736298

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SCVXXX10.1177/1089253217736298Seminars in Cardiothoracic and Vascular AnesthesiaSmith et al

Reviews
Seminars in Cardiothoracic and

Transfusion-Related Acute Lung Injury

Vascular Anesthesia
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Circulatory Overload (TACO) in Liver DOI: 10.1177/1089253217736298

https://doi.org/10.1177/1089253217736298
journals.sagepub.com/home/scv

Transplantation: A Case Report and

Focused Review

Natalie K. Smith, MD1, Sang Kim, MD1, Bryan Hill, MD1,

Andrew Goldberg, MD1, Samuel DeMaria, MD1, and Jeron Zerillo, MD1

Abstract
Liver transplantation (LT) is a complex procedure in a patient with multi-organ system dysfunction and coagulation
defects. The surgical procedure involves dissection, major vessel manipulation, and pathophysiologic effects of graft
storage and reperfusion. As a result, LT frequently involves significant hemorrhage. Subsequent massive transfusion
carries high risk of transfusion-associated complications. Transfusion-related acute lung injury (TRALI) and transfusion-
associated circulatory overload (TACO) are the leading causes of transfusion associated mortality. In this case report
and focused review, we present data that suggest that patients undergoing liver transplantation may be at higher risk for
TRALI and TACO than the general population. Anesthesiologists can play a role in decreasing these risks by increasing
recognition and reporting of TRALI and TACO, using point of care testing with thromboelastography to guide and
decrease transfusion, and considering alternatives to traditional blood products like solvent/detergent plasma.

Keywords
hemorrhage, reperfusion, coagulopathy, critical care, intraoperative assessment, point of care monitoring

Introduction ledipasvir/sofosbuvir (Harvoni), cirrhosis, and hepatocel-

Liver transplantation is a complex procedure involving
patients with multiple liver disease–related comorbidities,
including the pulmonary, renal, cardiovascular, and coagula-
tion systems. The surgical procedure itself involves intricate
dissection, manipulation of major blood vessels, and compli-
cations from graft storage and reperfusion. These challenges
are compounded by underlying coagulopathy often resulting
in significant hemorrhage requiring massive transfusion.
Transfusion-related complications add yet another challenge
for the anesthesiologist in an already complex scenario.
We present the case of a patient who underwent a com-
plex liver transplantation involving hemorrhage and mas-
sive transfusion who developed pulmonary complications
in the perioperative period. This case will frame a discus-
sion of transfusion-related acute lung injury (TRALI) and
transfusion-associated circulatory overload (TACO) in the
setting of liver transplantation.
Case Report
The patient was a 76-year-old man with a history of type 2
diabetes mellitus, hepatitis C virus (HCV) treated with
lular carcinoma (HCC) complicated by portosystemic
encephalopathy (PSE). He had undergone transarterial
chemoembolization (TACE) and trans-jugular intrahepatic
portosystemic shunt (TIPS). At the time of deceased donor
liver transplantation his tumor exception adjusted MELD
(model for end-stage liver disease) score was 36 (natural
MELD 12). Type and screen was antibody positive for
Anti-E, -K, -S, -Fya, -V, -Leb, and –Bg and he was cross-
matched for 20 units of packed red blood cells (pRBC), 20
units of plasma (FFP), and 3 apheresis-derived platelets
(PLT) prior to the start of the procedure.
Induction of general anesthesia and arterial and central
line placement were uneventful. He was transfused 2
pRBC and 1 of platelets prior to incision for a hematocrit
of 19% and 21% functionality of 60 × 103/µL platelets
1
The Icahn School of Medicine at Mount Sinai Hospital, New York, NY,
USA
Corresponding Author:
Natalie K. Smith, The Icahn School of Medicine at Mount Sinai Hospital,
1 Gustave L. Levy Place, Box 1010, New York, NY 10029, USA.
Email: natalie.smith@mountsinai.org
2 Seminars in Cardiothoracic and Vascular Anesthesia 00(0)
based on platelet function analysis (PFA). Dissection hem-
orrhage was treated with 6 pRBCs, 6 FFP, and 2 apheresis-
derived PLT. Thromboelastography (TEG) demonstrated
mild fibrinolysis without significant coagulopathy at the
end of the dissection phase (R, 6.2 minutes; K, 2.8 min-
utes; angle 57.9°; MA, 38.6 mm; LY30, 22.1%). Graft ves-
sel anastomosis during the anhepatic phase was
complicated by worsening diffuse hemorrhage from gas-
trointestinal varices. All previously cross matched units
were transfused and tranexamic acid (TXA) was adminis-
tered. Liver graft reperfusion occurred after 50 minutes of
warm ischemic time. An emergency shipment of partially
cross matched blood was obtained from the New York
Blood Center and transfusion continued. Prior to surgical
closure, a liver laceration continued to hemorrhage despite
hemostatic sutures. Because of persistent hemorrhage the
surgeons packed the abdomen and performed a temporary
abdominal closure with plans for a future re-exploration
and closure. Repeat TEG at the end of the procedure was
normal despite massive transfusion (R, 5.8 minutes, K, 2.2
minutes, alpha angle, 60.8°; MA, 52.5 mm; LY30, 0%). In
total, the patient received 46 pRBC, 50 FFP, 7 apheresis-
derived platelet units, and 15 units of cryoprecipitate.
In the intensive care unit (ICU), hepatic ultrasound
demonstrated normal hepatic vascular flow. However, the
patient continued to hemorrhage with hematocrit nadir of
16%, and thrombocytopenia to 12 × 103/µL. Creatinine
increased overnight from 0.86 to 1.95 mg/dL, consistent
with acute kidney injury (AKI). He received 4 pRBC, 3
FFP, and 4 apheresis platelets before returning to the oper-
ating room on postoperative day 1 (POD1).
In the operating room, baseline arterial blood gas (ABG)
revealed acute lung injury (ALI) with PaO2 of 99 mm Hg on
100% FiO2 (decreased from 363 mm Hg at the end of trans-
plantation). He was transfused 2 pRBC and 2 FFP initially.
PFA demonstrated 0% functionality of 16 × 103/µL platelets
and 44 minutes after the initial transfusion, 2 units of apher-
esis derived platelets were administered. The patient became
acutely hypoxic with severe pulmonary hypertension (pul-
monary artery pressure [PAP] increased from 50/25 to
96/60). Ventilation and oxygenation became challenging
with increasing airway pressure, decreasing oxygen satura-
tion and a PaO2 of 27 mm Hg on ABG. Copious pulmonary
edema fluid filled the endotracheal tube.
Epinephrine and milrinone infusions and inhaled nitric
oxide (iNO) were initiated. Emergent transesophageal
echocardiography (TEE) confirmed right heart strain with
severely decreased right ventricular (RV) function without
evidence of intracardiac clot. PaO2 remained 20 to 50 mm
Hg despite PAP improvement to 50/35. Surgery revealed a
right subhepatic hematoma with bleeding from the right
lobe laceration. Given persistent, profound hypoxemia, the
abdomen was packed and the patient returned to the ICU
prior to presumed impending demise.
Subsequent chest radiograph revealed new, bilateral,
diffuse pulmonary infiltrates (Figure 1A and B).
Continuous veno-venous hemofiltration (CVVH) was ini-
tiated at negative 200 mL/h to assist with pulmonary
edema and possible volume overload in the setting of AKI.
Severe hypoxia resolved approximately 5 hours after the
initial event and oxygen saturation improved to 100% with
PaO2 139 mm Hg on FiO2 100% and iNO 40 ppm (Figure
1C). Inotropic infusions were weaned off by POD 2.
Sedation was weaned on POD 4 and the patient awoke
with intact neurologic function. Abdominal packing was
removed and the abdomen was closed on POD 5.
The hospital course was complicated by C. difficile
colitis, and pneumonia with respiratory failure requiring
tracheostomy. He was transferred out of the ICU on POD
20 and discharged to a subacute rehabilitation facility on
POD 41. He was discharged home 6 months after trans-
plantation without neurologic or cardiac sequelae.
Discussion
Transfusion Risk
Transfusion is associated with several well-known risks.
TRALI and TACO are most frequently associated with
mortality, accounting for 62% of all transfusion related
deaths since 2011.1 The Serious Hazards of Transfusion
(SHOT) hemovigilance project identified a risk of 1 in 21
413 blood components issued for transfusion related major
morbidity in 20122 and a risk of death of 1 in 322 580
components issued. Viral transmission risk ranges from 1
in 1.3 million components issued for hepatitis B to 1 in 28
million components issued for hepatitis C.2 In the United
States, mandatory reporting to the Food and Drug
Administration revealed that the most common cause of
transfusion-related death was TRALI, accounting for 38%
of transfusion-related deaths. TACO represents the second
leading cause of transfusion-related mortality and accounts
for 24% of all deaths followed by non-ABO hemolytic
transfusion reactions (14%), ABO-compatible hemolytic
transfusion reactions (7.5%), microbial infection (10%),
and anaphylaxis (5%).1
Transfusion-Related Acute Lung Injury:
Definition
TRALI is a subtype of acute lung injury (ALI). In 2003,
The National Heart Lung and Blood Institute (NHLBI)
Working Group defined TRALI as new ALI within 6 hours
of transfusion in persons who did not have ALI before
transfusion and lack ALI risk factors.3 Similarly, the
Canadian Consensus Conference defined TRALI as new
ALI occurring within 6 hours of transfusion without preex-
isting etiology or risk factors.4 Clinical criteria for ALI
diagnosis include evidence of hypoxemia with a PaO2/FiO2
Smith et al
Figure 1. Patient chest radiographs. (A) Frontal portable
chest radiograph prior to liver transplantation, normal x-ray,
lung fields are clear, cardiomediastinal silhouette is normal
in size and contour. (B) Frontal portable chest radiograph
immediately after liver transplantation; compared to prior
study there is new opacity over the right lung base. (C)
Frontal portable chest radiograph after surgical re-exploration.
Compared with B there is worsening bilateral interstitial and
alveolar opacities.
3
ratio less than 300 or a SaO2 less than 90% on room air,
new, bilateral infiltrates on a chest radiograph and a lack of
evidence of circulatory overload caused by transfusion or a
cardiac pathology.4 Recognizing the challenge in diagnos-
ing TRALI in patients with comorbid diseases led the
Canadian Conference to define the phenomenon of “possi-
ble TRALI.” This entity is distinguishable from TRALI
when lung injury could result from: aspiration, pneumonia,
lung contusion, near drowning, severe sepsis/ shock,
trauma, burn injury, pancreatitis, cardiopulmonary bypass,
or drug overdose.4
Clinically, TRALI frequently presents within two hours
of transfusion.5 It presents with the rapid development of
tachypnea, cyanosis, dyspnea, fever, and often hypoten-
sion. Pulmonary findings include diffuse crackles and
decreased breath sounds on lung auscultation, acute
hypoxemia and decreased pulmonary compliance without
signs of circulatory overload. Chest radiographs consistent
with TRALI demonstrate bilateral, diffuse pulmonary
infiltrates.5
TRALI
TRALI: Proposed Mechanisms and Models
There are several accepted models for the mechanism of
TRALI. In the direct antigen-antibody hypothesis, patients
develop TRALI after alloantibodies in the donor blood
product cause activation of the recipient’s neutrophils
leading to an inflammatory process causing lung injury.3,6
This theory is supported by the presence of human leuko-
cyte antigen (HLA) antibodies and human neutrophil anti-
gen (HNA) antibodies in samples of donor plasma that
resulted in TRALI.3,5-9 Interestingly, case reports exist of
unilateral TRALI after lung transplantation where HLA-
antibodies from a transfused blood product directly reacted
with the cognate HLA antigen expressed on the donated
lung but spared the patient’s native lung that did not
express these same HLA antigens.6,7
Sachs and colleagues demonstrated that HLA antibod-
ies in plasma can bind to their cognate antigen on mono-
cytes, resulting in monocyte activation. When neutrophils
come in proximity to these activated monocytes, they in
turn become activated and demonstrate increased produc-
tion and release of reactive oxygen species and increase
endothelial permeability.10
In at least 15% of TRALI cases, HLA and HNA antibod-
ies are not identified in the offending product. Similarly,
TRALI patients do not always express the cognate antigen
to an antibody present in the donor product.6 Originally
described by Silliman et al,11 in the 2-event model, the
hypothesized first hit is already present as part of the
patient’s condition—as a prior ongoing inflammatory pro-
cess such as sepsis or surgery. It is thought that these
comorbidities prime neutrophils and enhance the response
4 Seminars in Cardiothoracic and Vascular Anesthesia 00(0)
to the “second-hit.”5-7,11-13 The second hit results from
inflammatory mediators, like lysophosphatidylcholines,
IL-6, and IL-8, present in stored blood products which are
thought to directly activate primed neutrophils.5,8,13
A third, more recently described, dynamic model of
TRALI has been proposed by Middelburg and van der
Bom.14 This model suggests that TRALI is a clinical entity
resulting from a “multi-causal” phenomenon.14 These
authors postulate that categorizing TRALI as a “2-hit”
model by grouping all patient-related risk factors together
in one “hit” and all transfusion-related factors together in a
second “hit” could hinder the identification of other, modi-
fiable contributors.14,15
Middelburg describes TRALI using threshold model-
ing (a concept derived from the work of Rosendaal16).
Middelburg and van der Bom14 describe 1 patient with
several different risk factors for TRALI including: severe
pneumonia requiring ICU stay, uncomplicated cardiac
surgery, hematologic malignancy, transfusion of one
blood product that has a low TRALI activation risk, and
finally transfusion of one blood product that carries a
high TRALI activation risk. Each risk factor alone is not
strong enough to cause TRALI, however, when certain
risk factors occur in close temporal succession—if for
example, the low-risk blood product is transfused while
the patient has severe pneumonia—TRALI can occur14
(Figure 2A). This type of multicausal threshold modeling
allows separation of different possible TRALI activators
which will aid clinical decision making for TRALI
prevention.
Regardless of the inciting events, the final common
pathway of TRALI results in neutrophil priming and neu-
trophil response causing tissue injury to the pulmonary
parenchyma.3,7,10,14 Neutropenia is a common clinical find-
ing in patients with TRALI, thought to be secondary to
neutrophil sequestration within the lungs.5 In histological
samples from early TRALI, neutrophils are seen in large
numbers in the pulmonary capillary vessels, in the later
stages of TRALI, neutrophils can extravasate into the alve-
oli leading to direct pulmonary injury.7 Neutrophil activa-
tion results in the release of inflammatory mediators that
leads to endothelial stimulation and causes a vicious cycle
of enhanced neutrophil adhesion and activation. This
sequence leads to a breakdown of the endothelial cell lung
barrier resulting in high-protein pulmonary edema and
lung injury.7
TRALI: Transfusion Risk Factors and Risk
Mitigation
Blood products implicated in TRALI usually contain at
least 50 mL of plasma.6 Although plasma and platelets
have been most frequently associated with TRALI, all
blood products have been implicated.5,6,17
Female donors are more likely to be implicated in cases
of TRALI. Previously parous women who have been
exposed to paternal leukocyte antigens from the fetus during
pregnancy are more likely to have antibodies.7 There is a
correlation between parity and the prevalence of HLA anti-
bodies with rates ranging from 1.7% in nulliparous women
to as high as 29.8% in women who have had 3 children.6 In
the United States, a retrospective review of suspected
TRALI fatality cases by the American Red Cross between
2003 and 2005 sought to quantify the impact of using male-
donor plasma.17 This study classified suspected cases as
either “probable TRALI” or “unrelated etiology.” Probable
TRALI included cases that met the Canadian Consensus
Conference definition of TRALI or possible TRALI, as well
as cases clinically consistent with TRALI (new acute lung
injury with hypoxemia within 6 hours of transfusion) in
patients without documented cardiac disease or circulatory
overload.17 The data revealed that 71% of probable TRALI
cases were related to female antibody-positive donors and
that female donors were significantly more likely to have
antibodies to HLA Class I and II, or HNA antibodies than
cases classified as “unrelated etiology” (40% vs 4%).17 A
prospective cohort study from 2007 also revealed an asso-
ciation between patients who developed TRALI and blood
components from female donors, the number of pregnancies
among donors, and donor units positive for anti-HLA II and
anti-granulocytes antibodies.18
Because antibodies in donor plasma have been associ-
ated with TRALI, worldwide antibody reduction was under-
taken in the mid 2000s.2,8,17,19 In 2003, the United Kingdom
began transfusing preferentially male plasma and this suc-
cessfully decreased the incidence of TRALI.8,17,19 Since
2007, the American Red Cross has undertaken a large
research initiative for TRALI risk mitigation strategies and
has found that decreasing exposure to female plasma donors
decreased the incidence of TRALI by 80%.19 As of 2014,
plasma and whole blood for transfusion must come from
donors who are male, females who have never been preg-
nant, or females who have tested negative for HLA antibod-
ies since their most recent pregnancy.19 Additionally,
washing blood products and leukocyte depletion may help
prevent TRALI mediators from being transfused.7
TRALI: Incidence
Unfortunately, the incidence of TRALI is widely believed to
be underestimated due to underreporting.2,4,5,20 The inci-
dence has been estimated at 1 in 5000 blood components
transfused with a mortality rate between 5 and 25%.5,10 A
multicenter, 3-year, prospective case-control study using
active surveillance of all transfused inpatients older than 6
months revealed an annual TRALI incidence of 2.57 cases
per 10 000 units transfused before 2007.8 Following imple-
mentation of TRALI risk mitigation, there was a significant
Smith et al 5

Figure 2. Threshold modeling. (A) Threshold modeling for transfusion-related acute lung injury (TRALI), adapted from Middelburg
and van der Bom14,15 (originally described by Rosendaal16). Red dashed line represents the threshold of neutrophil activation to
induce TRALI. Boxes A, B, and C each represent potential risk factors for TRALI. As examples; A = surgery, B = red blood cell
(RBC) transfusion, C = fresh frozen plasma (FFP) transfusion. Individually, A, B, or C does not induce enough neutrophil activation
for TRALI. Similarly, if A and B occur simultaneously, it does not result in TRALI. However, when A and C occur at the same
time (right panel), neutrophil activation reaches the threshold, TRALI occurs. (B) Threshold modeling for case report patient.
Liver disease is a stable risk factor occurring for the entire length of time. Left: Liver transplant is complicated by hemorrhage
and massive transfusion; neutrophil activation does not surpass the TRALI threshold. Right: the patient undergoes reoperation on
postoperative day (POD) 1, which also involves hemorrhage and platelet transfusion resulting in sufficient neutrophil activation to
surpass the TRALI threshold. Printed with permission from ©Mount Sinai Health System.

reduction to an annual incidence of 0.81 cases per 10,000
units transfused after 2009.8 In contrast, a retrospective
review using an active surveillance algorithm of all non-
cardiac surgical patients in 2004 (n = 1817) and again 2011
(n = 1562) revealed a consistent incidence of TRALI and
possible TRALI of 1.3%.20 TRALI rates did not decrease
after 2007 and TRALI cases in this study were more likely
to be related to red cell transfusion than plasma. Therefore,
TRALI risk mitigation may have decreased the incidence of
TRALI from plasma, but because other blood components,
including red blood cells, can still be collected from female
donors, small volumes of antibodies in plasma may still be
transfused.21 In fact, multiple studies suggest an increase in
the incidence of TRALI from RBC and nonplasma blood
components since TRALI mitigation.2,8,20
Liver Disease: A Risk Factor for TRALI
Multiple studies have found that liver disease is a strong
risk factor for TRALI.8,9,18,22 A retrospective review of
6 Seminars in Cardiothoracic and Vascular Anesthesia 00(0)
150 patients admitted to the ICU and transfused for gas-
trointestinal bleeding (GIB) revealed an incidence of
TRALI of 15%.22 End-stage liver disease (ESLD) was a
strong predictor for the development of TRALI in this
patient population; the incidence of TRALI in patients
with ESLD was 29% versus an incidence of 1% in
patients without ESLD.22 Toy and colleagues8 revealed
several patient risk factors correlating with the develop-
ment of TRALI, including septic shock, liver surgery
(primarily liver transplant), chronic alcohol abuse, posi-
tive fluid balance, peak airway pressures >30 mm Hg
while on mechanical ventilation and active smoking.
Additionally, 48% of TRALI cases in this study occurred
in the operating room or post anesthesia care unit
(PACU).8 Clifford et al20 found that surgical procedures
with the highest incidence of TRALI included vascular
surgery (2.7% incidence) and transplant surgery (2.2%
incidence). A dose response relationship was seen in both
studies whereby increasing the volume of blood products
transfused correlated with an increased rate of TRALI.8,20
Patients with TRALI had a profound in-hospital mortal-
ity rate of 28.9% versus a rate of 2.5% for patients trans-
fused without complications.20
TRALI in Liver Transplantation
TRALI occurs more frequently in patients undergoing
liver transplantation. Surgery, of any type, is a priming fac-
tor for TRALI and the evidence suggests that liver disease
is an independent predictor of TRALI risk.8,20,22
Transplantation represents a unique surgical procedure in
which a major ischemic reperfusion injury occurs with
graft release of inflammatory mediators that may further
increase the risk for TRALI. A small number of studies
have examined the phenomenon of TRALI in liver trans-
plant recipients (Table 1). Toy and colleagues8 demon-
strated that liver surgery, specifically liver transplantation,
was associated with an odds ratio of 12.1 for TRALI, even
after controlling for underlying liver disease, alcohol
abuse, and volume of transfusion. These authors suggested
that the only subtype of surgery with a significant associa-
tion with TRALI was liver surgery.8
Pulmonary complications occur frequently during liver
transplantation. Feltracco et al31 reviewed the risks of pul-
monary complications following LT and found an elevated
risk of pleural effusions (32%-47%), pulmonary edema
(4%-47%), and ARDS (0.8%-42%). Risk factors for post-
operative pulmonary complications include intraoperative
fluid volumes greater than 9 to 10 L, transfused blood vol-
ume >4 L, major bleeding > 800 mL, and fluid retention
with a positive fluid balance at the end of surgery.23,26,29,31
A fluid balance of less than or equal to negative 300 mL for
the first 3 postoperative days may be protective against
postoperative pulmonary complications.29
TRALI is a likely cause of pulmonary edema in LT. The
pulmonary edema during LT is commonly permeability
type pulmonary edema rather than hydrostatic pulmonary
edema, indicating pulmonary injury rather than cardio-
genic dysfunction.24,25 In one retrospective review of 91
consecutive LT patients, 25% developed “immediate” pul-
monary edema symptoms during LT and resolving within
16 to 24 hours postoperatively, 18% developed “persis-
tent” symptoms during LT and lasting beyond 16 to 24
hours and 9% developed “late” de novo pulmonary edema
beginning more than 16 to 24 hours postoperatively.25
“Late” pulmonary edema was more likely to be permeabil-
ity type pulmonary edema (as defined by a pulmonary
artery wedge pressure ≤18 mm Hg) as opposed to hydro-
static pulmonary edema (pulmonary artery wedge pressure
>18 mm Hg).25 In this study, those with “late” or “persis-
tent” pulmonary edema received larger total intraoperative
fluid and more FFP than those with no pulmonary edema
or “immediate” pulmonary edema.25
Retrospective review data estimate the incidence of
TRALI during LT in the 1.3% to 1.4% range.30,32 In these
reviews, all patients undergoing LT who developed TRALI
received high-volume transfusions of multiple products
(Table 1). Morita and Pretto32 found that TRALI in LT
tended to occur following reperfusion. This temporal rela-
tionship suggests that release of inflammatory mediators
contribute to the development of TRALI following the
ischemic graft reperfusion. In this retrospective analysis of
632 patients undergoing LT, nine patients developed severe
pulmonary edema, all of whom received blood products
before and after reperfusion. Eight of those patients (88%)
developed pulmonary edema following reperfusion.32
Patients undergoing liver transplantation have a multi-
tude of patient specific, surgical, and transfusion related
risk factors that prime them for the development of TRALI.
Liver transplant recipients are an excellent example of
Middelburg and van der Bom’s multicausal threshold
model of TRALI (Figure 2B).14 These patients have many
risk factors that are all present during the perioperative
period of transplantation making it easy for their summa-
tion to cross the threshold of TRALI activation during and
following the transplantation surgery.
TRALI: Treatment and Prevention
TRALI is well known to increase ICU and hospital length
of stay as well as in hospital mortality.22,28,30,32 For post–
liver transplant patients, hospital mortality may be as high
as 28% with TRALI versus 2.9% for patients who under-
went LT but did not develop TRALI.30 The treatment of
TRALI is primarily supportive. Oxygen therapy and low-
tidal volume/high PEEP (positive end-expiratory pressure)
ventilatory support strategies recommended by the
ARDSnet group are the primary therapeutic interventions.33
Smith et al
Table 1. Summary of literature describing associations between TRALI, liver disease, and transplantation.
Reference, Year
Studies identifying liver disease or liver surgery as a risk factor for TRALI
Gajic et al, 200718
9
Nakazawa et al, 2009
Benson et al, 201022
Toy et al, 20128
Studies assessing TRALI and pulmonary complications during LT
23
Snowden et al, 2000 Incidence of radiographic Retrospective review of
24
Yost et al, 2001 Determine etiology of
Aduen et al, 200325 Characterize pulmonary
Jiang et al, 200826 Evaluate fluid therapy and Retrospective review of 62
de Boer et al, 200827
Pereboom et al, 200928
Lin et al, 201029
Benson et al, 201130
7
Objectives Study Design Outcome TRALI Risk Factors Other
TRALI risk factors 2-year prospective case- TRALI incidence: 8% Risk factors: TACO
control cohort study. 901 Liver disease, chronic 7% ICU (69/901)
transfused MICU patients alcohol abuse
Incidence of TRALI with Prospective case-control Incidence possible TRALI Risk factor: Liver American-European
male-donor FFP vs mixed trial of surgical patients 3.6% (2/55) male only FFP dysfunction Consensus Conference
donor FFP ABG within 6 hours of FFP OR: 0.219 OR: 6.543 criteria
transfusion 11.1% (3/27) from mixed
donor
Incidence of TRALI in ICU Retrospective review of TRALI incidence: Risk factors: MELD, serum
patients transfused for EMR from 2002 to 2008 Overall 15%: albumin
GIB With ESLD 29%
No ESLD 1%
Incidence and risk factors Prospective, active TRALI incidence: Risk factors:
for TRALI before and surveillance 47 738 2.57:10 000 units in 2006 Liver surgery, chronic
after risk mitigation patients >6 months age 0.81:10 000 units in 2009 alcohol abuse, positive
screened for PaO2/FiO2 fluid balance
<300 mm Hg within 12
hours of blood transfusion
Incidence of pulmonary Pulmonary edema Many cases likely TACO
pulmonary edema in LT 34 LT edema associated with:
patients CXR: Overall: 47% (16/34) Blood loss: 11 495 vs.
Preoperative Immediate postoperative 3400 mL
Immediate postoperative 18% (6/34) FFP volume: 5250 vs 2750
16-20 h postoperative mL
Retrospective, observational Incidence of possible TRALI: Pulmonary edema within
acute pulmonary edema study of 1101 patients. 0.73% (8/1101) 6 hours of transfusion
during LT Comparison of 8 patients 6/7 fluid/plasma protein without risk factors
with pulmonary edema ratio ≥0.75 (permeability for ALI
during or immediately type edema)
after LT. (8th intraoperative
Fluid protein to plasma mortality: embolism)
protein ratio to determine
edema type.
Retrospective review of 93 Pulmonary edema ↑ FFP and total fluid
edema following LT LT patients. incidencea: associated with late or
Pulmonary edema diagnosed Immediate: 25% persistent pulmonary
on CXR, PaO2/FiO2 ratio Late: 9% edema (often
<300 mm Hg Persistent: 18% permeability type)
Overall pulmonary Risk factors for pulmonary Fluid balance ≤500 mL in
postoperative pulmonary LT postoperative complications: 46.7% complications: first 3 postoperative
complications pulmonary complications Pulmonary edema: 13.79% EBL >800 mL days:
Mild-ARDS 24.14% Transfusion >9 L Higher PaO2/FiO2 ratios
Severe ARDS 13.79% Shorter LOS
Investigate the effect of Retrospective study of 433 All blood products Risk factor for mortality:
transfusion on outcomes adult primary LT negatively associated with Blood transfusion:
after LT patient and graft survival Platelet: HR 1.377
Red blood cell: HR 1.057
Effect of platelet transfusion Retrospective review of 449 Platelet transfusion: Mortality from ALI/ARDS PT with platelet <50 ×
on graft loss and mortality adult primary LT. Graft Survival: 74% (92% without with platelet transfusion: 103 had lower survival
in LT and patient survival platelet) OR: 12.23 (n = 9) and graft survival
assessed at 90 days and Graft survival: 69% (85% if received platelet
1 year without platelet) transfusion
Mortality from ALI: 4.4%
(0.4% if no ALI)
Risk factors for pulmonary Retrospective review of Pulmonary complications: Risk factors: Complications:
complications after LT pulmonary complications Incidence: 60.7% MELD ≥25 Atelectasis,
in 107 LT within 30 days Mortality 18.5% Intraoperative fluid >10 L Pleural effusion,
(Mortality without Transfusion volume >4 L pneumonia, Acute
complications: 4.8%) respiratory failure,
Pulmonary edema
Incidence of postoperative Retrospective cohort study TRALI incidence: 1.3% Plasma and platelets 86% received RBC in
infections and TRALI of 525 LT from 2002 to (7/525) associated with TRALI operating room
with LT 2009 Mortality: 82% received FFP
TRALI Transfusions were guided
28.6% (2/7) by TEG
No TRALI Hydrostatic edema
2.9% (15/518) (TACO?): 0.76%
ICU LOS with TRALI: (4/525)
↑ 2 days
(continued)
8 Seminars in Cardiothoracic and Vascular Anesthesia 00(0)
Table 1. (continued)
Reference, Year Objectives Study Design
Feltracco et al, 201331 Review article of risk
factors for pulmonary
complications following
LT
Morita and Pretto, 201432 Investigate relationship Retrospective, observational Pulmonary edema incidence:
between severe study in 632 LT from 2007
pulmonary edema and to 2011
reperfusion in LT Severe pulmonary edema:
acute decrease in SaO2 to
<90%, secretions, new PEEP
requirement, no risk factors
for ALI before LT
Abbreviations: ABG, arterial blood gas; ARDS, acute respiratory distress syndrome; CXR, chest radiograph; EBL, estimated blood loss; EMR, electronic medical record;
ESLD, end-stage liver disease; FFP, fresh frozen plasma; GIB, gastrointestinal bleeding; HR, hazard ratio; LOS, length of stay; LT, liver transplantation; MELD, model for
end-stage liver disease; MICU, medical intensive care unit; OR, odds ratio; PEEP, positive end-expiratory pressure; TACO, transfusion-associated circulatory overload;
TEG, thromboelastography; TRALI, transfusion-related acute lung injury.
a
Refer to text for complete description of pulmonary edema definitions.
TRALI is typically self-limited, resolving within 72 to 96
hours with supportive care.6,24,34 There are no evidence-
guided treatment strategies specific to TRALI.
There are several strategies to attempt to minimize the
chances of developing TRALI. Some authors suggest the
use of solvent-/detergent-treated plasma (S/D plasma) in
lieu of fresh frozen or thawed plasma, since S/D plasma
has never been associated with the development of
TRALI.35,36 S/D plasma is compiled from apheresis col-
lected plasma and involves the inactivation of pathogens
as well as double sterile filtration to remove cell frag-
ments.35,36 Because S/D plasma is pooled from multiple
donors, antibodies from any one donor are thought to be
diluted to clinically inconsequential concentrations. In
fact, in one study, S/D plasma samples all tested negative
for HLA class I and II antibodies.37 S/D plasma has been
studied during liver transplantation35,36 and appears to be
non-inferior to FFP in both clinical outcomes and TEG-
based coagulation measures.36 In a prospective study, 63
patients undergoing LT were randomized to receive FFP or
S/D plasma based on a standard protocol following TEG to
guide factor transfusion.36 Patients who received S/D
plasma had lower levels of factor V, factor XII, and protein
S at the end of surgery.36 Interestingly, patients random-
ized to receive S/D plasma required a lower total volume
of plasma transfusion than those randomized to receive
FFP in order to achieve the same therapeutic goal as indi-
cated by TEG correction.36
Anesthesiologists can reduce the amount of plasma
transfused by using intraoperative viscoelastic testing.
Standard laboratory tests such as activated partial throm-
boplastin time (A-PTT) and international normalized ratio
(INR), though often elevated, do not always correlate with,
and may over-predict the degree of coagulopathy leading
to unnecessary plasma transfusion.38,39 In a study of coag-
ulopathic patients in the ICU undergoing tracheostomy,
Outcome TRALI Risk Factors Other
Pulmonary complications
after LT:
Effusion: 32%-47%
Pulmonary edema: 4%-47%
ARDS: 0.8%-42%
Median time:
1.4% (9/632) Transfusion to edema:
Mortality: 11% (1/9) 79 min
Reperfusion to edema: 34
min (8/9 patients)
those with an INR of ≥1.3 were further evaluated with
TEG which was normal in 27 of 28 patients. Those 27
patients underwent tracheostomy without prophylactic
FFP transfusion and had no bleeding complications.39
More specifically, standard tests revealing elevated INR
and PTT in patients with chronic liver disease may overes-
timate bleeding risk because of complex changes to both
pro- and antihemostatic regulation.40 ESLD patients have
been hypothesized to have rebalanced hemostasis;
increased INR, PTT, and thrombocytopenia are likely bal-
anced by decreased production of anti-coagulants like pro-
tein C and protein S, increased von Willibrand factor and
changes to the fibrinolytic system.40 As such, more spe-
cific testing with TEG should be used to guide goal-
directed prophylaxis and treatment of coagulation
abnormalities in ESLD patients. Reduction of total trans-
fusion can decrease exposure to plasma and could decrease
the incidence of TRALI.
Other prophylactic measures require further study. One
recent study in rat models of liver transplant found that
dexmedetomidine infusion prior to liver transplantation
was protective against lung injury.41 However, human
studies are necessary to further elucidate this potential
benefit. Pharmacologic therapies studied for treatment of
ARDS patients including aspirin, corticosteroids, inhaled
beta agonists, statins, and renin-angiotensin axis blockers
have had controversial results and require more robust tri-
als to assess their efficacy in preventing lung injury.42
TACO
TACO: Definition
The second leading cause of transfusion-related morbidity,
transfusion-associated circulatory overload (TACO) is
often difficult to discern from TRALI in clinical practice.
Smith et al
TACO is defined by the International Society of Blood
Transfusions as the development of at least 4 of the follow-
ing symptoms occurring within 6 hours of transfusion:
acute respiratory distress, acute or worsening pulmonary
edema on chest radiograph, a positive fluid balance,
increasing blood pressure or tachycardia.2,43 Signs and
symptoms may include diaphoresis, anxiety, cough, dys-
pnea, orthopnea, hypoxemia, rales, ronchi or wheezing,
use of accessory muscles of respiration, increased central
venous pressure, jugular venous distension, increased
brain natriuretic peptide (BNP), and transthoracic echocar-
diography, or TEE findings of left heart failure.20,44 Chest
radiographic evidence of circulatory overload includes the
presence of Kerley B-lines, alveolar or interstitial edema,
or cardiomegaly.45 To truly differentiate TACO from
TRALI, both TEE to evaluate for left heart overload, and
pulmonary artery catheter to measure pulmonary capillary
wedge pressure are necessary.46 TACO and TRALI can
also be differentiated by the composition of the pulmonary
fluid with hydrostatic fluid associated with TACO and
high-protein fluid associated with TRALI.25,47
TACO: Incidence and Risk Factors
TACO is the second most morbid transfusion reaction,
accounting for 18% of transfusion-related death.2 The inci-
dence of TACO is reported between 1 in 356 to 1 in 100
000 transfused products, however, like TRALI, the inci-
dence is thought to be significantly underestimated due to
under recognition and underreporting.2 A recent prospec-
tive study using an active surveillance method, which
screened for chest radiographs ordered within 12 hours of
transfusion, reported an incidence of TACO of 1 in 100
patients transfused (1 in 617 transfused products).48
However, the incidence is likely higher in the critically ill
population as a prospective study of medical ICU patients
using active surveillance reported an incidence of TACO
of 1 in 13 patients (69 cases, 916 patients transfused).18
TACO is more common in certain populations particu-
larly the elderly (mean age between 75 and 80 years),45
pregnant patients, infants,2 and patients with cardiac or
renal disease2 and chronic obstructive pulmonary dis-
ease.48 A recent case-control cohort study examined risk
factors for TACO using an active surveillance model
which monitored posttransfusion ABG results for new
hypoxemia. In this study, risk factors for TACO include
chronic renal failure or history of heart failure, hemor-
rhagic shock, positive fluid balance, and number of blood
products transfused.47 There was an association with pre-
transfusion mechanical ventilation, and surgery within 48
hours—particularly in cardiac (odds ratio [OR] 10.2), vas-
cular (OR 6.6), and liver surgery (OR 7.5).47
To date there have been no studies on the characteriza-
tion of TACO in LT. Patient’s undergoing LT are likely at
9
increased risk for TACO from the high risk of massive
hemorrhage and massive transfusion. Patients at particular
risk include those with hepatorenal syndrome who have a
decreased ability to clear excess fluid. However, further
studies are needed to elucidate these potential risk factors.
TACO: Treatment
Most cases of TACO resolve within 24 to 72 hours.48
Important management strategies include terminating the
transfusion and administering supplemental oxygen, and
there may be benefit in changing to an upright, supine
position allowing venous pooling of intravascular vol-
ume.45 TACO may improve after the administration of
diuretic agents to assist renal fluid excretion.48 The risk of
TACO is decreased with slower rates of transfusion or if
transfusion products are split into small aliquots.2,45
Conclusion
Our patient had multiple patient-specific risk factors
including cirrhosis, high MELD, and multiple antibodies,
increasing his risk for transfusion reactions. He required a
massive transfusion, complicated by difficulty obtaining
fully matched blood products. Despite the transfusion vol-
ume, continued hemorrhage and AKI, he did not develop
clinically significant pulmonary injury in the immediate
postoperative period. Approximately 16 hours after com-
pletion of the transplant, our patient returned to the operat-
ing room for hemostasis but developed severe, acute
pulmonary injury immediately after platelet transfusion.
Our patient developed acute oxygen desaturation, dif-
ficult ventilation, high airway pressures, pulmonary
edema, and acute pulmonary hypertension with right ven-
tricular failure on TEE following surgical stress with mas-
sive transfusion. The diagnosis of TRALI is corroborated
by the acute, severe hypoxemia on serial ABGs and pre–
and post–orthotopic LT chest radiograph revealing new,
bilateral, diffuse infiltrates. This patient did not have pul-
monary injury prior to his initial liver transplantation but
developed many risk factors during transplantation: mas-
sive hemorrhage/transfusion, transfusion of partially
cross-matched blood, reperfusion injury, acute kidney
injury and prolonged mechanical ventilation. This patient
fits well into the multicausal model14 of TRALI as many
risk factors came together to contribute to the specific tim-
ing of TRALI (Figure 2B).
This case also demonstrates the difficulty in differenti-
ating between TRALI and TACO. During the transplanta-
tion course the patient developed AKI. His decreased renal
clearance along with ongoing massive transfusion put him
at high risk for fluid overload which likely also contributed
significantly to his clinical picture. Pulmonary capillary
wedge pressures were not obtained intraoperatively and
10
pulmonary edema fluid was not examined for transudate
versus exudate, this information would have been useful
for elucidating fluid overload as a second potential mecha-
nism of pulmonary injury.
What is clear is that this case demonstrates the crux of
the difficulty in studying TRALI and TACO in liver trans-
plant patients. This patient was never explicitly diagnosed
with either of these transfusion related pathologies due to
the complex nature of his presentation and the difficulty in
making a single diagnosis. The incidence of TRALI is very
difficult to define in this clinical population which is a
major contributor to its underreporting. Many patients
may present similarly, where multiple diagnoses may
account for the presentation. Alternatively, other cases of
TRALI after LT may be clinically silent and self-limited;
transplant candidates may present with subclinical hypox-
emia and pulmonary infiltrates in the perioperative period
which clinicians may attribute to congestive heart failure,
atelectasis, or the stress of their disease and the surgery
itself.
Diagnosing TRALI and TACO in liver transplant
patients remains challenging. Clinicians should actively
work to record all possible cases and pool this data across
multiple centers to better elucidate the impact that com-
mon factors have in increasing the risk of developing these
deadly conditions. Minimizing the risks of TRALI and
TACO in liver transplantation patients is an important and
worthy goal to improve transplant outcomes and survival.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
The author(s) received financial support from the Department of
Anesthesiology, Perioperative and Pain Management, Icahn
School of Medicine at Mount Sinai.
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