Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

Contents lists available at ScienceDirect

Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article

Management of Challengin

g Cardiopulmonary Bypass

This research did no1Address reprint req

60 � 20132, Milan, It

E-mail address: d

https://doi.org/10.105

1053-0770/� 2020 El

Separation

Fabrizio Monaco, MD*, Ambra Licia Di Prima, MD*,1

,Jun Hyun Kim, MDy, Marie-Jo Plamondon, MDCMz,x,

Andrey Yavorovskiy, MDk,{, Valery Likhvantsev, MDk,**,Vladimir Lomivorotov, MDyy,*****,

Ludhmila Abrah~ao Hajjar, MD*,zz, Giovanni Landoni, MD*,xx,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

*Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, ItalyyDepartment of Anesthesiology and Pain Medicine, Inje University Ilsan Paik Hospital, Goyang, South Korea

zDepartment of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, CanadaxThe Ottawa Hospital, Ottawa, Canada

kDepartment of Anesthesiology and Intensive Care, First Moscow State Medical University, Moscow, Russia{Intensive Care Department, Moscow Regional Research and Clinical Institute, Moscow, Russia

**V. Negovsky Reanimatology Research Institute, Moscow, RussiayyDepartment of Anesthesiology and Intensive Care. Novosibirsk State University Novosibirsk, Russia

zzDepartment of Cardiopneumology, Instituto do Coracao, University of S~ao Paulo, Hospital SirioLibanes,S~ao Paulo, Brazil

xxFaculty of Medicine, Vita-Salute San Raffaele University, Milan, ItalykkCardiothoracic Anesthesiology and Intensive Care, Department of Anesthesiology and Intensive Care

Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic{{Department of Cardiac Anesthesia, King Abdullah Medical City-Holy Capital, Makkah, Saudi Arabia***Department of Anesthesia and Intensive Care, Cardiovascular Institute Dedinje, Belgrade, Serbia

yyyDepartment of Anesthesiology, Hospital de Santa Maria, Lisbon, PortugalzzzDepartment of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical

University, Xi’an, ShaanxixxxDepartment 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 ArabiayyyyCardiothoracic Intensive Care Unit and Anesthesia Department, Mohammed Bin Khalifa Cardiac Center,

Riffa, BahrainzzzzDivision of Cardiac Anesthesiology, Department of Anesthesiology and Pain Medicine, University of

Ottawa Heart Institute, School of Epidemiology and Public Health, University of OttawaxxxxDepartment of Anaesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia*****Department of Anesthesiology and Intensive Care, E. Meshalkin National Medical Research Center,

Novosibirsk, Russia

t receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

uests to Ambra Licia Di Prima, MD, Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina,

aly

iprima.ambralicia@hsr.it (A.L. Di Prima).

3/j.jvca.2020.02.038

sevier Inc. All rights reserved.

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1623

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.

� 2020 Elsevier Inc. All rights reserved.

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

Table 1

How to Calculate Vasoactive and Inotropic Scores

Vasoactive and Inotropic Score

(VIS)=

dopamine dose (mg/kg/min) +

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

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

1624 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

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

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 cm�5, or systemic vascular resistances

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

Fig. 2. Causes and treatment modalities for perioperative vasoplegia.

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; CCB, cal-

cium channel blockers; CPB, cardiopulmonary bypass; RASS, renin-angioten-

sin-aldosterone system; SIRS, systemic inflammatory response syndrome.

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1625

indices <1800 dyne s cm�5 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-

tension is secondary to a deficit of vascular smooth muscle cell

contraction. In fact, the hyperpolarization of the plasmatic

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

addition to nitric oxide, natriuretic peptide, and adenosine,

activating the adenosine triphosphate sensitive potassium

channel antagonizes smooth muscle cells contraction which

further worsens the hypotension.36 In cardiac surgery, CPB

triggers a massive inflammatory response with nitric oxide

production and vasopressin deficiency plays a pivotal role in

the development of vasoplegia26 (Fig. 2).

Systemic vasodilation and reduced mean arterial pressure are

common after CPB owing to the re-establishment of normother-

mia and to hemodilution. Under most circumstances, this prob-

lem is easily treated using a vasoactive drug (eg, norepinephrine,

phenylephrine, or vasopressin). However, when vasoplegia is

refractory to these medications, treatment consists of transfusing

with a target Hb level of at least 9 g/dL and administrating

epinephrine, steroids, and diphenhydramine.27 This relatively

high transfusion trigger, although controversial,28,29 is supported

by the observation that anemia and hemodilution are trigger fac-

tors for vasoplegia.30 A next step may include the administration

of methylene blue. However, its usage depends on the presence

or absence of risk factors for the development of serotonergic

syndrome (pre-operative use of serotonin norepinephrine re-

uptake inhibitors, selective serotonin re-uptake inhibitors, clomip-

ramine) or glucose 6-phosphate dehydrogenase deficiency.31 If

the risk of serotonin syndrome is high, 5 to 10 g intravenous of

hydroxocobalamin is indicated and 10 to 40 ng/Kg/min of angio-

tensin II is a valid alternative (if the risk of thrombosis or reactive

airway disease is low). When the risk for the development of

serotonergic syndrome is low, a slow bolus of 2 mg/kg of methy-

lene blue followed by a continuous infusion of 0.25 mg/kg/h for

1626 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

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.

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

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.

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1627

1628 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

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,49�51 the authors suggest to reserve the

administration of levosimendan to patients several hours

before surgery for optimal resuts.

Moderate Pulmonary Hypertension and Normal RVFunction

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

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

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1629

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. Hanch�e 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

1630 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

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

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

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1631

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

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 2.5-5 L/min 4-10 L/min

Contraindications PAD, AAA, moderate-severe AI,

severe aortic disease, aortic

dissection

LV thrombus, severe aortic stenosis,

prosthetic aortic valve, ventricular

septal defect, severe RV failure,

PAD, aortic dissection

PAD, severe AI, futility, inability to

tolerate anticoagulation, aortic

dissection

Advantages Easily available, less vascular

complication, pulsatile flow, not

anticoagulation dependent, bedside

insertion, and removal

Increase CO more than IABP, stable

rhythm not needed for function,

direct ventricular decompression

Longer duration of support, stable

rhythm not needed for function,

single device for biventricular

failure, relatively low cost

Disadvantages Minimal CO support, stable rhythm

needed for synchronization,

immobilization of patient

Vascular complications, continuous

flow, surgical cut down needed for

5.0, significant cost, obligatory

anticoagulation

Vascular complications, continuous

flow, higher need of

anticoagulation, need for

perfusionist support

Complications limb ischemia, bleeding, aortic

dissection, thrombocytopenia,

hemolysis

Ventricular arrhythmia, limb

ischemia, bleeding, hemolysis, LV

perforation.

Thrombosis, embolism, upper body

hypoperfusion, bleeding

Duration of therapy Days to weeks 7 d Days to weeks

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

disease

Table 3

Pragmatic Evaluation of Diastolic Dysfunction During Challenging Cardiopul-

monary Bypass Separation Adopted at the San Raffaele Scientific Institute.

Parameter Impaired Relaxation Pseudonormal Restrictive Filling

E’ <10 cm/s <10 cm/s <10 cm/s

E/A 0.8 0.8-1.5 �2DT >200 ms 160-200 ms <160 ms

1632 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

and maintenance of the target blood pressure with less over-

shoot.110 On the contrary, nicardipine owing to a longer half-life

compared with clivedipine is not routinely used in the setting of

cardiac surgery.99,100

Long-acting vasodilatory drugs (eg, clonidine or angioten-

sin-converting enzyme [ACE]-inhibitors) during challenging

CPB separation scenarios are not used owing to the possibility

of sudden hemodynamic changes.

E/E’ �8 9-12 �13Ar-A <0 ms �30 ms �30 ms

ValsDE/A <0.5 �0.5 �0.5Abbreviations: A, transmitral late filling peak velocity; Ar-A, duration of the

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

Left Ventricular Diastolic Dysfunction

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.

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

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1633

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.

References

1 Fromes Y, Gaillard D, Ponzio O, et al. Reduction of the inflammatory

response following coronary bypass grafting with total minimal extracor-

poreal circulation. Eur J Cardiothorac Surg 2002;22:527–33.

2 Shann KG, Likosky DS, Murkin JM, et al. An evidence based review of

the practice of cardiopulmonary bypass in adults: A focus on neurologic

injury, glycemic control, hemodilution, and the inflammatory response. J

Thorac Cardiovasc Surg 2006;132:283–90.

3 Edmunds LH Jr. The evolution of cardiopulmonary bypass: Lessons to be

learned. Perfusion 2002;17:243–51.

4 Denault AY, Tardif JC, Mazer CD, et al. Difficult and complex separation

from cardiopulmonary bypass in high-risk cardiac surgical patients: A

multicenter study. J Cardiothorac Vasc Anesth 2012;26:608–816.

5 Kloner RA, Przyklenk K, Kay GL. Clinical evidence for stunned myocar-

dium after coronary artery bypass surgery. J Card Surg 1994;9:397–402.

6 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.

7 Ranucci M, Castelvecchio S, Conte M, et al. The easier, the better: Age,

creatinine, ejection fraction score for operative mortality risk stratification

in a series of 29,659 patients undergoing elective cardiac surgery. J

Thorac Cardiovasc Surg 2011;142:581–6.

8 Ad N, Holmes SD, Patel J, et al. Comparison of EuroSCORE II, Original

EuroSCORE, and The Society of Thoracic Surgeons Risk Score in Car-

diac Surgery Patients. Ann Thorac Surg 2016;102:573–9.

9 Ahmed I, House CM, Nelson WB. Predictors of inotrope use in patients

undergoing concomitant coronary artery bypass graft (CABG) and aortic

valve replacement (AVR) surgeries at separation from cardiopulmonary

bypass (CPB). J Cardiothorac Surg 2009;4:24.

10 Surgenor SD, O’Connor GT, Lahey SJ, et al. Predicting the risk of death

from heart failure after coronary artery bypass graft surgery. Anesth

Analg 2001;92:596–601.

11 Rao V, Ivanov J, Weisel RD, et al. Lactate release during reperfusion pre-

dicts low cardiac output syndrome after coronary bypass surgery. Ann

Thorac Surg 2001;71:1925–30.

12 Maslow AD, Regan MM, Panzica P, et al. Precardiopulmonary bypass

right ventricular function is associated with poor outcome after coronary

artery bypass grafting in patients with severe left ventricular systolic dys-

function. Anesth Analg 2002;95:1507–18.

13 Ranucci M. Which cardiac surgical patients can benefit from placement

of a pulmonary artery catheter? Crit Care 2006;10(Suppl 3):S6.

14 Rocha Ferreira GS, de Almeida JP, Landoni G, et al. Effect of a perioper-

ative intra-aortic balloon pump in high-risk cardiac surgery patients: A

randomized clinical trial. Crit Care Med 2018;46:e742–50.

15 Zangrillo A, Pappalardo F, Dossi R, et al. Preoperative intra-aortic

balloon pump to reduce mortality in coronary artery bypass graft: A

meta-analysis of randomized controlled trials. Crit Care 2015;

19:10.

16 Santarpino G, Onorati F, Rubino AS, et al. Preoperative intraaortic bal-

loon pumping improves outcomes for high-risk patients in routine coro-

nary artery bypass graft surgery. Ann Thorac Surg 2009;87:481–8.

17 Vakamudi M. Weaning from cardiopulmonary bypass: Problems and

remedies. Ann Card Anaesth 2004;7:178–85.

18 Greenberg JW, Lancaster TS, Schuessler RB, et al. Postoperative atrial

fibrillation following cardiac surgery: A persistent complication. Eur J

Cardiothorac Surg 2017;52:665–72.

19 Macle L, Cairns J, Leblanc K, et al. 2016 Focused update of the Canadian

Cardiovascular Society Guidelines for the Management of Atrial Fibrilla-

tion. Can J Cardiol 2016;32:1170–85.

20 Klinger RY, Thunberg CA, White WD, et al. Intraoperative magnesium

administration does not reduce postoperative atrial fibrillation after car-

diac surgery. Anesth Analg 2015;121:861–7.

21 Fall SM, Burton NA, Graeber GM, et al. Prevention of ventricular fibrilla-

tion after myocardial revascularization. Ann Thorac Surg 1987;43:182–4.

22 Mita N, Kagaya S, Miyoshi S, et al. Prophylactic effect of amiodarone

infusion on reperfusion ventricular fibrillation after release of aortic

cross-clamp in patients with left ventricular hypertrophy undergoing aor-

tic valve replacement: A randomized controlled trial. J Cardiothorac

Vasc Anesth 2019;33:1205–13.

23 Liu H, Yu L, Yang L, et al. Vasoplegic syndrome: An update on perioper-

ative considerations. J Clin Anesth 2017;40:63–71.

24 Levin MA, Lin HM, Castillo JG, et al. Early 61. on- cardiopulmonary

bypass hypotension and other factors associated with vasoplegic syn-

drome. Circulation 2009;120:1664–71.

25 Carrel T, Englberger L, Mohacsi P, et al. Low systemic vascular resis-

tance after cardiopulmonary bypass: Incidence, etiology, and clinical

importance. J Card Surg 2000;15:347–53.

26 Fischer GW, Levin MA. Vasoplegia during cardiac surgery: Current con-

cepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4.

27 Ortoleva JP, Cobey FC. A systematic approach to the Treatment of vaso-

plegia based on recent advances in pharmacotherapy. J Cardiothorac

Vasc Anesth 2019;33:1310–4.

28 Mazer CD, Whitlock RP, Fergusson DA, et al. for the TRICS Investigators

and Perioperative Anesthesia Clinical Trials Group. Six-Month Outcomes

after Restrictive or Liberal Transfusion for Cardiac Surgery. N Engl J Med

2018;379:1224–33.

29 Mazer CD, Whitlock RP, Fergusson DA, et al. for the TRICS Investiga-

tors and Perioperative Anesthesia Clinical Trials Group. Restrictive or

1634 F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635

Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med

2017;377:2133–44.

30 Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and meta-

bolic response to acute, severe isovolemic anemia. JAMA 1998;279:217–21.

31 Martino EA, Winterton D, Nardelli P, et al. The blue coma: The role of

methylene blue in unexplained coma after cardiac surgery. J Cardiothorac

Vasc Anesth 2016;30:423–7.

32 Wieruszewski PM, Nei SD, Maltais S, et al. Vitamin C for vasoplegia

after cardiopulmonary bypass: A case series. A A Pract 2018;11:96–9.

33 Noto A, Lentini S, Versaci A, et al. A retrospective analysis of terlipressin

in bolus for the management of refractory vasoplegic hypotension after

cardiac surgery. Interact Cardiovasc Thorac Surg 2009;9:588–92.

34 Shaefi S, Mittel A, Klick J, et al. Vasoplegia after cardiovascular procedures—

pathophysiology and targeted therapy. J Cardiothorac Vasc Anesth

2018;32:1013–22.

35 Haddad F, Couture P, Tousignant C, et al. The right ventricle in cardiac

surgery, a perioperative perspective: I. Anatomy, physiology, and assess-

ment. Anesth Analg 2009;108:407–21.

36 Kim JH, Lerose CC, Landoni G, et al. Differences in biomarkers pattern

between severe isolated right and left ventricular dysfunction after car-

diac surgery. J Cardiothorac Vasc Anesth 2020;34:650–8.

37 Michelena HI, Abel MD, Suri RM, et al. Intraoperative echocardiography

in valvular heart disease: An evidence-based appraisal. Mayo Clin Proc

2011;85:646–55.

38 Monaco F, Di Prima AL, De Luca M, et al. Periprocedural and periopera-

tory management of patients with tricuspid valve disease. Minerva Cardi-

oangiol 2018;66:691–9.

39 Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrase-

karan K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echo-

cardiographic assessment of the right heart in adults: A report from the

American Society of Echocardiography endorsed by the European Asso-

ciation of Echocardiography, a registered branch of the European Society

of Cardiology, and the Canadian Society of Echocardiography. J Am Soc

Echocardiogr 2010:685–713;quiz 786-8.

40 Feneck RO, Sherry KM, Withington PS, et al. Comparison of the hemo-

dynamic effects of milrinone with dobutamine in patients after cardiac

surgery. J Cardiothorac Vasc Anesth 2001;15:306–15.

41 Carmona MJ, Martins LM, Vane MF, et al. Comparison of the effects of

dobutamine and milrinone on hemodynamic parameters and oxygen sup-

ply in patients undergoing cardiac surgery with low cardiac output after

anesthetic induction. Rev Bras Anestesiol 2010;60:237–46.

42 Greco T, Calabr�o MG, Covello RD, et al. A Bayesian network meta-anal-

ysis on the effect of inodilatory agents on mortality. Br J Anaesth

2015;114:746–56.

43 Nielsen DV, Johnsen SP, Madsen M, et al. Variation in use of peropera-

tive inotropic support therapy in cardiac surgery: Time for reflection?

Acta Anaesthesiol Scand 2011;55:352–8.

44 Belletti A, Castro ML, Silvetti S, et al. The Effect of inotropes and vaso-

pressors on mortality: A meta-analysis of randomized clinical trials. Br J

Anaesth 2015;115:656–75.

45 Schwann NM, Hillel Z, Hoeft A, et al. Lack of effectiveness of the pulmo-

nary artery catheter in cardiac surgery. Anesth Analg 2011;113:994–1002.

46 Denault AY, Bussi�eres JS, Arellano R, et al. A multicentre randomized-

controlled trial of inhaled milrinone in high-risk cardiac surgical patients.

Can J Anaesth 2016;63:1140–53.

47 Gebhard CE, Desjardins G, Gebhard C, et al. Intratracheal milrinone

bolus administration during acute right ventricular dysfunction after car-

diopulmonary bypass. J Cardiothorac Vasc Anesth 2017;31:489–96.

48 Gebhard CE, Rochon A, Cogan J, et al. Acute right ventricular failure in car-

diac surgery during cardiopulmonary bypass separation: A retrospective case

series of 12 years’ experience with intratracheal milrinone administration. J

Cardiothorac Vasc Anesth 2019;33:651–60.

49 Chen QH, Zheng RQ, Lin H, et al. Effect of levosimendan on prognosis in

adult patients undergoing cardiac surgery: A meta-analysis of randomized

controlled trials. Crit Care 2017;21:253.

50 Cholley B, Caruba T, Grosjean S, et al. Effect of levosimendan on low

cardiac output syndrome in patients with low ejection fraction undergoing

coronary artery bypass grafting with cardiopulmonary bypass: The LIC-

ORN Randomized Clinical Trial. JAMA 2017;318:548–56.

51 Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for hemo-

dynamic support after cardiac surgery. N Engl J Med 2017;376:2021–31.

52 Westerhof BE, Saouti N, van der Laarse WJ, et al. Treatment strategies for the

right heart in pulmonary hypertension. Cardiovasc Res 2017;113:1465–73.

53 Magder S. Right atrial pressure in the critically ill: How to measure, what

is the value, what are the limitations? Chest 2017;151:908–16.

54 De Backer D, Vincent JL. Should we measure the central venous pressure

to guide fluid management? Ten answers to 10 questions. Crit Care

2018;22:43.

55 Eskesen TG, Wetterslev M, Perner A. Systematic review including re-

analyses of 1148 individual data sets of central venous pressure as a pre-

dictor of fluid responsiveness. Intensive Care Med 2016;42:324–32.

56 Biais M, Ehrmann S, Mari A, et al. Clinical relevance of pulse pressure var-

iations for predicting fluid responsiveness in mechanically ventilated inten-

sive care unit patients: The grey zone approach. Crit Care 2014;18:587.

57 Sardo S, Osawa EA, Finco G, et al. Nitric oxide in cardiac surgery: A

meta-analysis of randomized controlled trials. J Cardiothorac Vasc

Anesth 2018;32:2512–9.

58 Gebistorf F, Karam O, Wetterslev J, et al. Inhaled nitric oxide for acute

respiratory distress syndrome (ARDS) in children and adults. Cochrane

Database Syst Rev 2016:CD002787.

59 Landoni G, Lomivorotov VV, Nigro Neto C, et al. MYRIAD Study

Group. Volatile anesthetics versus total intravenous anesthesia for cardiac

surgery. N Engl J Med 2019;380:1214–25.

60 Tremblay JA, Couture �EJ, Albert M, et al. Noninvasive administration of

inhaled nitric oxide and its hemodynamic effects in patients with acute right

ventricular dysfunction. J Cardiothorac Vasc Anesth 2019;33:642–7.

61 Kalogeropoulos AP, Vega JD, Smith AL, et al. Pulmonary hypertension

and right ventricular function in advanced heart failure. Congest Heart

Fail 2011;17:189–98.

62 Hach�e M, Denault A, B�elisle S, et al. Inhaled epoprostenol (prostacyclin)

and pulmonary hypertension before cardiac surgery. J Thorac Cardiovasc

Surg 2003;125:642–9.

63 Fattouch K, Sbraga F, Sampognaro R, et al. Treatment of pulmonary

hypertension in patients undergoing cardiac surgery with cardiopulmo-

nary bypass: A randomized, prospective, double-blind study. J Cardio-

vasc Med (Hagerstown) 2006;7:119–23.

64 Elmi-Sarabi M, Deschamps A, Delisle S, et al. Aerosolized vasodilators for

the treatment of pulmonary hypertension in cardiac surgical patients: A sys-

tematic review and meta-analysis. Anesth Analg 2017;125:393–402.

65 Murphy GS, Hessel EA 2nd, Groom RC. Optimal perfusion during car-

diopulmonary bypass: An evidence-based approach. Anesth Analg

2009;108:1394–417.

66 Walsh SR, Tang TY, Kullar P, et al. Ischaemic preconditioning during cardiac

surgery: Systematic review and meta- analysis of perioperative outcomes in

randomised clinical trials. Eur J Cardiothorac Surg 2008;34:985–94.

67 Crescenzi G, Landoni G, Zangrillo A, et al. Management and decision-

making strategy for systolic anterior motion after mitral valve repair. J

Thorac Cardiovasc Surg 2009;137:320–5.

68 Shanewise JS, Cheung AT, Aronson S, et al. ASE/SCA guidelines for

performing a comprehensive intraoperative multiplanetransesophageale-

chocardiography examination: Recommendations of the American Soci-

ety of Echocardiography Council for Intraoperative Echocardiography

and the Society of Cardiovascular Anesthesiologists Task Force for Certi-

fication in Perioperative Transesophageal Echocardiography. J Am SocE-

chocardiogr 1999;12:884–900.

69 Lansdorp B, Lemson J, van Putten MJ, et al. Dynamic indices do not pre-

dict volume responsiveness in routine clinical practice. Br J Anaesth

2012;108:395–401.

70 Loulmet DF, Yaffee DW, Ursomanno PA, et al. Systolic anterior motion

of the mitral valve: A 30-year perspective. J Thorac Cardiovasc Surg

2014;148:2787–94.

71 Allen LA, Fonarow GC, Grau-Sepulveda MV, et al. Hospital variation in

intravenous inotrope use for patients hospitalized with heart failure:

Insights from Get With The Guidelines. Circ Heart Fail 2014;7:251–60.

F. Monaco et al. / Journal of Cardiothoracic and Vascular Anesthesia 34 (2020) 1622�1635 1635

72 Sanfilippo F, Knight JB, Scolletta S, et al. Levosimendan for patients with

severely reduced left ventricular systolic function and/or low cardiac out-

put syndrome undergoing cardiac surgery: A systematic review and

meta-analysis. Crit Care 2017;21:252.

73 Shahin J, DeVarennes B, Tse CW, et al. The relationship between ino-

trope exposure, six-hour postoperative physiological variables, hospital

mortality and renal dysfunction in patients undergoing cardiac surgery.

Crit Care 2011;15:162.

74 Maeda K, Takanashi S, Saiki Y. Perioperative use of the intra-aortic bal-

loon pump: Where do we stand in 2018? Curr Opin Cardiol

2018;33:613–21.

75 Khorsandi M, Dougherty S, Bouamra O, et al. Extra-corporeal membrane

oxygenation for refractory cardiogenic shock after adult cardiac surgery:

A systematic review and meta-analysis. J Cardiothorac Surg 2017;12:55.

76 Reynolds HR, Tunick PA, Grossi EA, et al. Paradoxical septal motion

after cardiac surgery: A review of 3,292 cases. Clin Cardiol

2007;30:621–3.

77 Wang DY, Richmond ME, Quinn TA, et al. Optimized temporary biven-

tricular pacing acutely improves intraoperative cardiac output after wean-

ing from cardiopulmonary bypass: A substudy of a randomized clinical

trial. J Thorac Cardiovasc Surg 2011;141:1002–8.

78 Gielgens RCW, Herold IHF, van Straten AHM, et al. The hemodynamic

effects of different pacing modalities after cardiopulmonary bypass in

patients with reduced left ventricular function. J Cardiothorac Vasc

Anesth 2018;32:259–66.

79 Dyub AM, Whitlock RP, Abouzahr LL, et al. Preoperative intra-aortic

balloon pump in patients undergoing coronary bypass surgery: A system-

atic review and meta-analysis. J Card Surg 2008;23:79–86.

80 Lavana JD, Fraser JF, Smith SE, et al. Influence of timing of intraaortic

balloon placement in cardiac surgical patients. J Thorac Cardiovasc Surg

2010;140:80–5.

81 Sylvin EA, Stern DR, Goldstein DJ. Mechanical support for postcardiot-

omy cardiogenic shock: Has progress been made? J Card Surg 2010;25:

442–54.

82 Wernovsky G, Wypij D, Jonas RA, et al. Postoperative course and hemo-

dynamic profile after the arterial switch operation in neonates and infants.

A comparison of low-flow cardiopulmonary bypass and circulatory arrest.

Circulation 1995;92:2226–35.

83 Gaies MG, Gurney JG, Yen AH, et al. Vasoactive-inotropic score as a

predictor of morbidity and mortality in infants after cardiopulmonary

bypass. Pediatr Crit Care Med 2010;11:234–8.

84 Licker M, Diaper J, Cartier V, et al. Management of weaning from cardio-

pulmonary bypass after cardiac surgery. Ann Card Anaesth 2012;15:206–23.

85 Mebazaa A, Pitsis AA, Rudiger A, et al. Clinical review: Practical recom-

mendations on the management of perioperative heart failure in cardiac

surgery. Crit Care 2010;14:201.

86 Pieri M, Sorrentino T, Oppizzi M, et al. The role of different mechanical

circulatory support devices and their timing of implantation on myocar-

dial damage and mid-term recovery in acute myocardial infarction related

cardiogenic shock. J Interv Cardiol 2018;31:717–24.

87 Cheng JM, den Uil CA, Hoeks SE, et al. Percutaneous left ventricular

assist devices vs. intra-aortic balloon pump counterpulsation for treatment

of cardiogenic shock: A meta-analysis of controlled trials. Eur Heart J

2009;30:2102–8.

88 Hausmann H, Potapov EV, Koster A, et al. Prognosis after the implanta-

tion of an intra-aortic balloon pump in cardiac surgery calculated with a

new score. Circulation 2002;106(12 Suppl 1):I203–6;Sep 24.

89 Rihal CS, Naidu SS, Givertz MM, et al. 2015 SCAI/ACC/HFSA/STS clini-

cal expert consensus statement on the use of percutaneous mechanical circu-

latory support devices in cardiovascular care: Endorsed by the American

Heart Assocation, the Cardiological Society of India, and Sociedad Latino

Americana de Cardiologia Intervencion; Affirmation of value by the

Canadian Association of Interventional Cardiology-Association Canadienne

de Cardiologie d’intervention. J Am Coll Cardiol 2015;65:e7–e26.

90 Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to eval-

uate the safety and efficacy of a percutaneous left ventricular assist device

versus intra-aortic balloon pumping for treatment of cardiogenic shock

caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8.

91 Schrage B, Ibrahim K, Loehn T, et al. Impella support for acute myocar-

dial infarction complicated by cardiogenic shock. Circulation 2019;

139:1249–58.

92 Teuteberg JJ, Chou JC. Mechanical circulatory devices in acute heart fail-

ure. Critical Care Clinics 2014;30:585–606.

93 Bartlett RH, Gattinoni L. Current status of extracorporeal life support

(ECMO) for cardiopulmonary failure. Minerva Anestesiol 2010;

76:534–40.

94 Ng KT, Chan XL, Tan W, et al. Levosimendan use in patients with preop-

erative low ejection fraction undergoing cardiac surgery: A systematic

review with meta-analysis and trial sequential analysis. J Clin Anesth

2019;52:37–47.

95 Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 conse-

cutive adult patients treated with extracorporeal membrane oxygenation

for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc

Surg 2010;139:302–11;311.e1.

96 Braun JP, Jasulaitis D, Moshirzadeh M, et al. Levosimendan may

improve survival in patients requiring mechanical assist devices for post-

cardiotomy heart failure. Crit Care 2006;10:R17.

97 Nordlander M, Sj€oquist PO, Ericsson H, et al. Pharmacodynamic, phar-

macokinetic and clinical effects of clevidipine, an ultrashort-acting cal-

cium antagonist for rapid blood pressure control. Cardiovasc Drug Rev

2004;22:227–50.

98 Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: Compara-

tive studies of clevidipine to nitroglycerin, sodium nitroprusside, and

nicardipine for acute hypertension treatment in cardiac surgery patients.

Anesth Analg 2008;107:1110–21.

99 Cruz JE, Thomas Z, Lee D, et al. Therapeutic interchange of Clevidipine

for Sodium Nitroprusside in cardiac surgery. P T 2016;41:635–9.

100 Cheung AT, Guvakov DV, Weiss SJ, et al. Nicardipine intravenous bolus

dosing for acutely decreasing arterial blood pressure during general anesthesia

for cardiac operations: Pharmacokinetics, pharmacodynamics, and associated

effects on left ventricular function. Anesth Analg 1999;89:1116–23.

101 McIlroy DR, Lin E, Hastings S, et al. Intraoperative transesophageal

echocardiography for the evaluation and management of diastolic dys-

function in patients undergoing cardiac surgery: A survey of current prac-

tice. J Cardiothorac Vasc Anesth 2016;30:389–97.

102 Oh JK, Hatle L, Tajik AJ, et al. Diastolic heart failure can be diagnosed

by comprehensive two-dimensional and Doppler echocardiography. J Am

Coll Cardiol 2006;47:500–6.

103 Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the

evaluation of left ventricular diastolic function by echocardiography: An

update from the American Society of Echocardiography and the European

Association of Cardiovascular Imaging. J Am Soc Echocardiogr

2016;29:277–314.

104 Gelzinis TA. New insights into diastolic dysfunction and heart failure

with preserved ejection fraction. Semin Cardiothorac Vasc Anesth

2014;18:208–17.

105 Angeja BG, Grossman W. Evaluation and management of diastolic heart

failure. Circulation 2003;107:659–63.

106 Apostolakis EE, Baikoussis NG, Parissis H, et al. Left ventricular diastolic

dysfunction of the cardiac surgery patient; a point of view for the cardiac sur-

geon and cardio-anesthesiologist. J Cardiothorac Surg 2009;4:67.

107 Michaux I, Filipovic M, Skarvan K, et al. Effects of on-pump versus off-

pump coronary artery bypass graft surgery on right ventricular function. J

Thorac Cardiovasc Surg 2006;131:1281–8.