ARTICLE IN PRESS

Journal of Cardiothoracic and Vascular Anesthesia 000 (2020) 114

Contents lists available at ScienceDirect

Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article
Management of Challenging Cardiopulmonary Bypass
Separation
Fabrizio Monaco, MD*, Ambra Licia Di Prima, MDy ,
,1

Jun Hyun Kim, MDz,x, Marie-Jo Plamondon, MDCMk,

Andrey Yavorovskiy, MDk,{, Valery Likhvantsev, MD**,
Vladimir Lomivorotov, MDyy, Ludhmila Abrah~ao Hajjar, MD*,zz,
Giovanni Landoni, MDxx, H. Rihakk, A.M.G.A. Farag{{,
G. Gazivoda***, F.S. Silvayyy, C. Leizzz, N. Bradicxxx,
M.R. El-Tahan****, N.A.R. Bukamalyyyy, L. Sunzzzz,
C.Y. Wangxxxx, Collaborators (to appear in Pubmed and possibly in
Scopus)
*
Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
y
Department of Anesthesiology and Pain Medicine, Inje University Ilsan Paik Hospital, Goyang, South Korea
z
Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, Canada
x
The Ottawa Hospital, Ottawa, Canada
k
Department of Anesthesiology and Intensive Care, First Moscow State Medical University, Moscow, Russia
{
Intensive Care Department, Moscow Regional Research and Clinical Institute, Moscow, Russia
**
Department of Anesthesiology and Intensive Care, State Research Institute of Circulation Pathology, Novo-
sibirsk, Russia
yy
Department of Anesthesiology and Intensive Care. Novosibirsk State University Novosibirsk, Russia
zz
Department of Cardiopneumology, Instituto do Coracao, University of S~ ao Paulo, Hospital SirioLibanes,
S~ao Paulo, Brazil
xx
Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy
kk
Cardiothoracic Anesthesiology and Intensive Care, Department of Anesthesiology and Intensive Care Medi-
cine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
{{
Department of Anesthesia, King Abdullah Medical City-Holy Capital, Makkah, Saudi Arabia
***
Department of Anesthesia and Intensive Care, Cardiovascular Institute Dedinje, Belgrade, Serbia
yyy
Department of Anesthesiology, Hospital de Santa Maria, Lisbon, Portugal
zzz
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical Uni-
versity, Xi’an, Shaanxi
xxx
Department of Cardiovascular Anesthesiology and Intensive Care Medicine, and the Clinical Department of
Anesthesiology, Resuscitation and Intensive Care Medicine, University Hospital Dubrava, Zagreb
****
Anesthesiology Department, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
yyyy
Cardiothoracic Intensive Care Unit and Anesthesia Department, Mohammed Bin Khalifa Cardiac Center,
Riffa, Bahrain
zzzz
Division of Cardiac Anesthesiology, Department of Anesthesiology and Pain Medicine, University of
Ottawa Heart Institute, School of Epidemiology and Public Health, University of Ottawa
xxxx
Department of Anaesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
1
Address reprint requests to Ambra Licia Di Prima, MD, Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina,
60  20132, Milan, Italy
E-mail address: diprima.ambralicia@hsr.it (A.L.D. Prima).

https://doi.org/10.1053/j.jvca.2020.02.038
1053-0770/Ó 2020 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114

SEPARATION from cardiopulmonary bypass (CPB) after cardiac surgery is a progressive transition from full mechanical circulatory and respi-
ratory support to spontaneous mechanical activity of the lungs and heart. During the separation phase, measurements of cardiac performance
with transesophageal echocardiography (TEE) provide the rationale behind the diagnostic and therapeutic decision-making process. In many
cases, it is possible to predict a complex separation from CPB, such as when there is known preoperative left or right ventricular dysfunction,
bleeding, hypovolemia, vasoplegia, pulmonary hypertension, or owing to technical complications related to the surgery. Prompt diagnosis and
therapeutic decisions regarding mechanical or pharmacologic support have to be made within a few minutes. In fact, a complex separation from
CPB if not adequately treated leads to a poor outcome in the vast majority of cases. Unfortunately, no specific criteria defining complex separa-
tion from CPB and no management guidelines for these patients currently exist. Taking into account the above considerations, the aim of the
present review is to describe the most common scenarios associated with a complex CPB separation and to suggest strategies, pharmacologic
agents, and para-corporeal mechanical devices that can be adopted to manage patients with complex separation from CPB. The routine manage-
ment strategies of complex CPB separation of 17 large cardiac centers from 14 countries in 5 continents will also be described.
Ó 2020 Elsevier Inc. All rights reserved.

Key Words: anesthesia; intensive care; cardiopulmonary bypass; inotropes; ventricular dysfunction; weaning; separation; discontinuation

CARDIOPULMONARY BYPASS (CPB) has multiple adverse
effects on the cardiovascular system including transcapillary
plasma loss secondary to an increase in vascular permeability,
vasoconstriction, and destruction of platelets and red blood cells.1,2
Separation from CPB is the gradual transition from extracorpo-
real circulation to the native cardiac activity with the aim of pro-
viding satisfactory oxygen through the pulmonary and systemic
circulations. This process is considered completed after the
administration of protamine and the removal of the venous and
arterial cannulae.3 While pharmacologic and temporary mechani-
cal circulatory support (MCS) of the cardiac function can be insti-
tuted before surgery when complex CPB separation is
anticipated, a prompt diagnosis has to be made in case of unex-
pected failed discontinuation from the extracorporeal circulation.
No single definition of challenging separation from CPB
exists. However, a difficult CPB separation can be defined as
the need of at least 2 inotropes or vasopressors to successfully
accomplish the separation from CPB. A very difficult wean-
off CPB occurs when the first weaning process fails or the
patient requires a mechanical device to be separated from
CPB.4 Complex CPB separation is a life-threatening complica-
tion associated with high perioperative mortality, especially
when acute right heart failure also occurs.5
At the San Raffaele Scientific Institute and University in
Milan, Italy, the Vasoactive and Inotropic Score (VIS) is cur-
rently used for decision making in patients with complex CPB
separation. Table 1 shows how to calculate VIS.6 The authors
constructed the following 3 categories of CPB separation accord-
ing to VIS values: <10 is “easy”; 10 to 30 is “difficult”, >30 is
“complex”, and in the latter case an MCS such as an intra-aortic
balloon pump (IABP) is usually added to the inotropic support.
The association between the need for high dose vasoactive drugs
and poor outcome is widely addressed in literature.4,5
Because there are no guidelines on the management of com-
plex separation from CPB, the aim of the present review is to
describe the most common scenarios associated with complex
CPB separation, and to suggest management strategies adopt-
ing pharmacologic agents and paracorporeal mechanical devi-
ces. In addition, the management of patients with difficult
CPB discontinuation is summarized from information coming
from 17 hospitals distributed in 5 continents.
Predictors of Complex CPB Separation
Complex CPB separation is a life-threatening condition that
increases perioperative morbidity and mortality.4 The identifica-
tion of factors associated with complex CPB separation is a valu-
able and often underestimated field of research. The scores
commonly used in cardiac surgery to stratify the perioperative
risk of the patient (ie, ACEF [age, creatine, ejection fraction],7
Society of Thoracic Surgery Risk Score, logistic EuroSCORE 8)
consider only preoperative variables and fail to account for intra-
operative events such as complex CPB separation. Thus, in daily
practice they fail to “fully” predict the outcome. Unfortunately,
there are no scores in the literature able to fill this gap predicting
a rough intraoperative course. In a sub-analysis of the BART trial,
Denault et al.4 observed that age, previous myocardial infarction,
depressed ejection fraction, mitral surgery, previous cardiac sur-
gery, partial thromboplastin time, and CPB duration were inde-
pendent predictors of complex CPB separation. Notably, not all
cardiac surgeries carried the same risk of complex CPB separa-
tion. For example, isolated aortic valve replacement for aortic ste-
nosis was associated with “easy” CPB separation in a higher
percentage of cases than mitral surgery. In another case series,
when aortic valve replacement was performed together with coro-
nary artery bypass graft (CABG) surgery, the inotropic support
was required in 52% of patients to allow CPB separation.9 Long
CPB and aortic cross-clamp time expose the myocardium to
ischemic insult for long periods of time and are probably the
Table 1
How to Calculate Vasoactive and Inotropic Scores
Vasoactive and Inotropic Score dopamine dose (mg/kg/min) +
(VIS)=
dobutamine dose (mg/kg/min) +
enoximone dose (mg/kg/min)
100 £ epinephrine dose (mg/kg/min) +
100 £ norepinephrine dose (mg/kg/min)
10 £ milrinone dose (mg/kg/min) +
10.000 £ vasopressin dose (U/kg/min)
Modified from Zangrillo A, Alvaro G, Pisano A, et al. A randomized controlled
trial of levosimendan to reduce mortality in high-risk cardiac surgery patients
(CHEETAH): Rationale and design. Am Heart J 2016;177:66-73.6
 ARTICLE IN PRESS
F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
main determinants of severe hemodynamic instability during
CPB separation.10 Biomarkers of tissue hypoperfusion may antic-
ipate complex CPB separation. Rao et al.11 found that increased
myocardial lactate during reperfusion predicted the occurrence of
low cardiac output (CO) syndrome.
In the modern era, TEE is a powerful tool in the manage-
ment of patients undergoing cardiac surgery. Before the begin-
ning of surgery, TEE can easily detect a preexisting left
ventricle (LV) and RV failure, which are both strong risk fac-
tors for high inotropic requirements and mortality.12 At the
beginning of CPB, TEE can detect LV distention during cardi-
oplegia administration or mispositioning of the cardioplegia
cannula, both of which are leading causes of suboptimal myo-
cardial protection. After CPB, TEE can identify prosthetic
valve dysfunction, paravalvular leaks, or interventricular
defects that along with coronary embolization (air or debris)
may represent the leading causes of complex CPB separation.
Patients with anticipated complex CPB separation can
receive a pre-emptive non-pharmacologic and pharmacologic
treatment. The use of prophylactic IABP is still a matter of
debate. Ranucci et al.13 and Rocha Ferreira et al.14 did not
observe a reduction in the rate of major postoperative morbid-
ity in high risk patients undergoing non-emergent CABG
which were treated with prophylactic IABP. On the contrary,
meta-analytic 15 and retrospective data 16 suggested a benefi-
cial effect of prophylactic IABP. the authors report that at San
Raffaele Hospital, they do not routinely start IABP preopera-
tively in high-risk patients, preferring a “wait-and-see”
approach. They do, however, position the IABP introducer
before CPB often. With regard to the administration of vasoac-
tive agents, they might use preemptive administration of levo-
simendan or phosphodiesterase 3 inhibitors but they choose
catecholamines based on TEE findings and hemodynamic
parameters after the initiation of CPB separation.
Separation from CPB
At the end of CPB, the heart recovers its mechanical activity
and begins to deliver oxygenated blood to the whole body. Heart
rate, rhythm, atrioventricular conduction, and ST analysis are
assessed by electrocardiogram. In the authors’ institution, before
starting to reduce CPB support, temporary wires are routinely
sutured to the right atrium and right ventricular free wall and are
then connected to a standard external dual-chamber pacemaker in
order to promptly treat alteration of cardiac rhythm. In particular,
sinus bradycardia is managed with atrial pacing in the absence of
atrioventricular conduction block. A right atrioventricular pacing
is primarily used with atrioventricular block because this modal-
ity is associated with dyssynchrony and a reduction in CO when
compared with atrial pacing.
Supraventricular tachycardia and AF, if not chronic cases,
require treatment with electrical cardioversion. Amiodarone,
esmolol, and calcium channel blockers may be used in the
event of persistence or early relapse of a supraventricular
tachyarrhythmia,17 with bradycardia, hypotension, and heart
failure considered as possible side effects.18 Digoxin can be
considered for rate control as second-line therapy.19 In a
3
double-blind, placebo-controlled trial on 389 patients undergo-
ing cardiac surgery, Klinger et al.20 found that 50 mg/kg of
magnesium administered after the induction of anesthesia fol-
lowed by an infusion of 100 mg/kg for 3 hours did not reduce
the occurrence of postoperative AF.
Ventricular fibrillation occurs between 10% and 80% of
patients after aortic clamp release, owing to ischemic and
ischemia-reperfusion injury,21 and can be associated with sub-
endocardial damage. Recently, Mita et al.22 found that the pro-
phylactic use of amiodarone is more effective than lidocaine
in preventing ventricular fibrillation in patients with left hyper-
trophic ventricle undergoing aortic valve replacement.
A transitory ST segment elevation in the inferior leads,
along with regional wall motion abnormalities of the inferior-
posterior wall, is commonly observed immediately after aortic
cross clamp release and is often attributed to air embolism of
the right coronary artery. An increase of blood pressure may
resolve the problem of “spilling out” the air from the coronar-
ies (increasing the aorto-coronary gradient). Sustained ventric-
ular arrhythmia in absence of electrolyte abnormalities should
raise suspicion for ischemia. Electrocardiography and TEE are
useful at this stage. In fact, a persistent ST segment elevation
and detection of new regional wall motion abnormalities are
both suggestive of coronary occlusion. In this circumstance, it
is important to promptly exclude ischemia determinants which
may depend on graft pathology in CABG (stenosis, kinking,
anastomotic narrowing, incomplete revascularization, or poor
distal run-off), suture of the circumflex coronary artery in
mitral valve surgery, or coronary occlusion in surgery involv-
ing the aortic root. Surgical re-exploration and/or a new aortic
coronary graft may be required to solve this condition.
The diagnosis of hypovolemia and the determination of the
right amount of blood products and fluids to be infused should
be done in conjunction with TEE and hemodynamic data (ie,
central venous pressure [CVP] and wedge pressure).4,17 Dur-
ing CPB separation, it is crucial to avoid overdistension of the
RV and careful fluid expansion is required. However, complex
separation from CPB still occurs in about 10% to 45% of
patients even after preload optimization.10 TEE is the corner-
stone of diagnosis for complex CPB separation causes after
fluid status has been corrected. Figure 1 summarizes the etiolo-
gies of a complex separation from CPB in normovolemic con-
ditions and in absence of structural or dynamic abnormalities.
As a practical rule, if the LV shows a low CO output with low
filling pressures, fluid administration is recommended and the
residual blood present in the venous reservoir can be used.17
Contrarily, low CO with elevated CVP and wedge pressure
usually occurs in the event of heart failure and requires ino-
tropes. The hemodynamic data are usually integrated with
those of the TEE along with the direct inspection of the RV.
Vasoplegic Syndrome
Vasoplegic syndrome is defined by the following criteria:
hypotension (mean arterial pressure <50 mmHg or systolic
blood pressure <85 mmHg), low systemic vascular resistance
(<600-800 dynes s cm5, or systemic vascular resistances
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4 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114

Fig. 1. Assessment and management of difficult cardiopulmonary bypass separation.

5
indices <1800 dyne s cm m2), normal or high systemic
flows (cardiac index >2.5 L min m2), normal or reduced cen-
tral filling pressures (CVP < 10 mmHg and pulmonary wedge
pressure <10 mmHg), and by an increased need for vasopres-
sors (0.2-0.5 mg/kg/min of norepinephrine with normal intra-
vascular volume).23 In this case, TEE examination usually
reveals good contractility with hyperkinetic LV.
As reported by Liu et al.,23 the incidence of vasoplegic syn-
drome in cardiac surgery with CPB is around 9%. Vasoplegic
syndrome mortality typically ranges from 5% to 15% but may
be as high as 29% when lasting >48 hours.24,25
Under the pathophysiologic point of view, vasoplegia hypo- Fig. 2. Causes and treatment modalities for perioperative vasoplegia.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; CCB, cal-
tension is secondary to a deficit of vascular smooth muscle cell
cium channel blockers; CPB, cardiopulmonary bypass; RASS, renin-angioten-
contraction. In fact, the hyperpolarization of the plasmatic sin-aldosterone system; SIRS, systemic inflammatory response syndrome.
membrane uncouples the activated voltage-dependent channel
from the influx of calcium in the cytoplasm, preventing the
vasoconstriction even with high doses of catecholamines. In epinephrine, steroids, and diphenhydramine.27 This relatively
addition to nitric oxide, natriuretic peptide, and adenosine, high transfusion trigger, although controversial,28,29 is supported
activating the adenosine triphosphate sensitive potassium by the observation that anemia and hemodilution are trigger fac-
channel antagonizes smooth muscle cells contraction which tors for vasoplegia.30 A next step may include the administration
further worsens the hypotension.36 In cardiac surgery, CPB of methylene blue. However, its usage depends on the presence
triggers a massive inflammatory response with nitric oxide or absence of risk factors for the development of serotonergic
production and vasopressin deficiency plays a pivotal role in syndrome (pre-operative use of serotonin norepinephrine re-
the development of vasoplegia26 (Fig. 2). uptake inhibitors, selective serotonin re-uptake inhibitors, clomip-
Systemic vasodilation and reduced mean arterial pressure are ramine) or glucose 6-phosphate dehydrogenase deficiency.31 If
common after CPB owing to the re-establishment of normother- the risk of serotonin syndrome is high, 5 to 10 g intravenous of
mia and to hemodilution. Under most circumstances, this prob- hydroxocobalamin is indicated and 10 to 40 ng/Kg/min of angio-
lem is easily treated using a vasoactive drug (eg, norepinephrine, tensin II is a valid alternative (if the risk of thrombosis or reactive
phenylephrine, or vasopressin). However, when vasoplegia is airway disease is low). When the risk for the development of
refractory to these medications, treatment consists of transfusing serotonergic syndrome is low, a slow bolus of 2 mg/kg of methy-
with a target Hb level of at least 9 g/dL and administrating lene blue followed by a continuous infusion of 0.25 mg/kg/h for
 ARTICLE IN PRESS
F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
6 hours may treat vasoplegia. A rescue therapy consists in the
administration of Vitamin C (1.5 g every 6 hours) and thiamine
(especially in thiamine depleted patients). In fact, Vitamin C is
involved in the synthesis of catecholamines and as shown by
Wieruszewski et al.,32 it may spare vasopressors. Because terli-
pressin has a longer half-life (5-6 hours) when compared with
vasopressin (6 minutes) it could play a role in the management of
refractory vasoplegia if administered either as continuous perfu-
sion (1.3 mg/kg/min) or bolus (1 mg).33 However, the persistent
CO decrease owing to prolonged increase of the systemic vascular
resistances and the reduction of platelet count limit its used in this
setting.34
Figure 3
Right Ventricular Failure
Severe RV failure post-CPB is associated with high mortal-
ity rates up to 86%.35 The contractility of the RV may be
affected by poor myocardial inotropism (secondary to pre-
operative coronary artery disease, post-CPB myocardial stun-
ning, poor myocardial protection, and arrhythmias) or by myo-
cardial hypoperfusion (secondary to air embolism or
thromboembolism in the right coronary artery, kinking of the
venous graft after CABG surgery, low aorta-coronary pressure
gradient secondary to left ventricular dysfunction).36
After CPB separation, acute RV dysfunction is usually asso-
ciated with high CVP in the context of an enlarged RV with
depressed contractility. A tricuspid annular plane systolic
excursion below 16 mm and/or an S’ wave at the Tissue Dopp-
ler index below 10 cm/sec are TEE characteristics of right ven-
tricular failure. A right mid-cavity diameter greater than
42 mm and a longitudinal diameter greater than 92 mm are
signs of right ventricular enlargement. Right fractional area
change assessed in midesophageal 4 chambers view is a time
effective and easy method to evaluate the RV during CPB sep-
aration. A right fractional area change below 30% or a
decrease of 20% compared with the baseline are suggestive of
RV dysfunction. However, the right ventricular geometry is
complex and therefore the assessment of the RV function in
clinical practice often remains qualitative.37 Usually, a TEE
with a D-shaped LV on trans-gastric short axis view is also
suggestive of RV volume overload and failure. The need for
reducing RV volume by sequestering volume into the reservoir
while the venous cannula is in place, avoidance of further or
overzealous transfusion from the reservoir through aortic can-
nula are reasonable strategies in the face of a dilated, poorly
functioning RV. The use of diuretics may improve a failing,
dilated RV post-decannulation or in perioperative period.
Therapeutic interventions in RV dysfunction aim to opti-
mize the preload, reduce the afterload, and improve the con-
tractility.38 The RV is particularly sensible to increments in
pulmonary vascular resistance. As reported in the supplement
(Supplemental Table 1), when CPB separation is challenging
because of RV failure, there is a general agreement regarding
what should be the first line of therapy and simple measures
such as gas exchange and preload optimization should be
applied before moving toward more aggressive treatments.
5
With respect to the next steps, the strategies are largely heter-
ogenous owing to the lack of convincing data and systematic
trials on the effect of inotropes and vasopressors and MCS on
clinically relevant outcomes in the setting of acute right heart
failure. Generally speaking, the treatment of RV dysfunction
is functionally linked to the occurrence of pulmonary hyper-
tension. In the absence of pulmonary hypertension, the vast
majority of centers use dobutamine or epinephrine (with or
without norepinephrine according to blood pressure values). In
few hospitals, nitroglycerine, dopamine, and vasopressin are
considered as second-line options. If RV failure is associated
with pulmonary hypertension, inodilators and/or inhaled nitric
oxide are widely applied on top of catecholamines.
For moderate RV dysfunction, defined as an RV area change
between 17% and 30%, dobutamine is likely the drug of
choice.39 Epinephrine, however, is the first line therapy in case
of severe RV failure, with hypotension and/or associated left
ventricular failure.39 If there is high pulmonary vascular resis-
tance, a selective phosphodiesterase III inhibitor such as milri-
none or enoximone may be considered. Notably, in a recent
retrospective experience, Nielsen et al. reported a higher risk
of death at 30-days and 1 year when intraoperative milrinone
was used compared with dobutamine.40 There are only 2 ran-
domized controlled trials (RCTs) comparing dobutamine and
milrinone as single inotropes for the management of low CO
syndrome after CPB separation. Feneck et al.40 reported that
milrinone and dobutamine were equally effective in the treat-
ment of low CO syndrome and pulmonary hypertension when
started within 2 hours from CPB separation. In particular,
dobutamine was associated with atrial fibrillation (AF) and
hypertension, whereas milrinone was associated with brady-
cardia. Similarly, a substantial equivalence between dobut-
amine and milrinone in terms of hemodynamic parameters
was reported by Carmona et al.41 and recently confirmed by a
network metanalysis.42
Unfortunately, despite a large use of these agents during
CPB separation, the scientific evidence on which drug is more
effective is substantially lacking. In fact, to the best of the
authors’ knowledge there are no randomized trials focusing on
clinically relevant endpoints. Thus, it is not unexpected, as
reported by Nielsen et al.,43 that the perioperative choice of
inotropic support remains strongly related to the cardiac anes-
thesiologists’ attitude and to hospitals’ internal protocols.43 In
addition, Belletti et al.44 found that inotropes and vasopressors
in cardiac surgery are not detrimental per se, although an accu-
rate evaluation of risks and benefits is always required.44
Enoximone is not available in North America. However,
enoximone and milrinone share a similar mechanism of action
(phosphodiesterase III inhibitors) and act on the cardiovascular
system in a similar fashion. Enoximone has a half-life 10 times
longer than milrinone, with an active metabolite which further
prolongs the hemodynamic effects.35 Both were studied in
patients with heart failure and cardiac surgery. Catecholamines
show a greater increase in heart rate and mean arterial pres-
sure, whereas phosphodiesterase III inhibitors are more effi-
cient in reducing wedge pressure and increasing CO. The
major drawback to the use of phosphodiesterase IIII inhibitors
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6 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114

Fig. 3. Pathophysiology of vasoplegic shock related to cardiac surgery.

Abbreviations: A2A ADP, A2A adenosine receptor; AVP, vasopressin; BP, blood pressure; Ca+2, ionized calcium; cG NE, norepinephrine; CO, cardiac output; GTP,
guanosine triphosphate; Ip3, inositol 1.4,5-trisphosphate; KATP, potassium adenosine triphosphate channels; LV, left ventricle; MP, cyclic guanosine monophosphate; NO,
nitric oxide; PHE, phenylephrine; SIRS, systemic inflammatory response syndrome; SVR, systemic vascular resistance; V1, V1 receptor for vasopressor.
 ARTICLE IN PRESS
F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
is their vasodilator effects which may lead to hypotension, par-
ticularly in hypovolemic patients and/or those with high sys-
temic resistances. This side effect is important because
hypotension owing to low diastolic and coronary perfusion
pressure, rather than low CO, is associated with 30-day mortal-
ity in multivariate analysis (p = 0.005).45
In a randomized multi-center double-blind placebo-con-
trolled phase III study, Denault et al.46 demonstrated that in
high-risk cardiac surgery patients with pulmonary hyperten-
sion, the prophylactic use of inhaled milrinone (5 mg) was
associated with a better hemodynamic profile but had no effect
on the rate of complex separation from CPB, RV failure, and
mortality. Gebhard et al.47 reported that milrinone adminis-
tered in the tracheal tube during challenging CPB separation
secondary to severe RV dysfunction improves RV function,
decreases RV size, and increases end expiratory carbon diox-
ide. Notably, the same authors but in a retrospective analysis
observed that the intratracheal administration of 5 mg of milri-
none treated hemodynamic instability in 62% of patients,
reducing CVP and improving the RV performance assessed by
TEE and direct inspection.48 Nebulized and intratracheal milri-
none were not associated with hypotension (which is common
with the intravenous administration) and were equally effec-
tive in improving the RV performance. In addition, intratra-
cheal milrinone administration was much faster, cheaper, and
simpler than the inhaled route, making it particularly attractive
in the setting of a challenging CPB separation. In fact, nebu-
lized milrinone requires specific equipment and has an onset
time of 20 minutes.46 The role of levosimendan in the context
of RV dysfunction is poorly investigated. However, in light of
the recent evidences which questioned its efficacy in the peri-
operative setting,4951 the authors suggest to reserve the
administration of levosimendan to patients several hours
before surgery for optimal resuts.
Moderate Pulmonary Hypertension and Normal RV
Function
If there is moderate pulmonary hypertension (eg, systolic
pulmonary pressure between 35 and 60 mmHg)39 in the con-
text of normal right ventricular function and low preload
(defined as a CVP <10 mmHg and/or an inferior vena cava
diameter on TEE of less than 20 mm), a gradual filling of the
heart using the venous reservoir while constantly monitoring
RV shape and function, as well as hemodynamic parameters,
should be performed to assess if CO increases.
If the heart is already working on the plateau of the Frank-
Starling curve, the administration of fluids is detrimental (eg,
in patients who are not fluid-responsive) and may increase the
end diastolic pressure without further improvement in stroke
volume. In this context, further increments in end diastolic
pressure can lead to myocardial ischemia, a shift of the inter-
ventricular septum toward the LV (ventricular interdepen-
dence) and, eventually, to biventricular failure.52
CVP represents the relationship between venous return and
cardiac performance rather than preload.53 In spite of being set
aside by many authors in the last few years, CVP remains a
7
useful parameter in the daily clinical practice especially when
integrated with data on CO, contractility, and preload assessed
by the TEE. In fact, CVP values may depend on cardiac func-
tion, volemia, or venous resistance. With this approach, CVP
is crucial in making the diagnosis of heart failure. For exam-
ple, low CO with high CVP is suggestive of poor contractility,
low heart rate, or afterload augmentation. Low CO with low
CVP may be related to a decrease in blood volume or venous
dilation. A low CVP with high CO is a good marker of
improvement of the cardiac function. High CVP and high CO
may be secondary to increased venous return.
It is well known that CVP is a poor predictor of fluid respon-
siveness. Nevertheless, when associated with the assessment of
the CO by TEE or Swan Ganz catheter, CVP is helpful in the
interpretation of fluid responsiveness. Administration of fluids,
increasing the bulk of blood volume, leads to an increased
venous return, right heart preload and CO if the patient is on
the ascending part of the Frank-Starling curve (fluid
responder). On the contrary, if the CO does not change (non-
responders), the direction of CVP variation is useful in order
to know whether the fluid administered was insufficient or if
the heart is failing. In fact, when the CVP does not change
after fluid administration it may mean that an insufficient vol-
ume of fluids has been administered. By contrast, when the
CVP rises, the patient is on the flat part of the Frank-Starling
curve. Generally, extreme CVP values may guide the adminis-
tration of fluids better than intermediate values.54 In a recent
meta-analysis, Eskesen et al.55 observed that a CVP less than
8 mmHg was associated to a fluid responsiveness in two thirds
of the patients whereas a CVP above 12 mmHg in one third of
cases. Biasis et al.56 reported that the increase in stroke volume
after a fluid challenge was unlikely when the CVP was above
15 mmHg and was frequent when the CVP value was below
6 mmHg. Given the above considerations, CVP is not reliable
as a standalone parameter. However, extreme values when
integrated with measures of flow such as the ones made by
TEE assessment can be useful in guiding therapy.
High CVP (above 15 mmHg) should be treated with an
aggressive diuretic therapy39 if there is clinical or TEE evi-
dence of volume overload with RV or LV failure.
Severe Pulmonary Hypertension
Generally speaking, the RV tolerates chronic pulmonary
hypertension better than acute changes in afterload.39 The
impact of chronic PAH on outcome is related to the involve-
ment of the RV. In fact, a longstanding pulmonary hyperten-
sion may lead to RV dilatation and dysfunction, which in turn
decreases LV CO and coronary perfusion when the interven-
tricular septum shifts toward the LV.52 In addition, because
the RV coronary supply occurs during the entire cardiac cycle,
chronic pulmonary hypertension leading to high end systolic
and diastolic RV pressure puts the RV at high risk of ischemia
during CPB separation. Patients with chronic pulmonary
hypertension and RV failure show a high sympathetic tone and
concomitant downregulation of the catecholaminergic recep-
tors, deep anesthesia, by blunting the sympathetic tone, may
 ARTICLE IN PRESS
8 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
therefore further contribute to hypotension worsening even more
the RV function.38 An acute increase in pulmonary vascular resis-
tance (eg, causing an increase of mean pulmonary pressure above
40 mmHg) cannot be tolerated by the RV for a long period of
time and may lead to RV failure with a proportional reduction in
CO. In case of severe pulmonary hypertension with preserved
right ventricular function, a pharmacologic approach should lead
to a reduction in pulmonary vascular resistance without affecting
the systemic vascular resistance.
The first agents used to treat this condition are the inhala-
tional agents such as nitric oxide and iloprost (synthetic prosta-
glandin inhibitor 2 analog) even though a beneficial effect on
clinically relevant outcomes has not been demonstrated yet.52
Nitric oxide is a rapidly-acting selective pulmonary vasodila-
tor that, after diffusion into the smooth muscle cells, stimulates
cyclic guanosine monophosphate release. The side effects of
nitric oxide include the following: inhibition of platelet aggre-
gation, methemoglobinemia, and rebound pulmonary vasocon-
striction after abrupt discontinuation.
Recently, in a meta-analysis of 18 RCTs conducted in cardiac
surgery by Sardo et al.,57 it was demonstrated that inhaled nitric
oxide has a clinically negligible effect on the length of mechani-
cal ventilation and intensive care unit stay when compared with
any other vasodilator therapy. Even in patients with acute respira-
tory distress, Gebistorf et al.58 reported that inhaled nitric oxide
was associated with a transient improvement in oxygenation with
no effect on survival. Only in infants did inhaled nitric oxide lead
to a better composite outcome reducing the incidence of death
and the need for ECMO.57 However, it is important to recognize
that the vast majority of the studies on inhaled nitric oxide are
small and single-centered, putting them at high risk of bias.17
Moreover, clinical outcomes, such as mortality or duration of
hospitalization in cardiac surgery patients, depend on several fac-
tors including comorbidities, quality of surgical repair, length of
CPB, and intraoperative and postoperative supportive care. As a
matter of fact, inhaled nitric oxide is largely used in daily clinical
practice in postcardiotomy RV dysfunction with increased pul-
monary vascular resistance refractory to standard inotropic sup-
port.59 Owing to the risk of rebound pulmonary vasoconstriction
during the weaning from inhaled nitric oxide, sildenafil (a phos-
phodiesterase 5 inhibitor) therapy should be initiated.60
Iloprost is a stable analogous of prostacyclin. It stimulates
the production of cyclic adenosine monophosphate in the vas-
cular smooth muscle cells, and this leads to potent muscular
relaxation. This muscular relaxation reduces the pulmonary
vascular resistance, improves the RV performance, and
increases the CO. Iloprost might have antiplatelet and antipro-
liferative effects and its pulmonary vasodilatory effect is syn-
ergistic to inhaled nitric oxide. The use of intravenous
prostaglandin E1 and prostacyclin is limited by systemic hypo-
tension and subsequent ischemia that can worsen the RV per-
formance.61 To overcome these drawbacks, the pulmonary
route is usually preferred. This drug is particularly attractive
because it is cheaper, easier to administer, and has no toxic
metabolites when compared with inhaled nitric oxide. As
inhaled nitric oxide, prostaglandin E1 is a potent vasodilator
with selectivity toward pulmonary circulation and with a short
half-life that is degraded spontaneously at neutral pH. As
opposed to inhaled nitric oxide, it acts through the cyclic aden-
osine monophosphate instead of the cyclic guanosine mono-
phosphate pathway. Hanche et al.62 found that epoprostenol
was safe and more effective than a placebo in decreasing pul-
monary pressure in 60 patients with pulmonary hypertension
that were undergoing cardiac surgery. In comparison with
intravenous vasodilators, Fattouch et al.63 reported a cardiac
population with pulmonary hypertension in which prostaglan-
din E1 and inhaled nitric oxide equally improved the RV func-
tion by decreasing the pulmonary artery resistance. However,
both studies were single-center and underpowered to draw
clinically relevant conclusions. As a matter of fact, in a meta-
analysis of RCTs, Elmi-Sarabi et al.64 observed that the pre-
scription of aerosolized pulmonary vasodilators (milrinone,
iloprost, nitric oxide and prostaglandin E1) ameliorated the
performance of the RV more than placebo or intravenous vaso-
dilators (nitroglycerine or nitroprusside). No significant differ-
ences on hemodynamic parameters were observed.
Left Ventricular Failure
After CPB and ischemic cardioplegic arrest, the systolic per-
formance of the left heart may be reduced owing to suboptimal
cardiac protection and prolonged aortic clamping time.65 Ven-
tricular function is a major determinant of CO. Global or
regional dysfunction may also develop after CPB separation.17
Although several studies with limited sample size postulated
that halogenated anesthetics might provide additional myocar-
dial protection through an ischemic preconditioning mecha-
nism,66 Landoni et al.51 reported that in the largest RCT
comparing volatile agents versus total intravenous anesthesia
in patients undergoing on-pump CABG, there was no differ-
ence in 1-year overall mortality.
LV hemodynamic decompensation after CPB separation has to
be rapidly ruled out. Again, TEE allows determining whether the
hypotension is secondary to a depressed myocardial contractility,
to a decreased preload, or to an increased afterload.67
Preload
The qualitative estimation of the left ventricular end-dia-
stolic area in the transgastric midpapillary short axis view can
distinguish whether hypotension depends on cavity oblitera-
tion (“kissing” of the papillary muscles) or marked ventricular
dilatation (usually end-diastolic diameter for male 6.9 cm
indexed 3.7 cm/m2, female 6.2 cm indexed 3.8 cm/m2).68
Because the dynamic indices (pulse pressure variation, stroke
volume variation, and systolic pressure variation) are reliable pre-
dictors of fluid responsiveness under strict conditions including
closed thorax, absence of arrhythmias, and a tidal volume of 7 to
8 mL/kg, these parameters have a marginal role in the manage-
ment of patients with challenging CPB separation.69
A low preload may lead to systolic anterior motion (SAM)
of the anterior leaflet of the mitral valve. This is a unique con-
dition of hemodynamic instability that may mimic left ventric-
ular dysfunction when TEE is not available. SAM occurs in
 ARTICLE IN PRESS
F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
4% to 8% of all patients after mitral valve repair. SAM may be
responsible for complex CPB separation and should be treated
with: intravascular volume expansion; decrease of the heart
rate to 60 to 70 beats per minute (eg, reducing the rate of the
pacemaker if the heart is stimulated); stopping epinephrine
and /or switching to Beta-blockers; increase the afterload with
a1 agonists. In a few selected cases, mitral valve replacement
may be necessary.70 In the authors’ experience,67 92% of
SAM after mitral valve repair can be solved with 2-step con-
servative management which consists in intravascular volume
expansion and discontinuation of inotropic drugs (first step)
and afterload augmentation through manual compression of
the ascending aorta while administering esmolol (1 mg/kg)
(second step). With this approach, fewer than 10% of patients
require surgical revision for persistent SAM after mitral valve
repair. Similarly, Loulmet et al.70 who analyzed more than
1,900 patients undergoing mitral valve repair, observed that
the mainstay of SAM treatment is pharmacologic and based on
4 pillars: volume expansion, suspension of the inotropic sup-
port, any vasopressors, and b-blockers. Interestingly, this
strategy allowed successful conservative management of all
patients in whom SAM occurred after mitral valve repair.71
Contractility
After pre-load optimization of the LV, the next step is the
assessment of the contractility and of the wall motion of the
LV (eg, to rule out a depressed contractility and new regional
wall motion abnormalities). Regional dysfunction may be
present preoperatively, develop intraoperatively, or immedi-
ately after CPB separation.
As part of the San Raffaele protocol in patients with preop-
erative left ventricular dysfunction (ejection fraction<30%),
the authors started levosimendan preoperatively to enhance
the likelihood of a successful CPB separation at the first
attempt,72 and they positioned an IABP introducer to promptly
start MCS without the risks of a femoral puncture under full
anticoagulation.
In absence of evidence-based guidelines on the management
of patients with challenging CPB separation, and as previously
reported,43,71 the administration of inotropes varies substan-
tially from one hospital to another. The survey of 17 centers in
5 continents (Supplemental Table 2) that the authors per-
formed in also corroborates the above information.
Myocardial contractility is the most important determinant
of successful CPB separation. Mean arterial pressure, filling
pressure, and CO are the key parameters to consider at this
stage. Epinephrine is preferred when CO is low and the filling
pressure is high or normal. By contrast, if CO is insufficient
and systemic vascular resistance is elevated, inodilators can
increase myocardial contraction.72 If systemic resistance and
mean arterial pressure are decreased, norepinephrine can be
added. It is important to highlight that the use of inotropes is
independently associated with hospital mortality.73 This calls
for a shift in practice, from the CPB separation being accom-
plished with high doses of inotropes and vasopressors to an
approach in which earlier institution of MCS support is
9
preferred as a bridge to recovery.74 For example, patients with
post-cardiotomic cardiogenic shock refractory to inotropic and
IABP support Khorsandi et al.75 and showed that a prompt
VA-ECMO institution provides a survival benefit and a good
intermediate and long-term outcome.
Factors like interventricular dyssynchrony, paradoxical sep-
tal motion, and bundle-branch block are often observed during
CPB separation and may impair LV contractility and CO opti-
mization.76 In patients with severe LV dyssynchrony, the use
of biventricular pacing in the early postoperative period seems
to decrease the amount of inotropes and vasopressors required
after CPB separation while optimizing cardiac contractility
and biventricular synchronization.77 Gielegens et al.78 showed
that in patients with an left ventricular ejection fraction lower
than 35% and signs of dyssynchrony with or without pro-
longed QRS duration undergoing CABG, a biventricular pac-
ing is associated with significant higher dP/dtmax values and
mean arterial pressure when compared with right ventricular
pacing. As the use of biventricular pacing is easy and cost-
effective, it may have a role in hemodynamic optimization
during a complex separation from CPB. However, future stud-
ies have to assess the impact of this effect on arrhythmogene-
sis, morbidity, and mortality.
Evidence of myocardial ischemia at CPB separation defined
by ST segment changes and new wall motion abnormalities
has to be taken into account. When hemodynamic instability
persists, going back on CPB may be necessary. It is not
unusual to observe ST segments being significantly altered
with low mean perfusion pressure and to return to isoelectric-
ity with adequate mean arterial pressure. However, an ST seg-
ment elevation (eg, transmural ischemia) with corresponding
regional wall motion abnormalities justifies myocardial revas-
cularization. A low dose of nitroglycerine may be helpful if
the ST segment is depressed (eg, subendocardial ischemia)
and the mean arterial pressure is above 70 mmHg. In both sce-
narios the insertion of IABP must be considered.79
At the authors’ institution, strong indications for IABP
implantation include the following: pulmonary artery occlu-
sion pressure above 18 mmHg, cardiac index below 2 L min/
m2, and persistent systolic arterial pressure below 90 mmHg
despite VIS above 30.80,81 Because the amount of inotropic
support rather than the kind of drug administered is crucial, it
is useful to have a tool to compare the degree of pharmaco-
logic support among patients. The first version of the inotropic
score included dopamine, epinephrine, and dobutamine. It was
later expanded to include norepinephrine, vasopressin, and
milrinone.82,83 More recently, the VIS calculation was com-
pleted by the inclusion of levosimendan and phosphodiesterase
III inhibitors.84,85 The VIS, if integrated in a decision-making
algorithm, is a reliable and validated tool in selecting patients
with complex CPB separation who deserve a more aggressive
pharmacologic treatment and MCSs.
Out of the 17 hospitals surveyed, 13 use the IABP as second
line therapy in approaching the LV dysfunction refractory to
inotropic support (Supplemental Table 2). Interestingly, all but
one of the 17 hospitals used left ventricular assist device
(LVAD) or a VA-ECMO in the event of persistent cardiogenic
 ARTICLE IN PRESS
10 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
shock. Low CO, low systemic blood pressure, tachycardia, and
signs of poor peripheral perfusion are the main determinants of
stepwise interventions. Generally speaking, in patients with car-
diogenic shock after CPB separation, a MCS should be initiated
as soon as possible if fluid resuscitation and pharmacologic sup-
port fail to show any benefit. In fact, a prompt institution of MCS
support may mitigate the detrimental effects of systemic hypoper-
fusion, ischemia, and low CO syndrome.86
In patients suffering from low CO syndrome despite IABP
support, LVAD or ECMO are needed to achieve circulatory
recovery. The proper timing as to when to initiate MCS is the
key in improving the patients’ outcome. There should be a bal-
ance between giving the patients the opportunity to respond to
the ongoing extensive medical therapy and to the IABP sup-
port (to avoid the use of a more invasive device) and waiting
so long that the detrimental effects of high dose pharmacologic
therapy result in multiorgan failure.87,88
The choice of initiating the MCS depends on the presence of
right, left, or biventricular failure, the potential for myocardial
recovery, the lung-tissue gas exchange capability, and the
presence of peripheral vascular disease.85,86 After the insertion
of MCS, the goal is to achieve a mean arterial pressure >70
mmHg, a urinary output >1 mL/kg/h, and a SvO2 equal or
greater than 65%. After MCS insertion, it is critical to continue
to support RV function with inotropes and to optimize the pre-
load and the heart rate of the patient. Although an Impella is
seldom used for MCS support in patients failing the separation
from CPB, in the near future it may be considered for the treat-
ment of cardiogenic shock in cardiac surgery. In fact, it pro-
vides a greater hemodynamic support when compared with
IABP because it guarantees a stable CO in case of arrhythmias
and unloads the LV. By having a continuous flow generated by
an axial pump, it increases the mean arterial pressure and the
CO, and it reduces the myocardial oxygen consumption and
the LV end diastolic pressure.89 However, in patients with
myocardial infarction complicated by cardiogenic shock, the
Impella was not superior to the IABP in terms of in-hospital
and 2-year mortality despite providing a better CO.90 Interest-
ingly, in a retrospective propensity score matched study by
Schrage et al.,91 no difference in all-causes 30-day mortality
between the IABP and the Impella in patients with acute myo-
cardial infarction complicated by cardiogenic shock undergo-
ing early revascularization were observed. That being said,
bleeding and vascular complications were more common in
the Impella group. These findings deserve further considerations.
Of note, Scharge et al.91 conducted their work in the setting of
acute myocardial infarction. However, postcardiotomy cardio-
genic shock has a different pathophysiology than cardiogenic
shock secondary to acute myocardial infarction. Also in their
study, one third of the patients received an Impella 2.5 rather
than an Impella CP, while the latter could be more useful in the
setting of cardiac surgery to provide almost full support during
complex separation from CPB. The study was largely underpow-
ered to get any conclusive results on mortality. Finally, the 2
groups of patients were also unbalanced in terms of three-vessel
coronary disease, thrombolysis in the previous 24 hours, glomer-
ular filtration rate, and blood pressure levels.
Prosthetic aortic valve, RV failure, and peripheral vascular
disease are absolute contraindications to Impella implantation
after CPB. Compared with ECMO, it needs a much lesser
degree of anticoagulation and does not unload the RV. Until
now, strong indications for Impella include bridging to LVAD
and heart transplantation or bridging to recovery in patients
with advanced heart failure or cardiogenic shock.92 Its ease of
implantation and removal and its effectiveness in supporting
the LV render this option very attractive.86
In case of cardiogenic shock with or without respiratory fail-
ure, ECMO is considered the therapy of choice particularly in
patients with RV or biventricular failure.93 Postcardiotomy
cardiogenic shock potentially requiring VA-ECMO has an inci-
dence ranging between 0.5% and 1.5%.50 Notably, in a meta-
analysis of 24 retrospective cohort studies by Khorsandi et al.,75
patients with VA-ECMO and postcardiotomy cardiogenic shock
refractory to inotropic support and IABP showed a pooled sur-
vival-to-hospital discharge of 30.8%.94 Owing to high morbidity
and mortality, the decision to use VA-ECMO should consider
each individual risk profile. Although the risk factors influencing
early- or long-term outcome after VA-ECMO are not fully under-
stood, Rastan et al.95 found that age (>70 years), diabetes, renal
failure, obesity, and a logist EuroSCORE >20% are risk factors
of in-hospital mortality. VA-ECMO allows an acceptable inter-
mediate- and long-term outcome in an otherwise fatal clinical
state at the expense of prolonged length of stay and considerable
resource expenses. Central ECMO is preferred when a profound
cardiogenic shock occurs. Otherwise, ECMO with percutaneous
cannulation of the femoral vessels provides a satisfactory heart
support. Table 2 shows the advantages, disadvantages, and other
characteristics of the most commonly used MCS.
Afterload
Increased afterload has detrimental effects during the decannu-
lation of the ascending aorta and on bleeding and suture dehis-
cence. TEE detection of left ventricular systolic heart failure is
characterized by a reduction in systolic function and an increase
in diastolic dimension. An increase in afterload may lead to low
CO syndrome owing to a sympathoadrenergic reaction or to the
release of various vasoactive mediators from the nonphysiologic
perfusion that occurs during CPB.24 Therefore, the aim of the
pharmacologic therapy should be to support the heart and to help
in reducing the physiological load encountered after a cardiac
arrest.96 The management of patients with high systemic vascular
resistance includes short-acting vasodilatory drugs (eg, nitroglyc-
erine or nitroprussiate). In fact, a reduction in afterload may
improve the systemic blood flow. Clevidipine is a dihydropyri-
dine calcium channel blocker with a short half-life and a quick
onset and offset that reduces the blood pressure through a direct
arterial vasodilation.97 In the Evaluation of Clevidipine in the
Perioperative Treatment of Hypertension Assessing Safety
Events (ECLIPSE trials), Aronson et al.98 observed that there
was no difference in the rate of stroke, myocardial infarction, and
renal failure when clevidipine was compared with nicardipine,
sodium nitroprussiate, and nitroglycerine. In particular, clevidi-
pine was superior to sodium nitroprussiate in the achievement
 ARTICLE IN PRESS
F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114 11

Table 2
Principal characteristics, pro and cons of most used mechanical support devices.

IABP Impella 2.5 CO/5.0 VA-ECMO

Pump mechanism Pulsatile Continuous axial flow Continuous centrifugal flow

Augmentation of cardiac output 0.3-0.6 L/min
Contraindications PAD, AAA, moderate-severe AI,
severe aortic disease, aortic
dissection
Advantages Easily available, less vascular
complication, pulsatile flow, not
anticoagulation dependent, bedside
insertion, and removal
Disadvantages Minimal CO support, stable rhythm
needed for synchronization,
immobilization of patient
Complications limb ischemia, bleeding, aortic
dissection, thrombocytopenia,
hemolysis
Duration of therapy Days to weeks
2.5-5 L/min
LV thrombus, severe aortic stenosis,
prosthetic aortic valve, ventricular
septal defect, severe RV failure,
PAD, aortic dissection
Increase CO more than IABP, stable
rhythm not needed for function,
direct ventricular decompression
Vascular complications, continuous
flow, surgical cut down needed for
5.0, significant cost, obligatory
anticoagulation
Ventricular arrhythmia, limb
ischemia, bleeding, hemolysis, LV
perforation.
7d
4-10 L/min
PAD, severe AI, futility, inability to
tolerate anticoagulation, aortic
dissection
Longer duration of support, stable
rhythm not needed for function,
single device for biventricular
failure, relatively low cost
Vascular complications, continuous
flow, higher need of
anticoagulation, need for
perfusionist support
Thrombosis, embolism, upper body
hypoperfusion, bleeding
Days to weeks

Abbreviations: AAA, abdominal aortic aneurism; AI, aortic insufficiency; AV, aortic valve; CO, cardiac output; LV, left ventricular; PAD, peripheral artery
disease

and maintenance of the target blood pressure with less over-

Table 3
shoot.110 On the contrary, nicardipine owing to a longer half-life Pragmatic Evaluation of Diastolic Dysfunction During Challenging Cardiopul-
compared with clivedipine is not routinely used in the setting of monary Bypass Separation Adopted at the San Raffaele Scientific Institute.
cardiac surgery.99,100
Parameter Impaired Relaxation Pseudonormal Restrictive Filling
Long-acting vasodilatory drugs (eg, clonidine or angioten-
sin-converting enzyme [ACE]-inhibitors) during challenging E’ <10 cm/s <10 cm/s <10 cm/s
CPB separation scenarios are not used owing to the possibility E/A 0.8 0.8-1.5 2
of sudden hemodynamic changes. DT >200 ms 160-200 ms <160 ms
E/E’ 8 9-12 13
Ar-A <0 ms 30 ms 30 ms
Left Ventricular Diastolic Dysfunction Vals DE/A <0.5 0.5 0.5

Abbreviations: A, transmitral late filling peak velocity; Ar-A, duration of the

Separation from CPB may be challenged by diastolic dys-
function. The hallmark of diastolic dysfunction is the inability
of the ventricle to accept an adequate volume of blood, despite
a normal preload.101 As a result, myocardial contractility is
reduced but maintains a normal or almost normal systolic
function. Diastolic dysfunction may occur with or without a
concomitant systolic dysfunction. Although commonly
observed in cardiac surgery, diastolic dysfunction alone rarely
leads to failure of CPB separation. Nevertheless, in combina-
tion with factors such as supraventricular tachyarrhythmia or
reduced coronary perfusion or hypertension, diastolic dysfunc-
tion may contribute to the development or to the worsening of
postcardiotomy cardiogenic shock. In light of this, diastolic
dysfunction can be considered a marker of pending myocardial
ischemia.50 In the operating room, TEE allows both monitor-
ing the diastolic function and assessing the degree of diastolic
dysfunction.102 Despite recent guidelines recommending sev-
eral parameters to assess the LV diastolic dysfunction, not all
of them are easy to acquire in the dynamic setting of the oper-
ating room.103 Thus, in Table 3, the authors summarized the
most meaningful criteria of diastolic dysfunction that can be
assessed during a challenging separation from CPB that has
been adopted at the San Raffaele Scientific Institute.
pulmonary flow atrial reversal flow minus duration of the transmitral A wave;
DT, deceleration time; E’, peak tissue Doppler velocity in the early diastole; E,
transmitral early filling peak velocity; Vals, Valsalva maneuver
Diastolic filling abnormalities may become evident after volume
overload, tachycardia, ischemia, acute systemic hypertension, AF,
conduction abnormalities, or electrolyte abnormalities, all of which
reflect a reduced cardiac reserve.104 The diastolic dysfunction is a
heterogenous disease that requires tailored management. Patients
with impaired relaxation need a longer diastolic time (eg, relaxa-
tion time) and filling time so much that the heart rate must be con-
trolled.105 The avoidance of dissynchrony and the optimization of
the atrioventricular interval with dual chamber pacing can be use-
ful.92 Tachycardia should be managed with preload optimization,
and in the event of normal systolic function, b-blockers and cal-
cium antagonists can be used.105 AF requires a prompt cardiover-
sion and/or amiodarone infusion. Digoxin contributes to a better
ventricular filling, decreasing the heart rate when AF is chronic.
Phosphodiesterase III inhibitors and levosimendan are effective in
the treatment of diastolic dysfunction by increasing CO and
decreasing wedge pressure.106 The management of diastolic dys-
function in patients with hypertrophic cardiomyopathy (idiopathic
or secondary to aortic stenosis) is particularly challenging. In these
 ARTICLE IN PRESS
12 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2020) 114
patients, even small preload increase can result in high wedge pres-
sure, so the need of fluid expansion to maintain a sufficient stroke
volume should be balanced with the intrinsic risk of pulmonary
edema. To avoid pulmonary edema, fluid administration should be
guided by the monitoring of the wedge pressure.107 Finally, IABP
may play a role in the treatment of perioperative diastolic dysfunc-
tion by increasing coronary blood flow.106
Conclusions
The development of CPB is one of the most important advan-
ces in medicine in the 20th century. CPB separation is a progres-
sive transition from full MCS to spontaneous heart activity.84
The time taken for this process is “compressed” within the first
few minutes, and necessary interventions have to be performed
quickly to prevent myocardial damage.84 Despite the evolution of
CPB techniques and the successes to minimize complications, it
is essential that physicians respect the particularities of each
patient’s physiological and preoperative heart function. In this
context, the assessment by echocardiography plays a central role
in diagnosing and managing the patients.
A standardized approach for CPB separation that focuses on
simple hemodynamic targets under TEE assessment along
with a therapy involving vasopressors, inotropes, vasodilators,
and eventually MCS devices can potentially improve out-
comes. Large trials are urgently needed to validate suitable
algorithms for CPB separation and to identify the best cardio-
protective strategies in cardiac surgery.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Supplementary materials
Supplementary material associated with this article can be
found in the online version at doi:10.1053/j.jvca.2020.02.038.
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