ARTICLE IN PRESS

Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 118

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Journal of Cardiothoracic and Vascular Anesthesia

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Review Article
Intraoperative and Early Postoperative Management
of Heart Transplantation: Anesthetic Implications
Elmari Neethling, MB ChB, DA (SA), MMed (Anes),1FCA (SA)*,
Jacobo Moreno Garijo, MD, MSc, EDA*, ,
Thiruthani K Mangalam, MBBS, DNB, FICSy,
Mitesh V. Badiwala, MD, PhD, FRCSCy,
Phyllis Billia, MD, PhD, FRCPCz,
Marcin Wasowicz, MD, PhD, FRCPC*,
Adriaan Van Rensburg, MB ChB, MMed (Anes), FCA (SA), MD,
FRCPC*, Peter Slinger, MD, FRCPC*
*
Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, ON, Canada
y
Department of Cardiac Surgery, Toronto General Hospital, Toronto, ON, Canada
z
Department of Cardiology, Toronto General Hospital, Toronto, ON, Canada

The gold standard treatment for end-stage heart failure, with 50% mortality within 5 years of diagnosis, is considered heart transplantation. Despite the
improvements in immunosuppression, the period of highest mortality risk in the heart transplantation population is during the first year post-transplanta-
tion, with primary graft dysfunction being the leading cause of mortality. After adequate preoperative assessment of the recipient, including patients on
mechanical support, the intraoperative care of heart transplantation patients requires extensive monitoring followed by proficient management of anes-
thesia induction and maintenance, ventilation, and fluid therapy. The focus on weaning from cardiopulmonary bypass should be on preventing right
ventricular failure and high pulmonary vascular resistances, with protocolized blood conservation strategies and transfusion protocols. The early post-
operative care of a heart transplantation patient is focused on the post-cardiopulmonary bypass and transplantation status, with particular attention to
the presence of primary graft dysfunction, right ventricular performance, pulmonary pressures, and vasoplegia. The aim is early extubation, inotropic
and chronotropic support weaning, and chest tube removal to facilitate discharge of the patient from the intensive care unit.
The increased complexity of heart transplantation recipients, including the incremental use of pre- transplantation mechanical circulatory support and
extended criteria donor hearts, requires extensive and sophisticated preparation of the cardiac anesthesiologist. This article aims to provide an overview
of the intraoperative and early postoperative anesthesia management of heart transplantation patients.
Ó 2019 Elsevier Inc. All rights reserved.

Key Words: heart transplantation; primary graft dysfunction; right ventricular dysfunction; pulmonary hypertension; anesthetic management

END-STAGE heart failure (HF), as a result of both ischemic
and nonischemic etiologies, has a mortality rate of approxi-
mately 50% within 5 years of diagnosis.1,2 The gold standard
treatment for end-stage HF is considered to be heart transplan-
tation (HT) or left ventricular assistant device (LVAD)
1
Address reprint requests to Jacobo Moreno Garijo, MD, Department of
Anesthesia and Pain Management, Toronto General Hospital, 200 Elizabeth
St. EN 3-443, Toronto, ON, Canada, M5G 2C4.
E-mail address: Jacobo.Moreno@uhn.ca (J. Moreno Garijo).
implantation.1,3 Short- and long-term survival after HT has
improved with an excellent survival rate of up to 88.1% and
75.3%, at years 1 and 5, respectively. An overall median sur-
vival is documented to be 11.9 years, likely secondary to sig-
nificant advances in immunosuppressive therapy.4,5
However, despite the improvements in immunosuppression,
the period of highest mortality risk in this group of patients is
during the first year post-transplantation. Mortality primarily is
due to graft failure, acute rejection, and infections. Primary graft

https://doi.org/10.1053/j.jvca.2019.09.037
1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118

dysfunction (PGD) is the leading cause of mortality in this Table 1). The timing of induction before the arrival of a
group, which has been documented as high as 40.2% in the first donor’s allograft is multifactorial and should take into consid-
month post-transplantation.2,6 In addition, with a growing eration the expertise of the team and patient-specific factors.
increased complexity of HT candidates combined with the use This time may need to be extended if the recipient has had a
of extended donors’ organs, there has been an incremental use prior sternotomy or LVAD to allow for a safe redo sternotomy.
of mechanical support that exceeds 50% of cases. This is related If the heart comes from a multiorgan donor, coordination is
to patients with end-stage HF living longer and necessitating HT even more complex. Similarly, the key factors for the recipient
at a more advance age. This cohort of patients now is 3.3% of relates to the time of anesthesia induction, placement of moni-
the adult HT population, a 40% increase compared with previ- toring catheters, and time required for heart dissection and car-
ous decades.7 The criteria for extended donor hearts for expan- diectomy. The combination of these factors is best managed
sion of the potential pool of donors are discussed in Table 1.8-10 through frequent communication between anesthetic and sur-
All these factors increase the risk of poor outcomes, causing gical teams to achieve optimal coordination.
new challenges in the anesthetic management of this specific
population.3,4,11,12 HT requires sophisticated monitoring, with Preoperative Assessment
proficient management of ventilation and discriminate transfu-
sion protocols. With this in mind, this article aims to provide an Depending on the specific indication for HT, recipients can
overview of the intraoperative and early postoperative anesthe- present either as ambulatory or critically ill patients with multi-
sia management of patients undergoing HT. ple inotropes or mechanical assist devices.14,15 Because of the
emergency nature of the procedure, there is often not enough
Preoperative Management time to perform an extensive assessment of these patients. How-
ever, initial assessment for listing has usually been performed;
Optimal synchronization between organ retrieval and graft patients scheduled for cardiac transplantation have had an
implantation is of paramount importance to minimize the graft extensive multidisciplinary assessment before listing. In the
ischemic time and the duration of cardiopulmonary bypass authors’ institution, all patients have a pulmonary artery catheter
(CPB). Ischemia time should be kept well below 300 minutes (PAC) placed in the cardiac intensive care unit (ICU) before
and preferably below 240 minutes.13 This becomes particu- their arrival to the operating room to ensure that there has been
larly important with the use of marginal donor hearts (see no change in pulmonary vascular resistance (PVR) or transpul-
monary gradient before transplantation. The presence of irre-
Table 1 versible pulmonary hypertension, diagnosed as PVR > 3
Extended Donor Criteria10 Woods units (>240 dynes-sec/cm5) or transpulmonary gradient
Allograft characteristics
(TPG) > 12 mmHg, and pulmonary arterial (PA) systolic pres-
Projected cold ischemic time >240 min may be acceptable* sure > 50 mmHg are considered to be contraindications to
Left ventricular ejection fraction (%) >45 HT.16 From an anesthesiologist’s perspective, it is essential to
Left ventricular hypertrophy Left ventricular posterior wall <14 take a focused history including a review of systems and assess-
mm ment of the special investigations.
Coronary artery disease Nonflow limiting minor lesions
Received cardiopulmonary Acceptable
resuscitation Implantable Device Management
ECG assessment Minor abnormalities of ST/T waves
TTE cardiac abnormalities Secundum ASD/normal functioning
Pacemakers or Implantable Cardioverter Defibrillator
bicuspid aortic valve/moderate Cardiac resynchronization therapy, internal cardiac defibril-
valve regurgitation are acceptable
Donor characteristics
lators, and permanent pacemaker devices are often implanted
Age May be >60 yr*,8 in patients awaiting HT. The implantation of a cardiac defibril-
Thoracic trauma history Acceptable lator as antiarrhythmic prophylaxis is a class IIa recommenda-
Diabetes or hypertension Not excluded tion by the American College of Cardiology/American Heart
Substance abuse history Not excluded Association/Heart Rhythm Society in patients awaiting trans-
Troponin I 1-10 (mg/L) acceptable9
Procalcitonin May be >2 (ng/L)
plantation who otherwise would have not qualified for the pro-
Serology HBV/HCV and HIVy not excluded cedure.17 There are multiple reasons for device interference
Inotropes/dobutamine/dopamine Dopamine < 20 (mg/kg/min) and during surgery; therefore, alternative measures should be taken
similar for other inotropes in the event of pacemaker or defibrillator malfunction, includ-
Abbreviations: ASD, atrial septal defect; ECG, electrocardiogram; HBV, ing the use of external electrode pads placed preoperatively.
hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency The indwelling intracardiac portion of the leads are removed
virus; TTE, transthoracic echocardiography. during excision of the recipient’s heart. Device explanation
* In donors younger than 45 years old, longer ischemic time may be possible and extraction may present challenges at the end of surgery
due to sufficient reserve; in those 45-55 years old, prolonged ischemic because of adhesion and ingrowth, whereby the leads are
time should be avoided; and in those >55 years old, prolonged ischemic
time should only be used if the survival benefit exceeds the risk of trans- incorporated into the vessel wall. This becomes particular rele-
planting a heart with limited cardiac reserve. vant if the device has been in place for more than 18 months.18
y If the recipient is HIV-positive, this is acceptable. Retained lead fragments have been associated with
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postoperative complications such as embolization, superior
vena cava (SVC) stenosis, mediastinal erosion deep venous
thrombosis, and infection.18 These retained fragments are also
a contraindication for magnetic resonance imaging if needed
later in life. If manual extraction proves to be difficult, laser
lead extraction can be implemented after surgery.18,19
Mechanical Circulatory Support Devices
Short-Term Devices.In the setting of transplantation, CentriMag
(Abbott, Abbott Park, IL) ventricular assist systems are
approved for short-term bridge to transplantation (BTT).
Patients with these devices are given higher priority on the
transplantation list if associated criteria are met.20 The most
commonly used devices for short-term BTT and their associ-
ated hemodynamic effects are discussed in Table 2.21-23
Recently, a temporary percutaneous right ventricular assistant
device (RVAD) capable of providing up to 4.5 L of flow has
been introduced, the TandemLife Protek Duo (TandemLife,
Pittsburgh, PA).24 The TandemLife Protek Duo has been
proved to be a safe and effective option for short-term right
ventricular (RV) support in isolation or with left ventricular
(LV) support devices for biventricular support.25 Short-term
devices are a risk factor for mortality when used directly
before transplantation to stabilize patients before HT.26,27
LVADs are a treatment modality for patients
Long-Term Devices.
with end-stage HF. These devices are placed to achieve the

Table 2
Short-Term Devices as a Bridge to Transplantation

Device IABP ECMO-VA TandemHeart Impella CentriMag (St Jude,

(Cardiac Assist, Inc, (Abiomed Inc, Minneapolis, MN)
Pittsburgh, PA) Danvers, MA)

Device characteristics21-23
Mechanism of action Diastolic BP Centrifugal Centrifugal Continuous axial flow Centrifugal
augmentation continuous flow continuous flow pump continuous flow
Afterload reduction with membrane Options: RV/LV/ Options: RV/LV/
oxygenator biventricular biventricular
Biventricular ECMO-integrated
cardiopulmonary Centrimag (Ec-
support VAD)
Location AO Central: RA!AO LA!FA LV!AO LA!AO
Peripheral: RA!PA RV!PA RA!PA
RA!FA
Maximum 0.5 L/min 7 L/min 2.5-5 L/min 3 devices: 9.9 L/min
contribution to Impella 2.5: 2-4 L/
cardiac output min
Impella CPP: 2-4
L/min
Impella 5.0: 5 L/
min
Duration of use FDA: 32 d FDA: 6 h FDA: 6 d FDA: 30 d (RV) 6 h
CE Mark: Protec CE Mark: 5 d (LV)
Duo venovenous
cannula 30 d
Anticoagulation If indicated ACT 160-180 ACT > 300 ACT 160-180 ACT 160-180
Complications Improper Increased myocardial Associated with Vascular injury, Associated with
augmentation, oxygen demand, transseptal puncture bleeding, sternotomy,
vascular occlusion, bleeding, and cannula thrombosis, device bleeding, stroke,
device migration, thrombosis, upper migration, vascular migration, renal complications,
balloon rupture, extremity hypoxia,* injury, bleeding, infection, stroke thrombosis,
spinal cord infection, air hemolysis, air infection, Ec-VAD
ischemia, visceral embolism, vascular embolism, stroke axillary
ischemia injury complications.
Hemodynamic effects1-3
RAP - # # # #
MAP " "" "" "" ""
PCWP # - ## ## -
Afterload # """ " # "
Preload - " ## ## ##
CPP "" - - " -

Abbreviations: ACT, active clotting time; AO, aorta; ASD, atrial septal defect; AV, aortic valve; BP, blood pressure; CE, conformity with health, safety, and
environmental protection standards for products sold within the European Economic Area; CPP, coronary perfusion pressure; ECMO, extracorporeal membrane
oxygenation; Ec-VAD, ventricular ECMO-integrated Centrimag; FA, femoral artery; FDA, Food and Drug Administration; IABP, intra-aortic balloon
counterpulsation; LA, left atrium; LV, left ventricle; MAP, mean arterial pressure; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; RA, right
atrium; RAP, right atrial pressure; RV, right ventricle; VA, venoarterial.
* This may occur in case of incomplete retrograde oxygenation; complications include coronary, cerebral, and upper extremity hypoxia.
 ARTICLE IN PRESS
4 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
following 3 main therapeutic goals: BTT, bridge to candidacy,
or as destination therapy in patients who are not transplantation
candidates.28 In BTT, these devices allow extended wait times
until a graft becomes available. They may reduce pulmonary
hypertension (PHT) and therefore may decrease the incidence
of RV dysfunction post-transplantation. The LVAD assists the
failing left ventricle and is placed via a sternotomy. Therefore,
all patients must be prepared for redo sternotomy with higher
risk of bleeding, as discussed later. At the author’s institution,
the Heart Mate 3 (Abbott) and Heartware (Heartware, Framing-
ham, MA) are used as long-term devices at similar rates.
After LVAD implantation, patients are treated with classical
HF medication, such angiotensin-converting enzyme inhibi-
tors, beta-blockers, nitrates, hydralazine, and angiotensin
receptor blocker. The use of these drugs can contribute to
refractory hypotension and vasoplegia in the perioperative
period.29
Anticoagulation reversal will be required during surgery,
and current options include the administration of vitamin K,
prothrombin complex concentrate (PCC), or fresh frozen
plasma (FFP).30 The consequence of using FFP is an
increased risk of allosensitization, transfusion-related lung
injury, volume needed for adequate reversal, and hemodilu-
tion. Because of the association between FFP from multipa-
rous blood donors and impaired pulmonary function
postoperatively, some institutions now avoid the use of FFP
from these donors.31 PCC can be administrated as a low-
volume alternative with comparable effect and significantly
reduces the need for FFP administration.32 The timing of
PCC administration is essential because PCC hemostatic
activity is maximal if dosing occurs after CPB. However,
withholding the full dose until weaning from CPB may lead
to severely decreased levels of thrombin generation of
<10%. Bleeding and coagulopathy may be exacerbated by
heparin. In conclusion, full or divided dosage of PCC before
CPB commencement may maintain the thrombin generation
levels and prevent low peak levels during HT.33
Special Considerations
Redo Sternotomy
Patients who have undergone previous cardiac surgery will
require redo sternotomy. In these patients, cardiac chamber or
great vessel proximity to the sternum markedly increases both
the short- and long-term perioperative mortality risk because
of an increased risk of hemorrhage, increased blood product
utilization, prolonged CPB time, and need for alternative can-
nulation sites.34 In these cases, it is especially important to
have large-bore intravenous access and devices capable of
rapid infusion of large volume blood products. Most institu-
tions require packed red blood cells in the operating room and
defibrillator pads attached and connected.
Antibiotic Prophylaxis and Immunosuppressive Therapies
With the aim of achieving a balance between preventing
infection and allograft rejection or dysfunction in the
postoperative HT period, antibiotic prophylaxis and immuno-
suppressive therapies are required preoperatively. Currently,
there is no consensus regarding the optimal immunosuppression
regimen and no data regarding the direct anesthetic implications
of these drugs. The protocols vary at different institutions. Inter-
nationally, about half of all transplantation programs currently
use an induction strategy to delay the initiation of nephrotoxic
immunosuppressive drugs and to aid in the weaning of gluco-
corticoids in the early postoperative period.35,36 At the authors’
institution, the protocol for induction is 1,000 mg of methyl-
prednisolone 30 to 60 minutes before skin incision, and an addi-
tional 500 mg methylprednisolone is administrated on cross-
clamp removal. The detailed approach of immunosuppression
currently being used at the authors’ institution is found in Fig 1
and was created based on local practice with the support of all
transplantation attendings (Heart Transplant Program, UHN
2017, unpublished).
Intraoperative Period
Monitoring Considerations
Before induction of anesthesia, the placement of a radial
arterial catheter and large-bore peripheral venous access
should be performed. The placement of a femoral arterial
cannula, in conjunction with a radial catheter, is often per-
formed because of the pressure gradient that develops in the
post-CBP period. This prevents the misdiagnosis of hemody-
namic instability.37 The placement of an intra-arterial cathe-
ter needs to be performed under ultrasound guidance for
patients with an LVAD because of a lack of pulsatility.
Ultrasonographic assessment of venous and arterial sites
should be performed to ensure venous patency before cannu-
lation is attempted because these patients often have had
multiple prior ICU admissions with central and arterial
accesses.
During history taking, special attention should be taken to
document possible chlorhexidine allergy or sensitivity
because patients may have had multiple exposures in the
past, predisposing them to the development of anaphylaxis.
Unless contraindicated, the placement of a chlorhexidine-
impregnated dressing is recommended.38 Invasive catheters
that are in place should be assessed for signs of infection and
removed before transplantation if there is any doubt. The
placement of a PAC before surgery assists with cardiac out-
put monitoring and pulmonary artery pressure measurement
at the start of surgery. Before dissection, the PAC should be
pulled back into the sterile sheath to at least 20 cm to prevent
it being snared to the SVC anastomosis.39 The intravenous
(IV) infusions administrated should use the PAC side port to
avoid contaminating the external protective sheath during
withdrawal. In patients who are being supported hemody-
namically with mechanical devices such as extracorporeal
membrane oxygenation (ECMO), LVAD, and intra-
aortic balloon pump (IABP), the device-monitoring screen
should be placed facing the anesthesiologist for continuous
monitoring.
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E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
Fig 1. Toronto General Hospital immunosuppression regimen.
Induction of Anesthesia
Timing of induction ideally should occur as soon as the har-
vesting team has confirmed suitability of the organ. The choice
of anesthetic induction technique is not as important as slow
titration of anesthetic agents during their administration. The
main goal is to render the patient unconscious without produc-
ing cardiovascular collapse, taking into account the risk of
acid aspiration. Because of the low cardiac output state, the
onset of action may be delayed. Patients with end-stage HF
have a high dependency on endogenous catecholamines, and
care should be taken to not completely abolish the sympathetic
drive.15 Initiating inotropic and vasoactive infusions before
induction of anesthesia may contribute significantly to hemo-
dynamic stability. The primary goals of induction are mainte-
nance of contractility, systemic vascular resistance, and
preload while minimizing the negative inotropic effects of
induction and preventing aspiration or an acute increase in
PVR.
Patients with end-stage HF experience downregulation of
the b-adrenergic receptors and may require higher doses of
b agonist inotropic support to achieve the same clinical
response.40 The preoperative inotropic and vasoconstrictor
support are continued during induction of anesthesia. A sum-
mary of the recommendations is found in Tables 3 and 4.
Transesophageal Echocardiography (TEE)
The placement of a TEE probe is performed after the induc-
tion of anesthesia, and a comprehensive examination is
5
performed. During the post-induction period, TEE can assist
with early detection of hemodynamic instability and guide
effective treatment. The presence of intracardiac clots second-
ary to low cardiac output should be determined because they
will require cautious manipulation of the heart to prevent dis-
lodgement and inadvertent embolization.41 In addition, the
presence of large pleural effusions may be identified and
drained when present because these affect ventilatory mechan-
ics and can contribute to RV failure post-HT.41
Ventilation Management
The main goal of ventilatory management should be to
minimize any increase in PVR and prevent its detrimental
effects on the right ventricle. Ventilation should be initiated
with moderate tidal volumes. The effects of lung volumes on
the intra-alveolar and extra-alveolar vessels are variable. As
lung volumes increase, the decreasing resistance of the extra-
alveolar vessels is outweighed by the rise of resistance in the
alveolar vessels and a concomitant increase in PVR.42 Hyp-
oxia, hypercarbia, acidosis, hypothermia, and increased sym-
pathetic activity have all been shown to increase PVR and
therefore increase RV afterload.
Fluid Therapy
Volume replacement strategies with the use of acetate-buff-
ered crystalloid solutions (eg, Ringer’s acetate) rather than
0.9% saline result in better hemodynamic stabilization, but at
the expense of inducing some vasodilation and mild metabolic
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6 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118

Table 3
Inotropic Agents

Drug Mechanism Advantages Dose Side Effects

Milrinone Phosphodiesterase inhibitor: Increases myocardial contractility 0.375-0.75 mg/kg/min High incidence of systemic
Increased levels of cAMP and reduces PVR hypotension
Dobutamine b1/b2 agonist Improves myocardial performance 2-20 b1 agonist: Increased myocardial
Ratio 3:1 by increasing cardiac contractility mg/kg/min oxygen demand
b2 agonist:
Systemic vasodilation with mild
hypotension
Epinephrine b1/b2: Low dose Increases coronary blood flow and 0.01-0.2 Tachycardia
a1: High dose blood pressure mg/kg/min Arrhythmia
Increases CO with improved Metabolic acidosis
contractility and HR Hyperglycemia
Vasopressor agents
Vasopressin V1 and V2 receptors on VSMC Improves hypotension, less direct 0.01-0.04 Arrhythmias
surface: Increases intracellular coronary and pulmonary U/min Hypertension
calcium via G-coupled receptors vasoconstriction Decreased CO (>0.4 U/min)
and phospholipase C Effect preserved under hypoxic Splanchnic and peripheral
Attenuation of NO production and acidotic conditions vasoconstriction-increased SVR
Norepinephrine a1 +++ Increases coronary blood flow and 0.01-0.3 mg/kg/min Direct toxic effect on cardiac
b1 + elevates blood pressure myocytes
Weak b2 Indirect effect on cardiomyocytes, Decreases pulmonary, cutaneous,
which release local vasodilators renal, splanchnic blood flow;
increases SVR

Abbreviations: cAMP, cyclic adenosine monophosphate; CO, cardiac output; HR, heart rate; NO, nitric oxide; PVR, pulmonary vascular resistance; VSMC,
vascular smooth muscle cells; SVR, systemic vascular resistance.

alkalosis.43,44 The use of 0.9% saline, because of chloride
excess, has been linked to adverse hemodynamic outcomes
and an increase in vasoactive medication compared with
acetate-buffered solutions.43,45 Postoperative arrhythmias are
significantly more common in patients treated with Ringer’s
lactate than Ringer’s acetate. Consequently, Ringer’s acetate
solution is an acceptable alternative.46
Preparations for CPB
Heparin Administration
Anticoagulation is required before the initiation of aortic cannu-
lation, with a typical dose of heparin between 300 and 400 U/kg.
The acceptable activated clotting time (ACT) level as endorsed by
the Society of Thoracic Surgeons/Society of Cardiovascular
Anesthesiologists and American Society of Extracorporeal Tech-
nology guidelines is 480 seconds.47 Recent guidelines published
by the European Association for Cardio-Thoracic Surgery and
European Association of Cardiothoracic Anaesthesiology recom-
mend the use of heparin levelguided administration over ACT-
guided administration.48 Unfortunately, patients presenting for HT
often have Antithrombin-III (AT-III) deficiency caused by pro-
longed infusion of heparin or liver congestion. Preoperative predic-
tors of heparin resistance include a continuous infusion, age > 65,
and platelet count > 300,000 cells/mm.3,49 In these patients, the
AT-III level may decrease by 30%.50 An extensive discussion on
the management of heparin resistance is beyond the scope of this
article; however, if a dosage > 600 U/kg has been administrated
with an ACT < 480, the need for AT-III or FFP should be
assessed.51 Exposure to heparin also increases the development of

Table 4
Inhaled Pulmonary Vasodilators in Patients with Right Ventricular Failure and Pulmonary Hypertension

Drug Mechanism Dose Considerations

Epoprostenol Prostaglandin I2 25-50 ng/kg/min Complicated administration and systemic exposure

Impaired platelet aggregation
Iloprost Prostaglandin I2 5-10 mg inhaled 6-9 times/d Longer half-life of 20-30 min
Shorter duration of mechanical ventilation
Easy to administer
Nitric oxide 1-20 ppm No systemic effect, Methemoglobinemia, peroxynitrite, and nitrogen dioxide.
Rebound PHT with abrupt cessation.
Milrinone 5 mg of 5 mL or Decreased systemic hypotension
6 mg/h continuous Limited efficacy in decreased LV function
inhalation

Abbreviations: PHT, pulmonary hypertension; LV, left ventricular; ppm, parts per million.
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antibodies against heparin-platelet factor 4 (PF4) complex. The
incidence of heparin-induced thrombocytopenia (HIT) in patients
undergoing HT has been described as 3.6% to 24%.52,53 This
increases the incidence of life-threatening thrombotic events.52-54
Routine screening for HIT is not recommended for all patients
undergoing transplantation; however, HIT is a common complica-
tion in patients requiring LVAD therapy before HT.54,55 In cases
in which the diagnosis of HIT occurred within the last 3 months or
there is evidence of clinical symptoms, the likelihood of circulat-
ing antibodies against PF4/heparin complex is high; hence it is rec-
ommended to use an alternative strategy for anticoagulation.55,56
Bivalirudin, with a short half-life (approximately 25 min) is a
direct thrombin inhibitor, and therefore HIT is not a problem.
Bivalirudin can be used safely with a better coagulation profile
and less bleeding, thromboembolic complications, and allogeneic
transfusions compared with heparin during ECMO.57-59 Unfortu-
nately, the experience with bivalirudin in cardiac surgery and HT
has been reported only in a few cases.60,61 Plasmapheresis used
perioperatively may reduce the level of PF4/heparin complex anti-
bodies and allow for the intraoperative administration of heparin,
followed by an alternative strategy postoperatively, with no
increase in thrombotic complications.62 This might circumvent the
problems associated with alternative anticoagulation strategies
such as bleeding, thrombosis, efficacy, and dosing. In patients who
have a history of HIT but now test negative for antibodies, it may
be safe to proceed with the intraoperative use of heparin.56
Maintenance of CPB
Anesthesia can be maintained by either vapor administration
or infusion of IV agents. It is important to note that anesthetic
vaporizers are not available at all intitutions equally, requiring
perfusionists to alter the circuit to incorporate the vaporizer.63
In Europe, the use of propofol as a total IV anesthetic is
favored because of the European Council Directive (93/42/
EEC, 1993), which bans the use of an anesthetic vaporizer
without a technical approval license. In North America the
incorporation of an anesthetic vaporizer is common practice.
The effect of hemodilution on all volatile and IV agents needs
to be appreciated. The recently published MYRIAD random-
ized controlled trial, which included 5,400 patients, failed to
show any benefit in primary (death at 1 year) or secondary out-
come (nonfatal myocardial infarction or death at 30 days) with
the use of IV versus volatile anesthesia; therefore, it can be
concluded that either technique is acceptable.64 It is important
to maintain an adequate level of anesthesia regardless of the
choice. During CPB, pulmonary blood flow ceases while bron-
chial artery blood flow continues. This leads to sequestration
of opioids and muscle relaxants in the pulmonary tissue.65 On
resumption of ventilation, these levels may increase in the
serum circulation.
Monitoring the depth of anesthesia during CPB remains a
challenge. It is known that cardiac surgical patients are at
higher risk of developing accidental awareness during gen-
eral anesthesia (1.1%-4.7% v 0.1%-0.2% in the general pop-
ulation).66,67 In addition, assessing sympathetic symptoms
of hypertension, tachycardia, and hyperventilation are not
7
possible. The use of end-tidal anesthetic concentration con-
nected to the membrane exhaust port could give an indica-
tion of serum concentration.68,69 The use of a processed
electroencephalogram may also have potential in reducing
awareness but is not superior to the use of end-tidal anes-
thetic concentration.67,70
Surgical Technique
There are 2 standard surgical techniques used for orthotopic
HT—biatrial and bicaval anastomoses. The biatrial approach
was the first described technique, which involves only 4 ana-
tomic anastomosis, including the aorta, pulmonary artery, and
right and left atrial cuffs, and relies on retaining both atrial
cuffs to facilitate the reimplantation of the donor heart.71 The
most commonly used technique worldwide is the bicaval
approach, devised with the primary aim of preserving the
donor right atrium and reducing the incidence of late right
atrial dilation, requirement of temporary pacing, supraventric-
ular arrhythmias, and tricuspid regurgitation.72,73 This tech-
nique consists of 5 areas of anastomosis—the left atrial cuff,
SVC, inferior vena cava (IVC), pulmonary artery, and aorta—
with a demonstrated favorable outcome on 30-day mortality
and overall survival.73
The bicaval technique, which is most commonly used at
the authors’ institution, starts with the opening of the right
atrium through its anterior wall following by incision of the
interatrial septum to allow the left ventricle to empty via the
mitral valve. The aorta and pulmonary artery are divided
just above their respective semilunar valves. The SVC is
transected at its cavoatrial junction, and a large cuff of IVC
is prepared by trimming the atrial wall, carrying it medially
through the ostium of the coronary sinus and laterally
through the floor of fossa ovalis. The left atrial cuff is pre-
pared by entering the roof of the left atrium and leaving a
generous part of its posterior wall where the pulmonary vein
orifices can be identified. At the same time, it is important
to ensure meticulous hemostasis of the posterior pericardial
region, otherwise it will be extremely difficult to visualize
this area after completion of the anastomosis.
At the authors’ institution, anastomoses
Left Atrial Anastomosis.
are routinely performed according to the following
sequence—left atrium, IVC, pulmonary artery, aorta and
finally SVC—to optimize the exposure for each of the anasto-
moses. After the left atrial anastomosis, the IVC follows
because of better surgical exposure and anastomosis technique
when the aorta and pulmonary artery are disconnected. The
pulmonary anastomosis is next in order before the aorta,
because of easier surgical technique when the aorta is retracted
and out of the surgical plane. Finally, the SVC is left until the
end because it is the easiest to visualize and anastomose. In
case of a long cross-clamp time, the authors perform the aortic
anastomosis just after the left atrium anastomosis, ensuring
adequate deairing of the left side in order to remove the aortic
clamp as soon as possible and thus reduce the duration of
ischemia. Being the most posterior side of the suture lines, the
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8 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
anastomosis of the left atrium begins adjacent to the recipient
superior left pulmonary vein and donor left atrium adjacent to
the base of the left atrial appendage.
IVC Anastomosis.The IVC anastomosis is conducted in an end-
to-end fashion by using a continuous everting suture, starting
from the posterior wall and continuing anteriorly. The IVC
anastomosis is more of an atrial anastomosis than a caval anas-
tomosis because cuffs of right atrial tissue have been left both
in recipient and donor hearts.
Aorta Anastomosis.During the aortic anastomosis, some redun-
dancy of aortic tissue is desirable because it permits visualiza-
tion of the posterior line of the aortic anastomosis. If the
recipient aortic tissue is suboptimal, a 2-layer suture can be
used, with an inner layer of horizontal mattress suture and an
outer layer of running suture. At the end of this anastomosis,
the cross-clamp is removed. A venting line is placed in the
ascending aorta for deairing and the remaining anastomoses
are performed on a beating heart.
The donor and recipient pulmonary
Pulmonary Artery Anastomosis.
arteries are trimmed to obtain a perfect match in terms of
length and width. The donor pulmonary trunk should be mea-
sured about 1 cm above the pulmonary valve to prevent kink-
ing after the completion of the anastomosis. The median raphe
on the pulmonary artery may help to orientate the surgeon
while conducting this anastomosis. This anastomosis is per-
formed before the aortic anastomosis if the aortic cross-clamp-
ing time is expected to be short.
SVC Anastomosis. The final anastomosis is the SVC. The recipi-
ent SVC anastomosis can be either the SVC or SVC entry site
in the right atrium. The length of SVC should be examined
carefully because its redundancy can result in kinking of the
vein.
Weaning of CPB
Before weaning the patient from CPB, TEE should focus on
the identification of air, especially within the apex of left ven-
tricle and areas of anastomosis. The patient may be placed in a
steep Trendelenburg position before removal of the aortic
cross-clamp to prevent embolization of air to the carotid arter-
ies.15 Ventilation strategies to reduce PVR should be initiated,
as previously discussed. The use of direct-acting inotropic
agents should be initiated because the denervated heart lacks
reflex-mediated physiological feedback loops. As a result of
cardiac denervation, the transplanted heart has a higher intrin-
sic rate (90-110 beats/min), reduced rate variability, and the
initial response via the Frank-Starling mechanism is critically
dependent on an adequate LV end diastolic volume.74,75 If
after removal of the aortic cross-clamp the implanted heart
resumes function spontaneously and the intrinsic heart rate is
high (90-110 beats/min), this usually indicates minimal ische-
mia-reperfusion injury of the graft.
The responsiveness of the patient to direct inotropic and
chronotropic agents still is intact but not to parasympatholytic
agents. Temporary pacemaker wires should be placed in the
donor atrium and ventricle. Factors increasing the requirement
for permanent pacemaker insertion include prolonged ische-
mic time, surgical biatrial versus bicaval anastomosis, and the
simultaneous procurement of lungs at the time of organ pro-
curement.71,76 The presence of damage to the donor sinoatrial
or atrioventricular nodes because of prolonged ischemic time
or surgical trauma may lead to bradycardia or arrhythmias,
requiring temporary pacing or direct b-agonist agents. Perma-
nent pacing post-HT is required in 4% to 12% of HT recipi-
ents.77 Tricuspid valvular regurgitation is the most common
single valvular dysfunction after HT. This can most commonly
be attributed to PHT, annular enlargement as a result of RV
dilation, papillary dysfunction, or surgical alteration of right
atrium morphology.78 Transient mild mitral regurgitation may
occur because of papillary edema.79,80
Right Ventricle Failure and Pulmonary Hypertension
Right ventricle failure (RVF) after HT is the most dreaded
complication post-HT. It is diagnosed by an RV ejection frac-
tion < 20% and fractional area change < 35% and is associated
with significant postoperative morbidity and mortality.81-83 The
mortality rate in the setting RVF after CPB has been described
as high as 86%.84 RVF post-HT has been described in up to
45% of cases as a result of PGD, which is discussed later.6,85
PHT, ischemia, reperfusion injury, and longer ischemic time are
paramount contributors to RVF post-HT because of the extreme
sensitivity to small increases in afterload of a healthy donor
right ventricle.85,86 Acute refractory RVF has been reported in
2% to 3% of patients after HT, with an initial salvage rate of
only 25% to 30%.82
PHT in cardiac surgery, including HT recipients, generally is
cardiac in origin at the pulmonary post-capillary level, classified
by the World Health Organization as group 2.87 The presence of
PHT post-HT can induce high RV afterload and subsequent
RVF; therefore, this is a key parameter to monitor post-HT.
When PHT is defined by absolute values of systemic pulmonary
pressure after aggressive diuresis, its severity tends to be underes-
timated, particularly in post-HT patients.88 Morbidity and mortal-
ity associated with PHT are more dependent on RV adaptation
rather than on the absolute value of systemic pulmonary pres-
sure.89 The use of the mean arterial pressure (MAP)/mean pulmo-
nary pressure ratio (MAP/mean pulmonary pressure normal value
> 4) in patients under general anesthesia seems to be more appro-
priate than systolic pulmonary artery pressure, with the highest
receiver operating curve value to predict hemodynamic complica-
tions (use of IABP, cardiac arrest, and use of vasoactive support
> 24 hours in ICU) after cardiac surgery.90
The intraoperative diagnosis of RVF is evident by the failure to
wean from CPB. In addition, the right ventricle can be seen in the
surgical field as overdistended and poorly contractile. The right
atrial pressures will increase to a central venous pressure exceed-
ing the pulmonary artery diastolic pressure and lead to a concom-
itant drop in mean pulmonary artery pressures.89 TEE will
demonstrate an impairment of the systolic performance of the
right ventricle, based on fractional area change < 35%, tricuspid
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E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
annular plane systolic excursion < 17 mm, or eccentricity index
> 1. The RV myocardial performance index (abnormal if >0.5)
is a load-independent parameter that can be used alternatively,
and dP/dt (abnormal <400 mmHg/s) is reserved in case of mod-
erate-to-severe tricuspid regurgitation.91
The main therapeutic goals for the treatment of RVF include
ensuring adequate coronary perfusion by maintaining aortic
pressure, optimizing preload, and maintaining adequate filling
pressures while preventing overdistention.86 Reducing PVR
and therefore reducing RV afterload will allow for improving
RV contractility, maintaining atrioventricular synchrony and
ensuring adequate cardiac output.
Ventilation
During CPB, ventilation ceases, pulmonary and bronchial
blood flow is decreased, and the lung therefore is rendered ische-
mic. Postoperative pulmonary dysfunction after CPB may occur
in 0.5% to 1% of patients.92 Alveolar and endothelial damage
may result in the development of pulmonary edema and the accu-
mulation of alveolar protein.93 These effects can be of severe
clinical consequences in transplantation patients at risk of RVF.
Ventilation after CPB should be initiated with strategies to
lower the PVR, as previously discussed. The application of lung
recruitment maneuvers with 10 cmH2O may improve atelectasis
and consequently the detrimental effects on PVR.94 Reperfusion
of oxygenated blood to the heart leads to calcium overload, release
of oxygen free radicals, and activation of pro-apoptotic factors,
triggering apoptosis.80,95 To mitigate ischemia-reperfusion injury
and avoid altered pulmonary endothelial integrity in the setting of
HT, a decrease in the inspired fraction of oxygen may be recom-
mended before the cross-clamp is removed.6,96 The literature
on the use of lung protective ventilation strategies currently is lim-
ited to the noncardiac population.97,98 In the HT population, post-
operative pulmonary complications can have detrimental effects
on RV function; therefore, moderate tidal volumes (6-8 mL/kg)
and moderate positive end-expiratory pressure (2-5 cmH2O) are
recommended.99 When comparing ventilation and continous posi-
tive airway pressure (CPAP) versus apnea during CPB, CPAP or
ventilation may improve oxygenation after CPB, but there is little
evidence that this is of clinical significance.94100-102
Inotropic Support
Inotropic and vasopressor support may be required to ensure
hemodynamic stability and prevent RV ischemia. There are
very few studies published on the efficacy of different vaso-
pressors or inotropes to support the right ventricle during
RVF. Addressing the cause may be the best approach. As a
practical approach, these strategies can be placed in the fol-
lowing 2 groups: RVF with normal PVR and RVF with PHT.
The summary of these recommendations can be found in
Tables 3 and 4.
In the presence of RVF, standard direct inotropic therapy to sup-
port the right ventricle is required with normal PVR. Epinephrine
is an endogenous catecholamine with high affinity for b1, b2, and
a1 receptors. RV contractility also may be improved as a result of
9
the enhancement of coronary blood flow through relatively
increased diastolic duration at a higher heart rate. Milrinone is a
direct inotropic agent that acts as a phosphodiesterase-3 inhibitor,
increasing the levels of cyclic adenosine monophosphate and offer-
ing simultaneous advantages for RVF management, increased
myocardial contractility, and reduced PVR. However, it is associ-
ated with a high incidence of decreased systemic vascular resis-
tance, leading to systemic hypotension.103 Dobutamine has been
proven to improve myocardial performance in RVF by increasing
cardiac contractility as a result of its b1-agonist action with mar-
ginal tachycardia; causing mild systemic vasodilation as a result of
its b2-agonist activity; and improving hemodynamic stability post-
HT.104 Levosimendan, currently not widely available, is an inodila-
tor with calcium sensitizer and adenosine triphosphatedependent
potassium channel opener properties with inotropic and cardiopro-
tective effects. In addition, levosimendan does not increase myo-
cardial oxygen consumption, the risk of arrhythmia or impaired
diastolic function. With these factors taken into consideration, it
could be the ideal agent; however, results from 3 randomized con-
trolled trails, namely CHEETAH105, LEVO-CTS,106 and LIN-
CORN,107 did not show improvement in outcome in patients
requiring hemodynamic support after cardiac surgery compared
with standard care or were deemed inconclusive.108 If there is
accompanying hypotension, vasopressin (at a dose of 0.01-0.4 U/
min) seems a better agent than norepinephrine because of less
direct coronary and pulmonary vasoconstriction than catechol-
amines, with its effects preserved under hypoxic and acidotic con-
ditions.104 Norepinephrine (at a dose of 0.01-0.3 mg/kg/min) has a
marked agonist effect over a1 and mild effect over b1 and b2,
increasing coronary blood flow as a result of elevation of the dia-
stolic blood pressure, but with the deleterious effect of inducing
decrease in pulmonary, cutaneous, renal, and splanchnic blood
flow and apoptosis in cardiomyocytes.104
When PHT is present, the PVR is elevated (>250 dynes/sec/cm5
or 3 Wood units) or when the patient has high RV afterload (TPG
> 12 mmHg), intravenous vasodilators (eg, nitroglycerin, nitro-
prusside, milrinone, enoximone, or dobutamine) or preferably
inhaled pulmonary vasodilators (eg, prostaglandins or nitic oxide
[NO]) are required.81 The most commonly used inhaled prostaglan-
din is epoprostenol (prostaglandin I2), which provides similar
hemodynamic effects and oxygenation as does inhaled NO but
with a longer half-life of 3 to 6 minutes compared with 2-6 seconds
of NO.81 The recommended dose of inhaled epoprostenol is 25 to
50 ng/kg/min or a fixed volume of 8 mL/h, with some degree of
systemic exposure.81 In the context of HT, epoprostenol should not
be administered systemically because it has been associated with
hypotension and nonselective pulmonary vasodilation, which can
worsen ventilation-perfusion matching.109 In addition, IV epopros-
tenol is a very potent anticoagulant, blocking platelet function. As
an alternative to epoprostenol, inhaled iloprost can be used, with a
longer half-life of up to 20 to 30 minutes and shorter duration of
mechanical ventilation.110 Inhaled iloprost is recommended at 5 to
10 mg inhaled 6 to 9 times/day. It is easy to administer, even in
extubated patients, but there is some degree of systemic exposure.81
NO is a selective pulmonary vasodilator, with no systemic effect
on blood pressure, allowing maintenance of low PA pressures,
reducing RV afterload, and sustaining normal vascular
 ARTICLE IN PRESS
10 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
permeability and attenuation of ventilation-perfusion mismatch.111
Dosing of inhaled NO is patient specific (recommended 1-20
ppm), but there is no additional improvement in PVR with escalat-
ing doses greater than 10 ppm. Therefore, because of its toxicity,
the lowest effective dose is advised, with avoidance of abrupt dis-
continuation because of potential rebound in PHT.81,112 Because of
the formation of nitrogen dioxide, peroxynitrite, and methemoglo-
bin (in particular with levels > 7%) with the use of NO, pulmonary
edema, surfactant dysfunction, cyanosis, and tissue hypoxia can
occur. Therefore, a prompt dose reduction or switching to an alter-
native pulmonary vasodilator should be considered.113 Unlike NO,
inhaled epoprostenol, in addition to reducing PVR also improves
RV stroke work index in patients with PHT undergoing cardiac
surgery.114 The use of inhaled milrinone (1 mg/mL into the proxi-
mal orifice of the tracheal tube at 6 mg/h of continuous inhalation)
should be considered as an alternative, with a demonstrated
improvement in RVF in two-thirds of patients and avoidance of
systemic hypotension; however, its efficacy is limited in cases of
decreased LV ejection fraction, increased fluid load, or previous
long CPB time.103 If despite medical treatment, there is persistent
RVF, supporting the patient with mechanical support, either via an
RVAD or ECMO, may be necessary to decompress the right ven-
tricle in the short term.115
Fluid Administration
RV preload must be optimized after HT. Slow infusion of
volume to optimize preload is the ideal situation. This should
be guided by TEE and trend in central venous pressure. Both
underfilling and overdistention should be avoided to maintain
optimal cardiac output. The PAC can be advanced after
removal of the SVC cannula for better monitoring.
Administration of Protamine
The administration of protamine for neutralization of sys-
temic heparin may start if there is no further need to return
to CPB. In post-HT patients, the administration of protamine
may be associated with worsening RV function because the
donor right ventricle is exquisitely sensitive to increases in
PVR. Therefore, it is recommended to administer protamine
by infusion over 10 to 15 minutes because this is associated
with less hemodynamic instability.116 When the administra-
tion of protamine was compared through the central vein ver-
sus given directly through the ascending aorta (bypassing
lung and heart), there was a statistically significant decrease
in the degree of hypotension when administrated through
the aorta. The study was small and requires further
investigation.117
Transfusion Management
Blood Conservation Strategies
Allosensitization through blood transfusion has been shown
to increase mortality in patients post-HT.118 Red cells and leu-
cocytes carry significant human leukocyte antigen (HLA) anti-
gen load; therefore, strategies to minimize blood transfusion
should be implemented.118 Evidence regarding blood conser-
vation techniques in the transplantation population is scarce;
therefore, general measures that may assist are discussed in
the following sections.
Acute Normovolemic Hemodilution
After heparin administration and before initiation of CPB,
blood is removed from the patient’s circuit, replaced 1:1 with
crystalloid, and stored for administration at the end of surgery.
The blood is sequestrated before exposure to the CPB-related
insults. The components of whole blood are preserved and
platelet activation is avoided.119 Acute normovolemic hemodi-
lution has been associated with fewer blood transfusions and
decreased total blood loss.119 This technique can be used only
if the patient’s hemodynamic status and hemoglobin level
allow for it.
Retrograde Autologous Priming
Retrograde autologous priming is used to minimize the need
for hemodilution and to maintain a higher hematocrit during
CPB. The process has 2 parts. Once the aortic cannula is placed
and the line pressure is checked, the perfusionist allows a vol-
ume of approximately 150 mL to drain from the aorta. This vol-
ume of blood displaces the same amount of priming fluid. Once
the venous cannula is inserted, the venous variable occlusion
clamp is removed and the volume is allowed to drain.120 This
technique has been shown to reduce the crystalloid priming vol-
ume by 400 to 800 mL, with reduced need for blood transfusion
but without effect on clinical outcome.119121 The authors rec-
ommend instituting the retrograde autologous priming pro-
cess only after venous cannulation because this decreases
the period of hypotension, hypovolemia, and associated
arrhythmia if the surgeon performs venous cannulation.
Antifibrinolytic Therapy
The Society of Thoracic Surgeons, Society of Cardiovascu-
lar Anesthesiologists, and recently published European guide-
lines on blood conservation, strongly recommend the use of
antifibrinolytics in cardiac surgery.48,122 The use of antifibrino-
lytic therapy is associated with a decreased need for blood
product transfusion and redo surgery for major bleeding and
tamponade.123,124 However, high-dose tranexamic acid (TXA)
is associated with an increased incidence of seizures in patients
undergoing cardiac surgery.125 This complication increased
significantly in patients undergoing open chamber surgery,
which would place HT patients in the higher-risk category.126
The exact mechanism of seizure development is unknown;
however, it is postulated that TXA increases the excitability of
the neural networks. The use of higher-dose infusions (45-
50 mg/kg and especially >100 mg/kg) of TXA is associated
with an increase in the occurrence of seizures.123,125,127,128
The risk of seizures versus benefit of decreased transfusion,
should be balanced in the optimal dosing regimen during HT.
Best current evidence for reduction in bleeding, administration
of blood products, and reexploration comes from studies that
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E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
used a maximum dose of 50 mg/kg as either a bolus or infu-
sion, especially in patients undergoing high-risk surgeries (eg,
redo sternotomy).123 In patients with preoperative renal dys-
function, which is a very common comorbidity in HT recipi-
ents, dosing regimens should be adjusted according to their
creatinine clearance.129 A valid alternative to TXA as a thera-
peutic inhibitor of fibrinolysis may be epsilon-aminocaproic
acid.130 Aminocaproic acid has been associated with an
increase in postoperative pericardial effusions in HT.131
Hemoglobin
The target hemoglobin to initiate the transfusion of packed
red blood cells has not been established in patients undergoing
HT. Studies assessing the ideal transfusion have shown no dif-
ference in outcome in liberal (hemoglobin <96 g/L) versus
restrictive (<75 g/L) transfusion in cardiac surgery. These
studies, however, excluded patients undergoing HT.132,133
Blood products should be cytomegalovirus-free for administra-
tion in patients who lack antibodies. HLA-matched blood
transfusion may be less immunogenic than unmatched units,
although the process of procuring these blood products is more
cumbersome.134
Blood Product Administration
The use of point-of-care hemostatic testing (POCT) throm-
boelastogram- and rotational thromboelastogram-guided blood
transfusion protocols in cardiac surgery is well estab-
lished.135,136 These algorithms are summarized in Fig 2.135
POCT-guided transfusion strategies significantly decreased the
transfusion of allogeneic blood products, with the most signifi-
cant reduction shown with the transfusion of platelets and
FFP.137 The further use of point-of-care platelet function anal-
ysis included in the algorithm may improve clinical out-
come.135 Current guidelines published by the European
Association for Cardio-Thoracic Surgery and European Asso-
ciation of Cardiothoracic Anaesthesiology in 2017 recommend
the use of POCT to guide the transfusion of blood products.48
During hemodilution, one of the first factors to be depleted is
fibrinogen, and low fibrinogen level therefore is a particularly
important cause of coagulopathy post-HT. The importance of
fibrinogen is 2-fold: it is a precursor of fibrin and it enhances
platelet aggregation.138 Fibrinogen can be replaced through the
use of either cryoprecipitate or fibrinogen concentrate. The latter
may have the benefit of faster reconstitution, less pathogen
transmission (because of purification and pasteurization pro-
cesses), and immune-mediated complications.139 The use of
PCC versus plasma to reverse warfarin anticoagulation pre-HT
has been associated with shorter time to chest closure and less
blood product use.140
Early Postoperative Care
The early postoperative care of an HT patient is focused on
hemodynamic stability, with particular attention to RV perfor-
mance, PA pressures, and vasoplegia by using a PAC or bedside
echocardiography. The focus is to maintain normothermia,
11
adequate oxygenation, volume status, and coagulation. Another
important goal is early extubation, followed by inotropic and
chronotropic support weaning and early chest tube removal to be
able to discharge the patient from the ICU. Induction protocols
of immunosuppression are continued according to institutional
protocols, while being cognizant of the risk of infection and kid-
ney dysfunction.
Common Complications and Management
Acute Kidney Injury
End-stage HF predisposes HT recipients to perioperative
acute kidney injury (AKI). The pathophysiology of this is
likely multifactorial and includes arterial hypotension
(renin-angiotensin-aldosterone system activation, arginine
vasopressin and sympathetic nervous system activation)
and venous congestion.141 AKI has an incidence of up to
72% in patients post-HT, one-third of whom require acute
renal replacement therapy and up to 1.5% require chronic
dialysis in the first year post-HT.142,143 Preoperative inde-
pendent risk factors associated with the development of
AKI are an estimated glomerular filtration rate of <60 mL/
min/1.73 m2, diabetes mellitus, body mass index > 40,
mechanical ventilation, and the requirement of renal
replacement therapy.144,145 Factors contributing to AKI
post-HT can be divided into those that are related to the
transplantation surgery directly (CPB, aortic cross-clamp-
ing, perioperative hemodynamic instability, and prolonged
graft ischemic time) and those related to perioperative graft
function and hemodynamic stability. Allograft function is
fully responsible for kidney perfusion.146
During HT, the systemic inflammatory response syn-
drome observed as a result of exposure to CPB, blood scav-
enging system, and hypothermia contributes to the
activation and infiltration of neutrophils, lymphocytes, and
macrophages into the renal parenchyma, followed by
recruitment of cytotoxic compounds, which promote the
development of AKI and potential progression to renal
fibrosis.147149 The maintenance of an adequate MAP is
the most important hemodynamic parameter to maintain
adequate kidney perfusion.150 Adequate preload should be
maintained without causing RV overload or venous con-
gestion.10,151 The use of goal-directed perfusion, which
consists of a bundled care approach to ensure an oxygen
delivery  280 mL/kg/m 2 and the avoidance of tempera-
ture of >37˚C on rewarming, significantly decreases the
development of AKI.152,153 The use of dexmedetomidine
in the perioperative period may be a promising strategy
to reduce the incidence of AKI because of improved renal
perfusion through a2-adrenergic agonistic action, with
inhibition of vasoconstriction and reduction of reactive
oxygen species.154156 Independent intraoperative factors
associated with AKI are prolonged CPB, hematocrit
levels < 21%, blood transfusion, bleeding, and cardiac
tamponade.143,149,157,158
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12 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
Fig 2. Toronto General Hospital cardiac surgery blood transfusion algorithm. From Karkouti et al.135 Reproduced with permission.
Post-HT, fluid overload contributes to RVF and associated
multiorgan dysfunction, including AKI.159,160 Despite this, the
optimal initiation time for renal replacement therapy has not
been well defined. An early initiation to achieve or maintain the
target fluid balance, if not previously achieved, may prevent the
detrimental effects of prolonged fluid overload.149,161,162
Early Graft Dysfunction
Early graft dysfunction can occur intraoperatively or within
the first 24 hours post-HT, presenting with left, right, or biven-
tricular dysfunction, leading to higher 30-day and 1-year mortal-
ity.6 Early graft dysfunction is divided into PGD, idiopathic in
nature or secondary causes, as a result of excessive volume or
pressure load on the right ventricle (ie, uncontrolled intraopera-
tive bleeding requiring massive blood product transfusions and
PHT, respectively); prolonged graft ischemic time; or hyperacute
rejection.163 PGD with LV dysfunction is defined by an ejection
fraction  40% or right atrial pressure (RAP) > 15 mmHg, pul-
monary capillary wedge pressure (PCWP) > 20 mmHg, and car-
diac index (CI) < 2 L/min/m2 for at least 1 hour.6 Depending on
inotropes dosing or mechanical support requirements, the sever-
ity is classified as mild, moderate, or severe.6 PGD with RV dys-
function is defined as RAP > 15 mmHg, PCWP < 15 mmHg,
and CI < 2 L/min/m2 with TPG < 15 and or pulmonary arterial
pressure (PAP) < 50 mmHg, or requirement of an RVAD.6
PGD has a 7.4% incidence and an associated 30% mortality at
30 days (70% multiorgan failure, 20% graft failure, or 10% sep-
sis) and 35% at 1 year.6 PGD is predicated on preexisting donor
heart disease (or acquired during brain death or older donors),
organ ischemia (>4 h) and preservation, and reperfusion
injury.13,163,164 PGD can be predicted by using the RADIAL
score, determined by recipient factors R (RAP > 10 mmHg), A
(age > 60 years), D (diabetes), I (inotropic dependence), and
donor factors (age > 30 years, length of ischemic time > 240
minutes).85 The therapeutic options for PGD are inotropic agents
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E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
to support RV and LV function, with vasodilators in case of PHT
with RVF, as previously described. When medical management
fails, mechanical support should be started early and includes
IABP, temporary VAD, or ECMO. The time for recovery is esti-
mated in days to weeks.
Hemodynamic Changes and Vasoplegia
A frequent complication post-HT is vasoplegia, with an
incidence between 11% and 54%. Vasoplegia presents with
low systemic vascular resistance and hypotension in the setting
of normal LV systolic function, despite conventional therapy
with fluid administration and vasoconstrictive pharmacologic
agents, as previously described.165,166 Causes of severe hemo-
dynamic instability with cardiogenic shock, unresponsive to
pharmacologic therapy, include hyperacute rejection, cardiac
tamponade, PGD, and elevated PVR with associated RVF.163
Transplantation patients are particularly at risk of this syn-
drome because of the increased presence of inflammatory
cytokines and an accentuated systemic inflammatory response
associated, respectively, with end-stage HF and exposure to
allograft antigens.166,167 In addition, the HF medications
(angiotensin-converting enzyme inhibitors, milrinone) also
can predispose patients to perioperative vasoplegia. The pres-
ence of a vasoplegia syndrome is associated with increased
perioperative morbidity, mechanical ventilation time, and hos-
pital length of stay, but no significant differences in survival or
allograft rejection at 1 year.165
The use of methylene blue for the treatment of refractory
vasoplegia syndrome during cardiac surgery has been
described previously.168,169 There is concern of increased PVR
mediated by the inhibition of soluble guanylyl cyclase and
NO, especially in the high-risk post-HT period. Recently the
use of IV angiotensin II for the treatment of refractory vasodi-
latory shock has been demonstrated successfully.170,171 Future
trials may shed light on its effective use and safety in HT
patients. High-dose hydroxocobalamin (vitamin B12) is a
potent binder and direct inhibitor of NO and most likely also a
functional inhibitor of NO synthase.172,173 Current data is lim-
ited to case reports and case series, but this agent seems to be
promising in patients with refractory vasoplegia or with con-
traindications to the use of methylene blue.174
Other Early Complications
Some of the most common postoperative complications post-
HT include recurrent pericardial effusions, which frequently can
present in a delayed manner because of a large pericardium as a
consequence of a dilated native heart (61.5%), arrhythmia
(41.8%), and mediastinal bleeding (8.4%).175 Other less common
significant complications are stroke (1.3%), low cardiac output
syndrome (2.5%), renal failure requiring renal replacement
(3.8%), sternal wound infection (2.0%), and inguinal lymphocele
(4.6%).175 During the first 30 postoperative days, the incidence of
respiratory complications occurs in 34.7% of patients, necessitat-
ing prolonged mechanical ventilation (mean > 64.6 h) and ICU
13
stay (mean > 9.7 d).176 Nonetheless, these patients have similar
length of stay in the hospital without increased mortality.176
TEE after CPB
Post-HT, transthoracic or TEE is recommended to monitor the
function of the new heart.41,163 The left ventricle tends to have
increased wall thickness and mass because of edema believed to
be secondary to ischemia-reperfusion injury or acute rejection
episodes. Changes in diastolic function as a result of stiff myocar-
dium may be a more sensitive marker to predict outcomes com-
pared with reduced ejection fraction when complications such as
ischemia or sepsis are ruled out.78 Cardiac allograft vasculopathy,
an accelerated form of coronary artery disease, occurs in 42% of
all HT patients 3 years after transplantation.177 New regional wall
motion abnormalities detected with TEE can signal graft vascul-
opathy. In addition, LV systolic dysfunction, enlarged left atrium,
and functional mitral regurgitation can also occur.78,178 The anas-
tomotic sites should be checked, especially in HT with bicaval
anastomosis, where the flow through the SVC and IVC should be
laminar with no evidence of flow acceleration as a surrogate for
stenosis. Acute graft rejection can be determined post-HT by
assessing the right ventricle for dilation or systolic performance.
It is important to note that the right ventricle can start to remodel
in response to the pulmonary pressures of the recipient heart.78
The use of the biatrial technique or the presence of graft vascul-
opathy, PHT, RV dilation, endomyocardial biopsies, or acute
rejection has been associated with severe tricuspid regurgitation
in up to 14% to 54% of HT recipients and is associated with a
higher mortality (»62.5%).179 Complications, such aortic dissec-
tion post-HT or tamponade post-endomyocardial biopsies, are
less common but can be catastrophic.180,181
Conclusions
Despite the improvements in many clinical fields, the clinical
care of HT recipients requires extensive experience and resources
during the intraoperative and early postoperative periods. The risk
of perioperative complications remains high. The increased com-
plexity of HT recipients, including incremental use of pretransplan-
tation mechanical circulatory support and extended criteria of
donor hearts, requires all-encompassing and sophisticated prepara-
tion of the cardiac anesthesiologist. The prevention of RV failure
and increase in PVR, combined with protocolized blood conserva-
tion strategies and transfusion protocols, are key interventions to
maximize favorable outcomes in these patients. Despite the com-
plexity of this population, enhanced recovery after surgery pro-
grams should be implemented in HT centers to improve
perioperative outcomes, decreasing immediate complication rates.
Conflicts of Interest
The authors do not have any conflict of interest in regard to
this work.
 ARTICLE IN PRESS
14 E. Neethling et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 118
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