Restrictive transfusion strategy should be employed as transfusions in patients with ALI worsen outcome (Gong, et al 2005) (19).
17. Using washed packed red blood cells and male only plasma containing blood products for future transfusions for patients with un resolving TRALI or with other ALI risk factors like ongoing sepsis (19).
18. Implementation of male only donor strategy for FFP. Female donors are associated with the onset of TRALI due to antibody formation during pregnancy (19).
Transfusion Reaction Types (12)
• Acute (12)
- Intravascular hemolytic transfusion reaction
- Febrile nonhemolytic transfusion reaction
- Allergic transfusion reaction
- Transfusion-associated circulatory overload (TACO)
- Transfusion -related acute lung injury (TRALI)
- Transfusion-associated graft-versus-host disease
- Fluid overload
• Delayed (12)
- Extravascular hemolytic transfusion reaction
- Graft-vs-host disease
- Transfusion Infections
Acute allergic reaction (12)
• Allergic reaction/ urticaria
• Asthma exacerbation
• Anxiety attack
• Cold urticaria
• Contrast induced allergic reaction
• Transfusion reaction
• Carcinoid syndrome
TRALI is a respiratory distress syndrome associated with transfusions constitutes a serious risk that maybe underestimated since it is often unrecognized and undertreated (11) thus this syndrome is under reported. TRALI was ranked as the second most frequent cause of transfusion-related complications after hemolysis as reported in the year 2000 (11). Physicians need to be aware of the existence of TRALI and its manifestations, to recognize it promptly and order appropriate life-saving treatment (11).
1. Boucher JT, Davis GL, Schraga ED, et al. Volume resuscitation: background, indications, contraindications. July 7, 2016. Https://emedicine.medscape.com/article/2049105-overview.
2. Alvarez P, Carrasco R, Romero-Dapueto C, et al. Transfusion-related acute lung injury (trali): current concepts. Open Respir Med J. 2015; 9: 92-96. Published online 2015 Jun 26. Doi: 10.2174/1874306401509010092. Https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541453/
3. Transfusion-associated lung injury (trali). Blood center of Wisconsin.
4. Kleinman S, Kor DJ. Transfusion-related acute lung injury (trali). May 11, 2017. UpToDate. https://www.uptodate.com/contents/transfusion-related-acute-lung-injury-trali/print?sourc...
5. May AK, Reilly JP. Use of blood products in the critically ill. Sep 28, 2017. UpToDate. https://www.uptodate.com/contents/use-of-blood-products-in-the-critically-ill/print?sourc...
6. Kim J, Na S. Transfusion-related acute lung injury; clinical perspectives. Korean J. Anesthesiol. 2015 Apr; 68 (2) 101-105. Published online 2015 Mar 30. Doi: 10. 4097/kjae2015.68.2.101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384395/
7. LabCE. Prevention of transfusion-related acute lung injury (trali). https://www.labce.com/spg404308_prevention_of_transfusion_related_acute_lung_injur.a...
8. Latham T. Transfusion related acute lung injury (trali). Effective 12/01/16. Originally prepared by: S. MacLennan for the Transfusion Medicine Clinical Policies Group.
9. Pham HP. Transfusion related acute lung injury (trali). PathologyOutlines.com. website.http.www.pathologyoutlines.com/topic/transfusionmedtrali/htlm. Accessed November 4th, 2017.
10. Subramaniyan R. Trali in a patient with hematological malignancy: complexities in the critically ill. October 4, 2016. Department of Transfusion Medicine, Yashoda Hospital Malakpet, Hyderabad, India. https://www.omicsonline.org/.../trali-in-a-patient-with-hematological malignancy-com.
11. Mariani SM. Conference report- transfusions and trali: what are the risks today? https://www.medscape.com/viewarticle/460253-2.
12. Modified last by Donaldson R. Transfusion-related acute lung injury, 9 September 2016. https:www.wikem.org/w/index.php?title=Transfusion-related_acute_lung_injury&oldid=99585.
13. Bogovic TZ, Mesaric J, Hrabac P et al. Possible transfusion-related acute lung injury (trali) in cardiac surgery patients Croat Med J. 2014 Apr, 55(2): 138 – 145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009714/.
14. Kumar R, Sedky MJ, Varghese SJ et al. Transfusion related acute lung injury (trali): a single institution experience of 15 years. Indian J Hematol Blood Transfus 2016 Sep; 32(3): 320-327. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930763/.
15. Transfusion-related acute lung injury (trali). Australian Red Cross Blood Service
16. Toy P, Gajic O, Bacchetti P et al. Transfusion- related acute lung injury: incidence and risk factors. Blood 2012 Feb 16. 119(7): 1757 – 1767. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286351/.
17. Singh VA, Zeltsman D. Trali syndrome complicated by retroperitoneal bleeding. Int J Angiol. 2011 Sep; 20(3): 173176. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331656/
18. Benson AB, Moss M, Silliman C. Transfusion-related acute lung injury (trali): a clinical review with emphasis on the critically ill. Br J Haematol 2009 Nov; 147(4): 431-443. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532338/.
19. Petrou E, Karali V, Vartela V. Journal of acute disease. Volume 4, Issue 3, August 2015, Pages 250-251
20. Jaipaul CK. Transfusion-related acute lung injury. Clinical Advisor. Powered by Decision Support in Medicine. https://www.clinicaladvisor.com/hospital-medicine/transfusion-related -acute-lung-injury/art...
21. Mitchell OJL, Oskuel A, Zakhary B. Transfusion related acute lung injury successfully managed with extracorporeal membrane oxygenation. American Journal of Respiratory and Critical Care Medicine 2017; 195: A 5946. Atsjournals.org/doi/abs/10.1164/ajrccm_conference.2017.195.1_MeetingAbstracts.A5946.
22. Hussain R, Saraiya A, Giacotto J et al. Early prone positioning to tract transfusion-related acute lung injury (trali). American Journal of Respiratory and Critical Care Medicine 2014; 189: A6190. www.atsjournals.org.AmJRespirCritCare Med 189,2014:A6190.
23. Vlaar A, Muller MC, Van Stein D et al. Male only fresh frozen plasma donation policy and the impact on the onset of transfusion related acute lung injury, a meta- analysis. American Journal of Respiratory and Critical Care Medicine 2014; 189: A5003