Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361

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Journal of Cardiothoracic and Vascular Anesthesia

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Review Article
Anesthesia for Combined Heart and Liver
Transplantation
1
Alan M. Smeltz, MD*, , Priya A. Kumar, MD*,y,
Harendra Arora, MD*,y
*
Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC
y
Outcomes Research Consortium, Cleveland, OH

A heart or liver transplantation procedure performed in isolation itself presents multiple challenges for the perioperative team. Accordingly, com-
bining both transplants yields a vastly more complicated surgery, with many unique multisystem and multidisciplinary considerations. Although
combined heart and liver transplantations are being performed with increasing frequency, nationwide experience is relatively limited at most
institutions. The aim of this review is to discuss the perioperative challenges presented to the anesthesiology teams and provide evidence-based
guidance for the management of these daunting procedures.
Ó 2020 Elsevier Inc. All rights reserved.

COMBINED HEART and liver transplantation (CHLT),
although a complex procedure, has been performed successfully
in adults and children for more than three decades. The first suc-
cessful CHLT was performed by Starzl et al. in 1984 on a six-
year-old girl with familial hypercholesterolemia and heart failure
secondary to coronary artery disease.1 The patient survived
eight years after the combined organ transplant. Two subsequent
patients who underwent CHLTs, which also were performed by
Starzl, unfortunately succumbed to postoperative complications.2
The major factor contributing to the fatal outcome of both cases
was a heart size mismatch between donor and recipient.
The number of CHLTs performed in the United States is
quite small relative to single-organ transplants, with only 344
cases between January 1,1988 and June 30, 2020. The number
has continued to increase over time, with 45 CHLTs in 2019
alone (see Fig 1).3 More than half of the total CHLT cases
were performed between 2014 and 2019. Two-thirds of all
CHLTs were performed on male recipients. More than half of
all CHLTs performed have been for recipients in the age group
of 18-to-34 years, whereas only 40 CHLTs were performed for
Funding: No special grant was received from funding agencies in the public,
commercial, or not-for-profit sectors.
1
Address correspondence to Alan M. Smeltz, MD, Department of Anesthesi-
ology, University of North Carolina at Chapel Hill, 101 Manning Dr, Chapel
Hill, NC 27514.
E-mail address: alansmeltz@gmail.com (A.M. Smeltz).
patients aged less than 17 years. Although more than 40 cen-
ters across the United States have reported at least one CHLT
case, the combined total from five centers account for approxi-
mately half of the total cases performed to date (see Fig 2).3
Over time, there has been a significant improvement in the
success rate of CHLT. In a survival analysis of 36 patients
with CHLT from 1998 to 2005, 84% of the patients survived
the first year and 74% of the patients survived three years after
transplantation.4 Cannon et al. described the survival data for
97 CHLT cases reported by the United Network for Organ
Sharing (UNOS) between 1987 and 2010.5 During the same
period, 96,033 orthotopic liver transplants and 67,852 ortho-
topic heart transplants were performed in the United States.
Liver graft survival in the CHLT cohort at one, five, and
ten years was 83.4%, 72.8%, and 71.0%, respectively, which
was very similar to that of the cardiac allograft (83.5%, 73.2%,
and 71.5%, respectively). Most importantly, graft survival
rates of CHLT were similar to that of isolated orthotopic heart
transplant and isolated orthotopic liver transplant. In a more
recent study, one-month, one-year, and five-year survival rates
for 15 CHLT patients were 93%, 93%, and 82%, respectively.6
Indications
Indications for CHLT can be categorized broadly into three
main groups: (1) patients who have end-stage heart and liver

https://doi.org/10.1053/j.jvca.2020.12.005
1053-0770/Ó 2020 Elsevier Inc. All rights reserved.
 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361 3351

Fig 1. The total number of combined heart-liver transplants that have been performed each year in the United States.

Fig 2. The total number of combined heart-liver transplants that have been performed through 2019 in the United States, grouped by institution. “Other” includes
transplant centers having performed three or fewer.

disease of differing etiologies, (2) patients with end-stage heart reported indications for CHLT are familial amyloid polyneurop-
and liver disease of related etiology, and (3) patients with end- athy and heart failure with congestive cirrhosis.5,7-9 Mechanisms
stage heart disease undergoing liver transplantation to prevent of cardiac failure that lead to congestive cirrhosis include dilated
damage to the cardiac allograft (Table 1). The most commonly or restrictive cardiomyopathy and congenital heart disease.
3352 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
Table 1
Indications for Combined Heart and Liver Transplantation
Familial amyloidosis
Familial hypercholesterolemia
Hemochromatosis
Glycogen storage disease
Homozygous beta-thalassemia
Congenital heart disease with congestive hepatopathy or cardiac cirrhosis
Cardiomyopathy with related or unrelated liver cirrhosis
Idiopathic cardiomyopathy
Restrictive cardiomyopathy
Ischemic cardiomyopathy
Nonischemic cardiomyopathy
Alcoholic cardiomyopathy
Viral cardiomyopathy
Hypertrophic cardiomyopathy
Sarcoidosis
Cirrhosis with related or unrelated cardiomyopathy
Cryptogenic cirrhosis
Hepatitis C cirrhosis
Alcoholic cirrhosis
Primary sclerosing cholangitis
Primary biliary cirrhosis
Alpha-1 antitrypsin deficiency
Cystic fibrosis
Autoimmune hepatitis
Nonalcoholic steatohepatitis (NASH) cirrhosis
Familial amyloid polyneuropathy is an autosomal-dominant
disease due to mutations in the transthyretin (TTR) gene that
can lead to decreased stability of the corresponding protein
with subsequent extracellular deposition of amyloid in several
tissues, including the central nervous system, autonomic ner-
vous system, and peripheral nerves. Cardiac involvement is
the most common extraneurologic manifestation and observed
in 80% of the patients. Common clinical features of cardiac
amyloidosis include arrhythmias, syncopal attacks due to
conduction problems, and heart failure caused by restrictive
cardiomyopathy. Because the amyloidogenic mutated trans-
thyretin predominantly is produced in the liver, isolated liver
transplantation has been used widely to treat these patients.
However, amyloidosis patients with concurrent liver and car-
diac involvement are treated best with a CHLT because these
patients are particularly at risk of sudden death due to rhythm
disturbances related to cardiac autonomic dysfunction. Patients
with familial amyloid polyneuropathy also may have associ-
ated severe renal involvement in which combined heart-
liver-kidney transplantation may be indicated.
With improvement in life expectancy, CHLT increasingly is
being performed in patients with previously surgically cor-
rected congenital heart disease. In patients with congenital
heart disease, cardiac cirrhosis is the most common hepatic
indication for CHLT. Bryant et al., in their retrospective
review of 190 CHLT patients from the UNOS database,
reported congenital heart disease as the indication in 21% of
the patients.8 Accumulation of iron in the heart and liver in
patients with homozygous beta-thalassemia or hereditary
hemochromatosis are also indications for CHLT. Other indica-
tions for CHLT include familial hypercholesterolemia,
cryptogenic cirrhosis with underlying cardiomyopathy, alco-
holic cardiomyopathy, and glycogen storage diseases.
Patient Selection/Preoperative Evaluation
Early diagnosis and careful selection of transplant candi-
dates are of paramount importance, given the high risk associ-
ated with combined transplants of two major organs.
Moreover, organs are a scarce resource and, therefore, should
be appropriately allocated. Because coordination of combined
transplants requires multiple teams to work in conjunction,
transplant centers pursuing CHLT should have a carefully
designed institutional protocol for workup and patient selec-
tion. Preoperative evaluation should include comprehensive
screening to establish not only the functional status of the indi-
vidual organs to be transplanted, but also a thorough workup
to assess patients’ ability to tolerate the stress of the surgery
and the demands of postoperative recovery. Patients should
undergo an extensive cardiopulmonary evaluation, testing to
assess end-organ damage, liver enzymes, bilirubin level, and
prothrombin time/international normalized ratio to assess liver
function, as well as screening to rule out occult infection or
cancer (see Table 2).10 In addition to the standard medical
evaluation, there should be a thorough psychological evalua-
tion to assess patients’ social support network. After major
organ transplantation, patients need to comply with lifelong
changes in lifestyle, complicated medication regimens, fol-
low-up appointments, and frequent laboratory testing.
When a patient is being considered for a CHLT, both the
heart and the liver transplant selection committees should
work together to ensure that the patient meets full listing crite-
ria for both organs. There are no universally accepted exclu-
sion criteria for transplantation when it comes to factors such
as age, body mass index, or frailty. However, these factors
should be considered, because they have a significant impact
on postoperative outcomes. Some of the contraindications for
CHLT include malignancy (diagnosed within the last five
Table 2
Preoperative Testing for Combined Heart and Liver Transplantation
Liver biochemical and function tests
Liver biopsy
Transabdominal ultrasound with Doppler imaging to assess the hepatic
vasculature
Serologic workup for underlying liver diseases (viral or other)
Serologies for CMV, EBV, varicella, HIV, HAV, HBV, HCV, RPR
Cardiopulmonary exercise testing
Cardiac catheterization (right and left heart)
Pulmonary function testing
Evaluation of end organ effects of chronic disease (eg, renal function)
Contrast enhanced chest and abdominal computed tomography
Bone density scan
Dental examination
Cancer screening (colon, breast, prostate, cervical cancer screening)
Psychological evaluation
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, HBV,
and HCV, hepatitis A, B, and C viruses, respectively; HIV, human
immunodeficiency virus; RPR, rapid plasma regain.
 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
years), severe systemic infection, human immunodeficiency
virus infection, severe neurologic deficits, active substance
abuse, and major psychiatric illness. Patients with advanced
liver disease, as well as cardiac disease, may have significant
pulmonary hypertension. Because moderate or severe pulmo-
nary hypertension has prognostic significance, pulmonary-spe-
cific vasodilator therapy should be attempted. Severe
pulmonary hypertension, including portopulmonary hyperten-
sion (PoPHT), which is irreversible with vasodilator therapy,
is a contraindication to CHLT.11 Patients with PoPHT who
exhibit a positive response to vasodilator therapy should be
given consideration for CHLT because liver transplantation
itself improves PoPHT, even when severe. In these patients,
bridging therapy with pulmonary-specific vasodilators should
be used as necessary throughout the perioperative period.
Donor Selection/Organ Allocation
Over the years, demand for multiorgan transplantation
(MOT) has increased, including that for CHLTs. This likely is
due to an aging population with congenital heart disease as
well as hepatic congestion secondary to heart failure. Organ
Procurement and Transplantation Network/UNOS policy pri-
oritizes MOTs such that when a patient receives an offer for
the primary organ that the patient is waitlisted, the second
organ (non-primary organ) automatically is allocated from the
same donor to the recipient, regardless of the waitlist priority
for the second organ.12 Organ allocation for CHLT candidates
is more likely to be based on the heart priority rather than the
liver. However, if a patient has a high Model for End-Stage
Liver Disease score due to the liver disease, allocation will be
prioritized based on the liver priority list rather than the heart.
MOT patients have lower rates of acute and chronic rejec-
tion postoperatively compared with single organ transplant
patients.12 This protection from both acute and chronic rejec-
tion for the transplanted heart seems to occur regardless of the
additional transplanted organ, whether it is a liver, kidney, or
lung. Liver allografts also have better immune protection
when transplanted concurrently with other organs.13 The pro-
tective effect is present only if MOTs are received from a sin-
gle donor. Moreover, it is logistically quite challenging to
coordinate organ donation and harvesting from two separate
donors because time is of the essence when it comes to multi-
organ transplantation.
Donor matching criteria, such as age and size of the organs,
should be decided by both the liver and heart selection com-
mittees. Ideally, the size of the donor organs should be 90% to
160% the size of the recipient’s.14 Because the liver has a lon-
ger acceptable ischemia time, it typically is transplanted after
the heart. Five-year survival after heart transplantation has
been shown to be 77% with a cold ischemia time (CIT) of
<4 hours, compared with five-year survival of >80% after
liver transplantation with a CIT of <12 hours.15,16 This should
be considered when determining preferences for distance from
where the donor organs will be acceptable. It is important to
accept good-quality organs for MOTs as opposed to marginal
donors. Close collaboration between the liver and the cardiac
3353
teams is paramount while determining organ acceptability.
The timing for taking the recipient to the operating room while
the procurement team goes to harvest the organs also should
be coordinated diligently to minimize CIT.
Surgical Considerations
Meticulous interdisciplinary discussions and planning
already should have occurred before the procedure and include
patient-specific details, surgical steps, plans for vascular
access, cardiopulmonary bypass (CPB) cannulation sites, and
ensuring availability of blood components based on the coagu-
lation profile. After a carefully planned induction of anesthe-
sia, the median sternotomy incision may be extended to a
laparotomy incision for a quick visual assessment of the liver
to verify the decision to proceed with both organs as planned.
The technique of abdominal dissection prior to heparinization
also may allow for adequate exposure and an expedited liver
transplantation in the patient with a freshly transplanted heart.
It is common to proceed with cardiac transplantation first, as
the allowable CIT for myocardial tissue is significantly shorter
compared with liver tissue. Additionally, a failing heart is
unlikely to tolerate the hemodynamic perturbations that would
be encountered, should liver transplantation be undertaken
first. However, the availability of organ perfusion and preser-
vation techniques may allow for a reversal of this order.17 The
bicaval technique of cardiac transplantation most frequently is
employed, followed by the biatrial technique.
There are case reports of both organs being transplanted
simultaneously (en bloc)18,19 or sequentially while on full
CPB to maintain hemodynamic stability and to avoid the car-
diac stresses of hepatic reperfusion. However, high heparin
doses and prolonged CPB durations are associated with greater
morbidity from long pump runs. Some cases have been per-
formed with a conversion to partial CPB during the liver trans-
plantation phase.20 Alternatively, venoarterial extracorporeal
membrane oxygenation (ECMO) may be used for hemody-
namic and respiratory support in patients with severe pulmo-
nary hypertension, right heart failure, or hypoxemia, which
offers the advantage of not requiring full anticoagulation com-
pared with CPB.
More commonly, once the cardiac transplantation is com-
pleted, the patient is weaned off CPB prior to the liver trans-
plantation procedure. Mean pulmonary artery pressure
35
mmHg, especially in the setting of reduced right ventricular
function, has been associated with perioperative mortality
>50%.21 However, it is unknown to what extent a newly trans-
planted heart with temporarily reduced function will recover,
and PoPHT has been shown to improve to some degree after
liver transplant.11 It is unknown if there are specific strategies
to optimize hemodynamics for the hepatic portion of the sur-
gery—such as how much inotropic support is considered safe
to tolerate the hemodynamic swings of hepatic reperfusion and
whether decision-making regarding venovenous bypass should
differ in CHLT versus isolated liver transplantation. In addi-
tion, venovenous bypass is not without its own complications,
namely vascular injury and embolization of debris. Some
3354 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
centers may elect to leave the superior vena cava cannula in
place to be used for a potential venovenous bypass during the
liver transplantation phase if a test inferior vena cava (IVC)
cross-clamp is not tolerated by the newly transplanted heart.
Liver transplantation usually is performed in the standard
bicaval or piggyback technique. Sternotomy and abdominal
incisions may be left open, with a sterile covering, to be closed
in a staged manner to allow for stabilization of fluid shifts and
a resolution of bleeding.
Barbara et al. performed a retrospective review on the
perioperative management of CHLT of 27 patients.9 They
found that 70% of recipients required inotropic support
prior to the procedure. The mean duration of surgery was
760 § 125 minutes and CPB duration was 134 § 40
minutes. In two of these patients, liver transplantation was
performed on CPB. Venovenous bypass was used in 14
patients (52%). Liver transplantation was performed prior
to cardiac transplantation in two patients, with the rationale
that the transplanted liver would help neutralize the high
titer of donor-specific antibodies.
Atluri et al. described a single-center (Hospital of the Uni-
versity of Pennsylvania) retrospective review of 26 CHLT
patients from 1997 to 2013, with 87% one-year and 83% five-
year survivals.12 In their case series, all hearts were trans-
planted prior to the livers, via a median sternotomy with the
standard aortic and bicaval cannulations. On completion of the
cardiac transplantation, CPB was weaned and patients were
decannulated; however, heparin was not reversed until after
the liver transplantation. All patients were placed on venove-
nous bypass via femoral and portal vein inflow and right atrial
outflow for the liver transplantation.
Intraoperative Anesthetic Considerations
Setup and Monitoring
For patients undergoing CHLT, complex physiologic moni-
toring and adequate vascular access are essential. For patients
on any kind of mechanical circulatory support, device function
should be monitored throughout its use. Any implanted pace-
makers and/or cardiac defibrillators should be reprogrammed
before surgery, and all patients should have external defibrilla-
tor pads in position throughout the procedure.
A radial arterial catheter commonly is placed before the
induction of general anesthesia. The catheterization of a more
central artery might be necessary if radial arterial monitoring
is inadequate, or it can be performed electively to obtain a sec-
ond site of arterial pressure monitoring. Reasons to do this
include better assessment of central arterial pressure in the set-
ting of high-dose vasopressor use and continuous blood pres-
sure monitoring during blood sample withdrawals and periods
of extreme traction that might lead to subclavian artery com-
pression between the rib cage and first rib.
The use of transesophageal echocardiography (TEE) in the
setting of elevated portal pressures, esophageal varices, and
coagulopathy, increases the risk of gastrointestinal hemor-
rhage. However, the risks are outweighed by the potential
benefits of TEE to help discern the underlying etiology of
hemodynamic instability after cardiac and liver transplants
amid a vast differential diagnosis. Real-time TEE provides
rapid feedback and can reveal multiple disease processes and
surgery-related complications that are not detectable by
standard hemodynamic monitors (see Table 3). This valu-
able ongoing feedback enables prompt treatment, including
fine adjustments in fluid, vasopressor, inotropes, and surgi-
cal manipulation, given the complexity of this surgery.
Indeed, the use of TEE has been shown to be safe for
patients undergoing isolated liver transplant.22 Certainly,
probe manipulation should be performed carefully, with a
sufficient amount of water-based, as opposed to oil-based,
lubricant in the event of excess material unintentionally
being introduced into the airway.23
For patients at increased risk of cerebral complications
related to hypoperfusion or emboli, cerebral oximetry also can
be used. Risk factors for perioperative stroke include old age,
history of cerebrovascular disease, heart failure, atrial fibrilla-
tion, and renal disease.24 Decreased cerebral oximetry meas-
urements should trigger further optimization of oxygen supply
and demand, by means such as increasing systemic blood pres-
sure, administration of packed red blood cells, prevention of
hyperglycemia, deepening of anesthesia, or cerebral cooling.
Although patients undergoing isolated liver transplants, with
severe encephalopathy and increased intracranial pressure,
also might benefit from invasive monitoring of intracranial
pressures, this practice is contraindicated in the context of
CHLT, given the need for high-dose anticoagulation for CPB
and the risk of catastrophic intracranial hemorrhage.25
Central venous access should enable the placement of a pul-
monary artery catheter, delivery of potent medications, and
rapid massive fluid resuscitation. Options to achieve this
include some combination of an 8.5F or 9F central venous
catheter with an introducer, a second central catheter, large-
bore peripheral intravenous access, and a 7F or 8.5F rapid-
infusion catheter in a large peripheral vein. Access sites that
best enable positioning of a pulmonary artery catheter include
the right internal jugular and left subclavian veins. Use of the
femoral vein should be avoided due to the planned clamping
Table 3
Factors That Can Be Detected/Evaluated Rapidly Using Transesophageal
Echocardiography During Combined Heart and Liver Transplantation.
Volume/preload status
Biventricular function
Regional wall motion abnormalities
Takotsubo cardiomyopathy
Valvular dysfunction
Dynamic left ventricular outflow tract obstruction
Patent foramen ovale
Extracardiac compression by pericardial fluid or other structure
Guidance of intravascular/intracardiac lines and devices during placement
Central vascular injury during cannulation
Intracardiac air
Anastomotic sites for evidence of stenosis
Intracardiac thromboembolism
 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
of the IVC. However, if venovenous bypass is planned, femo-
ral venous access will be needed, in addition to a modification
of the superior vena cava cannula.
Frequent laboratory measurements that should be performed
to guide appropriate therapy and blood product administration
include activated clotting time, arterial blood gases, hemoglo-
bin, platelet count, electrolytes, glucose, lactate, fibrinogen, and
viscoelastic coagulation tests. In addition to the use of cell sal-
vage, packed red blood cells and fresh frozen plasma should be
prepared preemptively and brought to the operating room. Vis-
coelastic testing can help guide the need for additional blood
products, such as cryoprecipitate, platelets, or factor concen-
trates. Additional items to prepare include the appropriate
immunosuppressants, antibiotics, antifibrinolytics, crystalloid
and colloid solutions, insulin, calcium, sodium bicarbonate,
emergency rescue medications (eg, epinephrine, vasopressin,
andnitroglycerin),neuromuscularblockers,andanalgesics.
General Perioperative Principles
Maintaining hemodynamic stability can be challenging for
patients undergoing CHLT (see Table 4). Specific hemody-
namic goals have not been outlined for either transplant sur-
gery in isolation, and management often is guided by ongoing
clinical assessment. Given the interconnection in hemody-
namic pathophysiology of both heart and liver disease, hypo-
tension during CHLT is common and can be a result of any
number of possible causes. There are numerous methods to
evaluate etiologies of hypotension and determine the appropri-
ate administration of fluids, vasopressors, inotropes, and other
supportive or rescue maneuvers.26,27 In particular, achieving
adequate volume resuscitation can be especially difficult for a
newly transplanted heart due to the pendulous swings in pre-
load conditions accompanying liver transplantation. Ideally,
there should be a balance between adequate tissue perfusion
and avoidance of volume overload, pulmonary congestion/
edema, and right ventricular distention/dysfunction. For this
reason, there should be a lower threshold to manage coagulop-
athy using factor concentrates instead of fresh frozen plasma
in these patients.
Although colloid and crystalloid solutions generally are
equivalent in restoring intravascular volume,28 patients with
liver disease are less likely to transude when fluid replacement
is accomplished preferentially with albumin. The decision to
transfuse red blood cells should be made balancing the benefits
of optimizing O2 delivery and minimizing the associated risks
of immunomodulation, graft dysfunction, and other adverse
effects. Although studies in other surgical contexts have shown
improved outcomes with more restrictive transfusion strategies
(ie, targeting a lower hemoglobin value), this have not been
investigated fully for either cardiac or liver transplant surger-
ies.29,30 At the authors’ institution, the aim is to maintain
hemoglobin >8 g/dL, a decision that is supplemented by clini-
cal clues, such as ongoing bleeding and monitoring of end-
organ function.
In addition to the baseline rebalanced equilibrium of hemo-
stasis in patients with advanced liver disease, CPB requires a
3355
high degree of anticoagulation and leads to both inflammatory
and dilutional coagulopathy and platelet dysfunction. Cell sal-
vage leads to the removal of plasma components, leading to
further dilution of coagulation factors. Extensive surgical
exposure and liver reperfusion can lead to hypothermia, further
exacerbating platelet dysfunction. These factors, in addition to
the turnover in blood volume accompanying massive bleeding
and resuscitation with blood products, lead to constant shifts in
the net potential for hemorrhage versus thrombosis. Due to
these dynamic fluctuations and the potentially damaging
effects of excessive blood product transfusion, the decision to
administer platelets and clotting factors should rely heavily on
rapid-turnover point-of-care tests, with the aim of being more
selective and restrictive.31 In particular, the use of viscoelastic
tests is becoming the standard of care in liver transplantation
and cardiac and trauma surgery. Numerous randomized con-
trolled trials have compared algorithm-based approaches using
viscoelastic tests to conventional methods in the perioperative
management of hemostatic dysfunction.32-34 These studies
have suggested that the use of viscoelastic test algorithms
decrease the number of transfused blood products and may
improve outcomes. Figure 3 illustrates the variables that are
derived from two commonly used viscoelastic tests, thromboe-
lastography (TEG) and rotational thromboelastometry
(ROTEM). Examples of TEG, ROTEM, and other hemostatic
assay thresholds that previously have been used to guide the
transfusion of blood products and other factors are outlined in
Table 5.34-37 Of note, both traditional and viscoelastic tests are
unreliable in detecting all types of platelet dysfunction. Visco-
elastic tests rely on platelet activation through protease acti-
vated receptors, thereby bypassing pathways that otherwise
would be inhibited in patients taking acetylsalicylic acid or
P2Y12 inhibitors.38 Given the potential benefit and low risk of
side effects, antifibrinolytics should be used throughout the
procedure.
Pulmonary hypertension is a known risk factor for sec-
ondary cardiac graft dysfunction.39 Confusing the clinical
picture, however, pulmonary artery pressure assessments
alone might not reveal elevated pulmonary vascular resis-
tance. This can occur if acutely increased pulmonary resis-
tance generates afterload for which the right ventricle is
unable to compensate, leading to the generation of low
pressure. In addition, general anesthesia, changes in func-
tional residual capacity, and redistribution of ventilation
can increase the degree of intrapulmonary shunting associ-
ated with hepatopulmonary syndrome.40 Efforts should be
made to minimize pulmonary vascular resistance, such as
the preferential use of vasopressin over other vasopressors
and the avoidance of pain, hypoxemia, hypercarbia, and
acidosis.41 In addition, as there are few risks beyond cost
and possible delayed extubation due to weaning of the
agent, an inhaled pulmonary vasodilator also may be pre-
emptively used. There does not seem to be compelling evi-
dence of efficacy suggesting one pulmonary vasodilator
should be used over the other. Patients undergoing heart or
lung transplantation, who were randomized to receive
either inhaled nitric oxide or epoprostenol, exhibited no
3356 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
Table 4
Proposed Care Pathway Outlining Specific Goals for Each Phase of a Combined Heart-Liver Transplantation
Phase of Procedure Hemodynamic Goals
Pre-operation Reprogram pacemaker-implantable
cardiac defibrillator, if present
Prepare emergency meds
Consider empiric iPVD
Pre-CPB MAP 65-85 mmHg, CI >2.2 L/min/m2,
CVP <20 mmHg, SvO2 > 65%
Evaluate ascending aorta cannulation
and cross clamp sites on TEE
Lower sBP to 100 mmHg during aortic
cannulation
CPB MAP 65-85 mmHg
If beginning on central VA ECMO,
anticipate transition to CPB with an
inotrope bolus bridge
Full TEE exam, especially looking for
air, atrial torsion or anastomotic flow
acceleration, RVOT obstruction, and
biventricular function
Begin inotropes after AXC removal
If RV dysfunction, increase inotropes,
begin iPVD, or mechanical support, as
appropriate
Post-CPB/ pre-anhepatic Determine need for VA ECMO or VV
bypass by test IVC clamping
Manage bradycardia with epicardial
pacing or systemic catecholamines
Consider volume to prepare for IVC
clamping while avoiding hypervolemia
Anhepatic MAP 65-85 mmHg, CVP <10 mmHg,
CI >2.2 L/min/m2, SvO2 >65%
Prepare for reperfusion
Reperfusion MAP 65-85 mmHg, CVP <20 mmHg,
CI >2.2 L/min/m2, SvO2 >65%
TEE to evaluate biventricular function,
volume status, and liver-IVC
anastomosis
Early post-operation MAP 65-85 mmHg, CI >2.2 L/min/m2,
SvO2 >65%
Maintain appropriate medical and
mechanical support
NOTE. Although specific numbers are provided as suggestions, goals may need to be individualized by clinical context.
Abbreviations: ACT, activated clotting time; AXC, aortic cross-clamp; CPB, cardiopulmonary bypass; CVP, central venous pressure; iPVD, inhaled pulmonary
vasodilator; IVC, inferior vena cava; MAP, mean arterial pressure; NGT, nasogastric tube; RSI, rapid-sequence induction; RV, right ventricle; RVOT, right
ventricular outflow obstruction; sBP, systolic blood pressure; SvO2, mixed venous oxygen saturation; TEE, transesophageal echocardiography; VA ECMO,
venoarterial extracorporeal membrane oxygenation; VV, venovenous.
differences in the reduction in mean pulmonary artery pres-
sure or central venous pressure (CVP).42 Preconditioning
with these agents might have the added advantage of
reducing ischemic reperfusion injury.43 However, pretreat-
ment with either agent has demonstrated comparable atten-
uation of liver enzyme elevation after liver ischemic insult
in a rat model, again providing no evidence to choose one
over the other.44 One difference between the agents is the
lower cost of epoprostenol over nitric oxide.42
Hemostatic Goals Other Goals
Reverse anticoagulation, if appropriate Multidisciplinary coordination of teams
Prepare necessary blood products and timing of procedure
Ongoing labs and efforts to correct Obtain appropriate consents
hemostatic defects Ensure immunosuppressive and
antibiotic medications available
Ongoing labs and efforts to correct Begin immunosuppression, as
hemostatic defects appropriate
Anticoagulate to achieve ACT >450 s Consider RSI versus slowly titrated
before CPB induction
Begin antifibrinolysis, to continue for the Consider pre-induction NGT or
remainder of the case paracentesis to minimize aspiration
risk
Secure adequate intravenous access and
monitoring
Reassess hemostasis labs during Close communication with perfusionist
rewarming Ensure labs, etc. are adequate in
Maintain ACT >450 s preparation for separation from CPB
Protamine to reverse heparin to achieve Hemoglobin >8 g/dL
ACT <120 s Transfer of care to liver team
Minimize hypothermia
Ongoing labs and efforts to correct
hemostatic defects
Ongoing labs and efforts to correct Correct hyperkalemia
hemostatic defects Correct acid-base imbalance
Ongoing labs and efforts to correct Manage electrolytes and acidosis
hemostatic defects Trend lactate for liver graft function
Cardiac surgical team may need to return
to close the chest
Ongoing labs and efforts to correct Delay extubation until stable
hemostatic defects Handoff of care involving all involved
teams
Specific Challenges for Each Phase of the Procedure
Induction of Anesthesia
Due to the compensatory catecholamine dependence in
patients with liver disease, the sympathetic nervous system-
blunting effects of general anesthesia in the setting of poor car-
diac function can lead to catastrophic hemodynamic collapse.
Slow titration of anesthetic agents, balanced with benzodiaze-
pine and opioid agents, use of more hemodynamically stable
 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361 3357

Fig 3. Graphic illustration of the variables derived from viscoelastic testing. There are some shared, as well as other parameters, which are unique to either throm-
boelastography (TEG) or rotational thromboelastometry (ROTEM). x-axis, time; y-axis, magnitude of clot firmness; CT, clotting time; LY30, clot lysis index at 30
minutes; MA, maximal amplitude; MCF, maximal clot firmness; R, reaction time.

Table 5
Hemostatic Assays Used to Guide Management of Coagulopathy During CHLT

TEG ROTEM Other Treatment

RTEG/RhTEG >2 CTINTEM/CTHEPTEM >1.5 ACT >160 s Protamine

RhTEG >14-20 min CTEXTEM >110s PTT >60 s FFP or PCC
or CTHEPTEM >260 s
MA <40-45 mm MCFHEPTEM <35 mm Platelet count <30,000/mL Platelets, DDAVP
or MCFEXTEM <40 mm or <50-100,000/mL + bleeding
or MCFHEPTEM 35-40 mm + MCFFIBTEM >8 mm or antiplatelet agent use + bleeding
a angle <45˚ MCFFIBTEM <8 mm Fibrinogen <100-150 mg/dL Cryoprecipitate or fibrinogen concentrate
LY30TEG >7.5% MCFAPTEM/MCFHEPTEM >1.5 a2-Antiplasmin <80% Antifibrinolytic
or LYmaxEXTEM >15% or fibrin degradation products

NOTE. Ranges are given to account for differences in reported thresholds in the literature. TEG can be performed either with (hTEG) or without heparinase.
ROTEM (rotational thromboelastometry) can be performed with added heparinase (HEPTEM), antifibrinolytic (APTEM), platelet inhibitor (FIBTEM), expediting
agent (EXTEM), or without additional additives (INTEM). In general, hTEG or HEPTEM should be used in heparinized patients instead of TEG, INTEM, or
EXTEM. Of note, ACT also can be affected by clotting factor deficiencies.
Abbreviations: ACT, activated clotting time; CHLT, combined heart and liver transplantation; CT, clotting time; DDAVP, desmopressin; FFP, fresh frozen
plasma; LY30, clot lysis index at 30 minutes; LYmax, maximal lysis index; MA, maximal amplitude; MCF, maximal clot firmness; PCC, prothrombin complex
concentrate; PTT, partial thromboplastin time; R, reaction time.

agents such as etomidate or ketamine, and preemptive cate- Pre-CPB

cholamine supplementation can help maintain hemodynamic
For patients on chronic anticoagulation prior to surgery, evi-
stability.41,45 Rapid-sequence induction and intubation often
dence supports the use of prothrombin complex concentrates
are warranted to prevent aspiration of gastric contents into the
over fresh frozen plasma or vitamin K to reduce blood product
airway, especially in unfasted patients and those with
transfusion, excessive volume, and the incidence of delayed
increased intraabdominal pressure secondary to tense ascites.
sternal closure.49 Heparinization should not preclude ongoing
Aside from reducing the risk of aspiration, large-volume para-
efforts to reduce underlying coagulopathy, as viscoelastic tests
centesis has the advantage of improving respiratory mechan-
with heparinase (ie, hTEG or HEPTEM) can remove the anti-
ics, oxygenation, and ventilation.46 When performed,
coagulant effect of this medication (see Table 5). Hyperglyce-
however, blood pressure may decrease as peritoneal fluid reac-
mia may be especially difficult to control due to impaired
cumulates. Therefore, intravascular volume expansion using
hepatic clearance, immunosuppressive corticosteroids, beta-
6-to-8 g of albumin per liter of ascitic fluid drained is
agonists, and the stress response to CPB—especially in
recommended.47
patients with diabetes. The systolic blood pressure generally is
Doses of medications that are eliminated by the liver or
lowered to 90- to-100 mmHg before central cannulation of the
the kidneys may need to be reduced in patients with
ascending aorta to minimize the risk of shearing vascular
hepatic and renal dysfunction. Medications that are affected
injury or intimal dissection.
include all types of intravenous anesthetics, benzodiaze-
pines, opioids (except remifentanil), and neuromuscular-
Separating From CPB
blocking agents (except atricurium and cisatricurium). In
addition, the minimum alveolar concentration of sevoflur- During the final stages of heart transplantation, as the patient
ane in patients with advanced liver failure is decreased by is rewarmed, appropriate pulmonary vasodilators and ino-
more than 20%.48 tropes are initiated and the patient is placed in Trendelenburg
3358 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361

Table 6
Complications After Liver Reperfusion

Complication Intraoperative Diagnosis Management

RV dysfunction "CVP despite #PAP, RV wall hypokinesis, dilated
RV with "TR, leftward shift of the
interventricular septum
Reperfusion syndrome MAP
30 mmHg lasting at least 1 minute within 5
minutes of reperfusion, myocardial dysfunction
Intracardiac thrombus and/or pulmonary embolism New echodensity on TEE, evidence of RV
dysfunction
Dynamic LVOT obstruction Systolic anterior motion of the mitral valve anterior
leaflet during systole ! turbulent LVOT flow and
eccentric MR
Takotsubo cardiomyopathy Regional LV wall dysfunction/thinning extending
beyond a single coronary territory
Pulmonary vasodilators, inotropic support,
mechanical support (RVAD or VA ECMO),
evaluation for pulmonary embolism
Inotropic and vasopressor support, correction of
electrolytes, VA ECMO
Anticoagulation, consideration for thrombolysis
(intravenous or catheter-directed) versus
thromboembolectomy (surgical or catheter-
directed), VA ECMO
Volume administration, heart rate reduction,
reduction of inotropic support
Inotropic and vasopressor support, mechanical
support (IABP, LVAD, RVAD, VA ECMO

Abbreviations: CVP, central venous pressure; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; LVOT, left ventricular outflow tract; MAP,
mean arterial pressure; MR, mitral regurgitation; PAP, pulmonary arterial pressure; RV, right ventricle; RVAD, right ventricular assist device; TEE,
transesophageal echocardiography; TR, tricuspid regurgitation; VA ECMO, venoarterial extracorporeal membrane oxygenation.

position to assist with de-airing prior to separation from CPB.
Transesophageal echocardiography is used to evaluate for
intracardiac air, integrity of anastomotic sites, and graft func-
tion.50 Graft dysfunction manifests as decreased myocardial
contractility and/or arrhythmias. Causes of graft dysfunction
include pre-existing donor heart disease, decreased levels of
catecholamines relative to those seen in a donor having suf-
fered brain death, ischemia-reperfusion injury, pH or electro-
lyte imbalances, pressure or volume overload affecting the
right ventricle, a flow-restricting anastomosis or kinked vessel,
and hyperacute rejection.25 The newly denervated heart is pre-
load-dependent, exhibits a higher baseline heart rate, and may
contain residual sinoatrial nodal tissue of the recipient that pro-
duces an extra, nonfunctional p wave on the electrocardio-
gram.51 Due to the inability of anticholinergic medications to
increase heart rate, bradycardia in this setting is managed with
either epicardial pacing or direct-acting agents, such as isopro-
terenol, epinephrine, and glucagon. Efforts should be made to
establish atrioventricular synchrony, by either sinus rhythm or
pacing, to optimize ventricular filling. Concurrent liver disease
may further exacerbate vasoplegia, coagulopathy, and hypo-
calcemia due to low vitamin D levels. Nearing the end of this
stage of the procedure, care is transitioned to the liver trans-
plant team after a thorough handoff by the surgeons, anesthesi-
ologists, and nurses.
Pre-anhepatic Phase
Hemodynamic goals often include maintaining adequate
mean arterial pressure for perfusion while avoiding volume
overload. In patients undergoing liver transplantation, mean
arterial pressure <40-to-50 mmHg has been associated with
acute kidney injury, early graft dysfunction, and 30-day mor-
tality.52-54 Regarding volume status during the pre-anhepatic
phase, randomized studies have shown that targeting CVP <5
mmHg or around 60% of baseline were associated with a
reduction in blood loss, transfusion requirements, and
postoperative pulmonary complications, as compared with
non-targeted standard management.55,56 However, lower CVP
also has been linked with increased norepinephrine use and
serum lactate and creatinine concentrations.57 Prevention of
hypervolemia and hypothermia can help minimize hepatic
bleeding. Either hemodynamic instability at baseline or mani-
festing with test-clamping of the IVC should prompt consider-
ation of either venovenous bypass or venoarterial ECMO for
the anhepatic phase. Venovenous bypass is used to shunt blood
from below the IVC clamp to the right ventricle, and may be
required if the patient does not have adequate venous (vari-
ceal) bypass circuits. Venoarterial ECMO should be consid-
ered if either ventricle is not capable of supporting cardiac
output immediately after CPB. However, ECMO will not alle-
viate the issues of poor IVC blood return unless the patient has
a femoral venous cannula placed. Disadvantages to these tech-
niques include the time required for setup that further increases
the duration of organ ischemia, exposure to synthetic circuits,
and the potential need for anticoagulation. Fortunately, either
of these options requires less anticoagulation than CPB. More-
over, there is evidence they may be performed safely without
any anticoagulation.58-60
Anhepatic Phase
After the IVC is clamped, fluid resuscitation should be
performed as necessary to maintain adequate perfusion, but
with care to prevent volume overload of the new cardiac
graft. Given the hypoalbuminemic state of patients with
liver failure and the desire to minimize interstitial fluid
extravasation, colloids are preferable to crystalloids. Coa-
gulopathy worsens with progressive acidosis and loss of
hepatic synthesis. Lactic acid accumulates due to hypoper-
fusion and loss of hepatic clearance.45 Additional efforts to
help prepare for reperfusion include lowering serum potas-
sium, correction of acid-base imbalance, and supplementing
magnesium and calcium.
 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
Reperfusion
With the release of the IVC and portal vein clamps, as the
liver is reperfused and cardiac preload is restored, cold acidic
perfusate is released from the donated liver into circulation.
The release of the portal vein clamp unleashes inflammatory
cytokines, cardiodepressants, and a high concentration of
potassium that collectively may lead to reperfusion syndrome.
The identification and management of this and several other
conditions that can occur during this critical time are summa-
rized in Table 6.41,61,62 Dysfunction of the new heart can lead
to hepatic venous congestion, compromised flow to the newly
implanted liver, and liver graft dysfunction. Bleeding should
be managed with blood products and supplemental factors, as
necessary. After abdominal closure, transition of care back to
the cardiac surgical team often is necessary for chest closure.
Postoperative Management
The patient should remain intubated, with supplemental ino-
tropes and other necessary support (eg, pulmonary vasodila-
tion, systemic vasopressors), and hemodynamic and laboratory
monitoring should continue. After demonstrating adequate
functional stability of the new grafts and other organs (which
are susceptible to collateral perioperative injury), efforts care-
fully can be made to begin weaning from pharmacologic and
ventilatory support. Throughout the recovery process and prior
to extubation, adequate multimodal analgesia should be bal-
anced to minimize both the physiologic stress of the pain
response and respiratory depressant side effects.
Future Directions
Due to the low number of CHLT procedures performed,
supportive evidence guiding management largely is derived
from studies of each transplant surgery performed in isolation.
There are several gaps in knowledge that warrant further
investigation to improve further upon this complex procedure.
There is evidence to suggest that the latest change in the
heart allocation system leads to worse post-transplant survival
and may need to be revised.63 In particular, this change has led
to the prioritization of allocated organs to the sickest patients,
namely those sustained on ECMO, and increased travel dis-
tance for matching, leading to increased organ ischemia time.
The impact of this on selecting CHLT candidates is unknown.
Novel ex vivo organ perfusion systems may affect donor allo-
cation area distance and resolve one of the drawbacks of the
new heart allocation system. In addition, it is unknown
whether these new technologies should change the organ trans-
plantation sequence and minimize the CIT of the liver.17
Specific hemodynamic goals are not defined clearly for
CHLT. There is particular uncertainty in identifying the opti-
mal blood pressure while on CPB. Some evidence suggests
lower blood pressure is associated with increased end-organ
dysfunction, such as acute kidney injury, whereas other evi-
dence suggests higher blood pressure that is sustained using
vasopressors is associated with increased surgical bleeding
3359
and lower cerebral O2 saturation.64,65 There are numerous
methods of determining volume status, including pulse- pres-
sure variation, pulmonary artery diastolic pressure, left ven-
tricular end-diastolic area index, transmitral Doppler changes,
and left ventricular outflow tract velocity time integral varia-
tion.27 It is unknown which of these parameters is best predic-
tive of fluid responsiveness with a newly transplanted heart
and an open chest.
Viscoelastic tests increasingly are becoming the standard of
care over standard hemostatic testing to guide blood product
management during complex procedures on account of yield-
ing quicker results and reducing the transfusion of allogeneic
blood products. However, metanalyses assessing its use in
both cardiac and complex noncardiac surgery thus far have
failed to show an improvement in clinical outcomes,
though these studies may have been underpowered and the
overall quality of evidence was graded as either low or very
low.33,66 Further, a variety of algorithms have been employed
and these pooled analyses grouped studies that used TEG with
those that used ROTEM. Given the small sample sizes of each
of these individual studies, it is difficult to determine which
formula is most optimal. In addition, it is unknown how best to
determine whether to manage hemostatic dysfunction with
blood products versus factor concentrates. One ongoing study
is randomizing patients undergoing liver transplantation to
receive either factor concentrates or placebo at the beginning
of the procedure.67
The role of intraoperative filtration to remove fluid thera-
peutically has not been established well for transplant surger-
ies. In particular, modified ultrafiltration for cardiac surgery
long has demonstrated improved outcomes in the pediatric
population and similar evidence has been emerging for the
adult population, as well.68 Early data suggest intraoperative
continuous renal replacement therapy may have utility in
patients with a history of renal insufficiency undergoing liver
transplantation.69,70 Similarly, the roles of either the preemp-
tive use of an inhaled pulmonary vasodilator or of venovenous
bypass in CHLT have not been defined.
Conclusion
Combined heart and liver transplantation is an uncommon
procedure that poses many perioperative challenges for the
surgical and anesthesiology teams. There are many aspects of
management that are especially difficult for patients undergo-
ing CHLT compared with the transplantation of either organ in
isolation. These include achieving adequate hemodynamics,
hemostasis and decisions regarding mechanical support, the
sequence of transplantation, and the coordination among the
various teams. As the incidence of CHLT procedures contin-
ues to increase, careful patient selection, preparation, and com-
munication will continue to be of paramount importance.
Conflict of Interest
None.
3360 A.M. Smeltz et al. / Journal of Cardiothoracic and Vascular Anesthesia 35 (2021) 33503361
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