Pharmacologic approaches to weaning from cardiopulmonary bypass and extracorporeal membrane oxygenation

Accepted Manuscript Pharmacologic approaches to weaning from cardiopulmonary bypass and extracorporeal membrane oxygenation Wilson W. Cui, MD PhD, Health Science Assistant Clinical Professor, James G. Ramsay, MD, Professor of Clinical Anesthesia PII:

S1521-6896(15)00019-1

DOI:

10.1016/j.bpa.2015.03.007

Reference:

YBEAN 851

To appear in:

Best Practice & Research Clinical Anaesthesiology

Received Date: 17 February 2015 Revised Date:

9 March 2015

Accepted Date: 20 March 2015

Please cite this article as: Cui WW, Ramsay JG, Pharmacologic approaches to weaning from cardiopulmonary bypass and extracorporeal membrane oxygenation, Best Practice & Research Clinical Anaesthesiology (2015), doi: 10.1016/j.bpa.2015.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pharmacologic approaches to weaning from cardiopulmonary bypass and extracorporeal membrane oxygenation

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AUTHORS *Wilson W. Cui, MD PhD Health Science Assistant Clinical Professor

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James G. Ramsay, MD

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Professor of Clinical Anesthesia

*Corresponding author

Department of Anesthesia and Perioperative Care

University of California San Francisco Medical Center

San Francisco, CA 94143, USA Tel: +1 415-476-2131 Fax: +1 415-476-9516

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Email: [email protected]

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521 Parnassus Ave, C450

Abstract

Cardiopulmonary bypass (CBP) and extracorporeal membrane oxygenation (ECMO) are two modalities of mechanical circulatory support. They provide hemodynamic stability for patients undergoing invasive cardiothoracic interventions and can be life-saving in emergencies resulting from cardiogenic shock or respiratory failure. Unlike implantable ventricular assist devices, CPB and ECMO are short-term solutions

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meant to last from hours to days, and the patient will need to be weaned from the mechanical support once the intervention has completed or when the underlying condition has improved. Weaning imposes major physiological strain upon the recovering cardiovascular and pulmonary systems, and usually

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requires pharmacologic support. This article focuses on the proper diagnosis of the underlying

pathophysiology, an understanding of the pharmacology of available agents, and a rational approach to

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the management of patients weaning from CPB and ECMO.

Keywords:

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Cardiopulmonary bypass; Extracorporeal membrane oxygenation; Extracorporeal life support; Mechanical circulatory support; Left ventricular dysfunction; Right ventricular dysfunction; Vasoplegic syndrome; Pulmonary hypertension; Inotropic agents; Vasoconstrictor agents

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I. Introduction

Mechanical cardiopulmonary support (MCS) is deployed when the native heart and lung functions have

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to be interrupted, whether this is necessitated by an invasive procedure or due to intrinsic organ failure. Two most common MCS techniques are cardiopulmonary bypass (CPB) and extracorporeal membrane

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oxygenation (ECMO). CPB is an essential component of cardiac surgery and successful separation from CPB constitutes a critical step in the intraoperative course. ECMO is more appropriately called extracorporeal life support (ECLS), as it can provide both cardiac and pulmonary support, but by convention will be referred to as ECMO in this article. It is deployed in a variety of peri-procedural and critical care settings ranging from an elective, invasive interventional cardiac procedure, to a life-saving intervention for someone in life-threatening cardiac or respiratory distress. While a patient can remain

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on ECMO support for an extended period, up to several weeks, separation from ECMO support is ultimately inevitable and remains a crucial and challenging step.

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Pharmacologic agents are usually necessary during weaning from MCS, as the native organs, likely still recovering from the recent intervention or injury, must resume their full physiologic function. The

choice of agents depends on the underlying pathophysiology likely to persist after separation. Common

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causes of hemodynamic instability include systemic vasodilation, left ventricular (LV) dysfunction,

pulmonary hypertension (PH) and associated right heart failure (RHF), respiratory failure, acidosis, and

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disturbance in normal hemostasis. Unsuccessful or premature weaning attempts may result in organ injury or dysfunction. Weaning of CPB takes place in the operating room; weaning of ECMO may be done in the intensive care unit (ICU) or operating room, and requires the close cooperation of cardiothoracic surgeons, interventional cardiologists, anaesthetists, cardiologists, intensivists,

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perfusionists and support staff.

This article is organized in three parts. The first part will focus on the common clinical scenarios and

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indications that require the use of CPB and ECMO. The indication for support helps predict the likely pathophysiology to emerge during the weaning process. This is followed by a brief discussion of the

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preparation before weaning from CPB or ECMO. Finally, common problems encountered during weaning and appropriate pharmacological treatments are discussed (Table 1). Attention is paid to each agent’s mechanism, relevant clinical indications and available evidence. There is significant overlap in the clinical problems encountered in CPB and ECMO, and the readers should be mindful that treatments should be dictated by the problems rather than the particular modality of MCS.

II. Clinical Scenarios

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II.A. CPB

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Today, CPB remains the most commonly used method of providing extracorporeal circulatory support in the operating room and makes cardiac surgery possible. CPB decompresses the heart, minimizes

bleeding in the surgical field, provides circulatory stability in the absence of cardiac function and,

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oxygenation and carbon dioxide removal in the absence of lung function. Full CPB includes a reservoir, oxygenator, and circulatory pump, and separate pumps to permit salvage of blood from the operative

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field, decompress the heart (“vent”) as well as provide cardioplegia when needed. CPB inevitably elicits a profound inflammatory response in the body[1], and either prolonged or insufficient administration of cardioplegia may lead to ischemic injury of the myocardium. The ease of separation from CPB is largely determined by the pre-bypass cardiac function and medical comorbidities, the length of bypass and

surgical intervention.

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ischemic times, the quality of myocardium protection during aortic cross clamp, and the success of the

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In some instances, CPB is deployed urgently or semi-emergently. One example is the use of CPB during lung transplantation. Modern bilateral lung transplantation involves the sequential implantation of the

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lungs. While acceptable gas exchange is often feasible with ventilation of the contralateral lung, it is not always possible due to hypoxia, respiratory acidosis, or exacerbation of PH and right heart strain. The surgeon may opt to place the patient on CPB either preemptively prior to explanting the native lung or do so emergently at any point during the operation when support is needed. Another example would be acute hemorrhage and instability during intrathoracic procedure where the heart or one of the great vessels is injured. The use of CPB will divert the blood away from the heart and allow the surgeon to inspect the source of bleed while the patient can be stabilized and resuscitated on the CPB circuit.

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II.B. ECMO

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Modern ECMO is a versatile technology that is relatively simple to deploy, can restore tissue perfusion and oxygenation in an unstable patient, and much more portable than the traditional CPB machine. Unlike CPB with a reservoir and multiple pump options, ECMO is a closed circuit without a reservoir or

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secondary pumps. ECMO has found its usefulness in a growing number of clinical settings and patient populations. Most patients are placed on ECMO emergently due either to life-threatening respiratory

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failure or cardiogenic shock. In such setting, it is potentially life-saving or life-extending. The goal is to temporarily relieve the physiological strain on the overwhelmed cardiopulmonary systems, buy time to initiate other therapies, and allow the patient to recover. Depending on the clinical situation, different ECMO modalities may be appropriate. In veno-arterial (VA) ECMO, blood is diverted from the right heart

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and, after oxygenation and CO2 removal, is returned to the patient’s systemic circulation via a large artery, similar to CPB. This has the advantage of providing both cardiac and pulmonary support and is equally effective in those with cardiogenic shock or respiratory failure. In general, VA ECMO is the

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preferred choice in an acutely decompensating patient. Alternatively, veno-venous (VV) ECMO removes deoxygenated blood but returns the oxygenated blood to the right heart. Because of this, it does not

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provide cardiac support and should only be used in those who do not have significant cardiac, especially RV, dysfunction. A patient with solely respiratory failure may be electively transitioned from VA to VV ECMO. On the other hand, someone on VV ECMO showing evidences of RHF may require emergent transition to VA ECMO.

Some patients may not, however, recover sufficiently to be successfully weaned off ECMO. One example is in the setting of acutely decompensated end stage lung disease where ECMO may stabilize the patient

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while waiting for a suitable donor lung, or to complete the evaluation for lung transplant. It is not uncommon at our institution that a potential recipient is placed on ECMO and optimized in the ICU, then undergoes lung transplantation either on intraoperative ECMO or CPB, returns to the ICU on ECMO due

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to concerns of RV or graft function, and recovers before weaning. Other examples include those with postcardiotomy heart failure or acute decompensated patients awaiting left ventricular assist device

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(LVAD) or heart transplantation.

Lastly, interventional cardiac procedures are increasingly being performed in high-risk patients with

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limited cardiopulmonary reserve. The use of ECMO in this population can provide hemodynamic stability during critical portions of the procedure. These procedures could vary in urgency, from an elective transcatheter aortic valve replacement to emergency percutaneous coronary angioplasty during an acute myocardial infarction. Upon completion of the intervention, the underlying pathology leading to

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the need for ECMO usually is unchanged, and significant pharmacologic support may be needed to

III. Preparation

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III.A. CPB

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enable weaning the mechanical support.

Preparation should be made to ensure that the initial separation from CPB is successful as an unsuccessful attempt can lead to ischemic injury to vital organs. Planning for separation requires good communication between the surgeon, the anaesthetist and the perfusionist. Most measures before weaning from bypass are routine and often standardized, such as correction of acid/base status, normalization of electrolytes, ensure the return of organized cardiac rhythm, and normothermia (Table

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2)[2]. The airway is suctioned, atelectatic lungs are re-expanded, and ventilation is resumed. The reversal agent for anticoagulation, protamine, and blood products and factors to correct any potential coagulopathy should be readily available. It is not infrequent for the heart to fibrillate after aorta is

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unclamped and the heart is reperfused. Anti-arrhythmic drugs such as lidocaine and magnesium are routinely given and internal defibrillation may be delivered. Temporary epicardial wires are often placed and external pacing may be necessary to ensure adequate heart rate (HR). Hyperfibrinolysis is common

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on bypass, and aminocaproic acid and tranexamic acid are two lysine-analogue antifibrinolytics that are currently available. Their use have been shown to reduce blood transfusion requirement in cardiac

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surgery[3]. Both agents are dependent on renal excretion, and the dosage should be adjusted accordingly. Based on the 2011 update from STS and SCA clinical practice guideline on blood conservation, treatment of non-surgical bleeding once heparin has been reversed with protamine should be directed by documented deficiency or dysfunction of platelets or coagulation factors[4].

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Fibrinogen deficiency (<200mg/dL) can replaced with cryoprecipitate or fibrinogen concentrate. Fresh frozen plasma can be transfused to replace deficiency of other pro-coagulant factors, with recombinant factor VII and prothrombin complex concentrates (PCC) can be used for refractory coagulopathy. Prior

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to the initiation of weaning, the team should discuss any concern and likely problems during and after weaning from CPB. Weaning from CPB commences with the gradual reduction in venous return into the

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pump, and decreasing of pump flow. The management strategies during weaning at most institutions are often not standardized, and are largely based on the clinical judgment of the surgeons and anaesthetists.

III.B. ECMO

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For elective, intraoperative ECMO, deployed for high-risk procedures, preparation before weaning is similar to that of CPB. However, when ECMO support is prolonged (days to weeks), the weaning process most likely begins in the ICU. Similar to CPB, prolonged ECMO induces a significant inflammatory

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response in the body and can cause significant morbidity. Exposure to the ECMO circuit can lead to thromboembolic complications with inadequate anticoagulation, while anticoagulation, consumption of factors, platelet activation and depletion can lead to excessive bleeding. The data on the use of rFVIIa

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and PCC in patients on ECMO support is limited to case reports[5]. Given that they carry high thrombotic risk and thrombosis of the ECMO circuit is catastrophic, many practitioners advise against the use of

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rFVIIa and PCC while the patient is on ECMO. Prolonged ECMO may cause other systemic complications. Hypovolemia from bleeding and volume overload and venous congestion due to resuscitation can both occur. Metabolic acidosis is common and can be due to malperfusion, excessive vasoconstrictor therapy, or renal failure. Renal replacement therapy (RRT) may be necessary. Patients on ECMO often suffer from

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acute lung injury and ECMO offers a resting period for recover by lowering oxygen exposure and airway pressure to avoid further injury. However, agitation and ventilator dyssynchrony are common, requiring sedation, tracheostomy and even neuromuscular paralysis which may mask new neurologic injury. Limb

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ischemia is another complication of peripheral cannulation and can cause compartment syndrome. Multi-organ failure carries very poor prognosis. Correction of these issues is paramount and remains a

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formidable challenge for the surgical and critical care team.

Unlike that of CPB, the end point of ECMO is often not predetermined and weaning can be a prolonged process. For those on extended ECMO support in the ICU, the recovery of the patient’s cardiac and pulmonary function can be monitored by a temporary decrease of ECMO flow rate based on hemodynamics and echocardiographic assessment. This may be done on a daily basis to assess the readiness to stop ECMO support. The entire weaning process may last days to even weeks. Nonetheless,

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the cardiovascular and pulmonary systems remain fragile and can be easily overwhelmed, which means prolonged pharmacologic support after separation is often necessary.

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IV. Clinical problems during weaning

IV.A. Systemic vasodilation

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The most common cause of hypotension during weaning from CPB is excessive systemic vasodilation. Ohm’s Law states that perfusion pressure is dependent on cardiac output (CO) and systemic vascular

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resistance (SVR). A number of factors may contribute to excessive vasodilation after CPB or ECMO. These include the duration of non-pulsatile flow, the degree of hypothermia during CPB, ongoing systemic inflammatory states induced by the CPB itself and possibly sepsis, and the use of certain preoperative medications[1]. SVR is readily determined by using the Ohm’s law. Hypotension defined as low mean arterial pressure (<60mmHg) in the setting of normal to high cardiac index (CI≥2.4 L/m2/min)

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would suggest low SVR (<1000dynes/sec/cm5) that requires treatment with vasoconstrictors. Prior to weaning from CPB, communication with the perfusionist can be useful to ascertain the overall

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vasoconstrictor requirement of the patient. On the other hand, if the patient has been on extended ECMO support, a review of the ICU course and discussion with the critical care team regarding the

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ongoing vasoconstrictor use will provide a good starting point on the choice of agent and dosage.

Catecholamines with alpha 1-adrenergic agonist activity are the first-line vasoconstrictors. In North America the principal agents are phenylephrine and norepinephrine; in higher doses, the alpha-1 effect of epinephrine is also apparent. Alpha-1 receptors are members of the G-protein coupled receptors that when activated start a cascade of intracellular signaling via the phospholipase-C (PLC) pathway which results in the influx of cytoplasmic calcium ions, smooth muscle contraction and increased vascular

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tone[6]. Norepinephrine is an endogenous catecholamine, released by the adrenal medulla as a stress hormone and by adrenergic neurons in the central nervous system. In addition to peripheral vasoconstriction via alpha-1 activation, it also activates beta-1 adrenergic receptors, but has a minimal

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beta-2 effect. Phenylephrine is a synthetic alpha-1 agonist that induces vasoconstriction but is less potent than norepinephrine and tachyphylaxis is not uncommon. The main adverse effect of alpha-1 agonists is excessive vasoconstriction resulting in hypoperfusion and ischemia of organs such as kidney,

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intestines and skin.

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Refractory hypotension post CPB not responsive to traditional (adrenergic) vasoconstrictor treatment is sometime termed vasoplegic syndrome (VS)[7]. It is associated with high CI, low SVR, low CVP, and increased fluid requirement. The reported incidence ranges from 8 to 20% after on-pump cardiac surgery[7–9]. Preoperative predictors include low LV ejection fraction (LVEF), recent coronary ischemia,

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intravenous heparin, angiotensin-converting-enzyme inhibitors (ACEIs) and calcium channel blockers. Vasopressin, a non-adrenergic vasoconstrictor, has been used as an alternative vasoconstrictor in VS. Otherwise known as antidiuretic hormone, it is a neurohormone that plays a significant homeostatic

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role in the control of body water and vascular tone. Similar to catecholamines, vasopressin receptor subtype 1 activation in the vascular smooth muscle cells is mediated via G-protein signal transduction

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and results in increased intracellular calcium and vascular tone. Studies have shown that while endogenous vasopressin level usually increases 100-fold with the commencement of CPB and remain elevated for hours in the post-bypass period[10], this phenomenon is absent in a subset of patients[7]. In addition, endogenous vasopressin stores may be depleted in prolonged stress and vasodilated states[11].In three randomized trials in patients on ACEI therapy, prophylactic treatment with low dose vasopressin (0.03unit/min) prior to CPB weaning resulted in fewer hypotensive episodes and lower norepinephrine requirement[12–14]. Similarly, the use of vasopressin significantly improved blood

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pressure in patients after LVAD implantation[15]. Combined vasopressin and norepinephrine treatment was shown to have higher blood pressure, lower norepinephrine dosage, lower HR, less arrhythmia, and better cardiac performance index than norepinephrine infusion alone[16]. Based on these studies, the

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clinical dose range of vasopressin for its vasoconstrictor effect is 0.03-0.04unit/min, rarely up to

0.1unit/min in severe refractory VS. An advantage of vasopressin is its minimal effect (in low dosage) on the pulmonary vascular resistance (PVR) and on glomerular filtration rate compared to that of

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phenylephrine and norepinephrine. With prolonged use, especially at higher doses than 0.04unit/min, vasopressin can cause excessive vasoconstriction and organ hypoperfusion such as mesenteric ischemia

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and skin or digit necrosis. Excessive hypertension and increased afterload can also increase myocardium demand and reduce CI.

The common intracellular signaling pathway that leads to vasodilation is the activation of guanylate

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cyclase (GC) that generates cyclic guanosine monophosphate (cGMP) in smooth muscle cells. Nitric oxide (NO) activates GC by binding to the iron-heme moiety in the enzyme complex. Increased NO level has been implicated in refractory vasodilatory shock[17]. Methylene blue (MB) is a competitive inhibitor

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of NO-dependent GC activation and thus can prevent the vasodilatory response of the vascular smooth muscle to pro-inflammatory mediators. In one study, 92.4% of patients suffering from VS after CPB

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responded to MB with increased arterial pressure and decreased norepinephrine requirement[18]. In one multi-center, randomized trial, vasoplegic patients receiving MB showed faster recovery and lower mortality and morbidity than those receiving placebo[19]. The prophylactic use of MB infusion in highrisk patients either preoperatively or during CPB resulted in less incidence of vasoplegia, lower vasoconstrictor requirement, and shorter ICU stay[20,21]. However, a recent propensity score matched study showed that the use of MB as rescue therapy post-bypass is associated with significant increase in morbidity and a trend in higher morbidity[22]. The therapeutic effect may be transient and refractory

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vasoplegia may require either repeated dosing or continuous infusion. Urine and skin discolouration is a unique side effect of the MB administration, but it is transient and not clinically relevant. MB has

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significant light absorption at 660nm and will interfere with the proper function of pulse oximeters.

IV.B. LV dysfunction

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LV dysfunction is another common finding during weaning from CPB. For open cardiac surgery, the cross-clamping of ascending aorta interrupts coronary perfusion, and the myocardium is protected from

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ischemia with a combination of cardioplegia-induced electrical-mechanical quiescence, ventricular decompression, and myocardium cooling. Inadequate myocardial protection, prolonged cross-clamp duration, and reperfusion can result in myocardial injury and reduced ventricular function after bypass. In some patients, there is pre-existing LV dysfunction, which may be the result of myocardial infarction,

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hibernating myocardium due to chronic ischemia, or progressive valvular disease. The benefit of surgical intervention, whether it is coronary revascularization or valve repair, may not be immediately apparent after CPB. The patient’s preoperative systolic and diastolic function, advanced age, chronic kidney

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disease, reoperation, the need for inotropic agents prior to CPB, the length and complexity of procedure, the length of bypass and cross clamp times, and the effectiveness of the surgical intervention can

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predict the likelihood of LV failure during weaning[2]. Therefore, post-bypass low cardiac output syndrome (LCOS) is common, usually manifests as elevated left atrial or pulmonary arterial occlusive pressure (PAOP), reduced CI (defined by various group as <2-2.4L/m2/min), and normal or elevated SVR. On transoesophageal echocardiography (TEE), the LV may have regional or global hypokinesis, and appears distended with a reduced LVEF. Similarly, LV dysfunction is common for patients on ECMO as cardiogenic shock and low LVEF are common indications for ECMO.

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Positive inotropic agents are the treatment of choice in the setting of LV dysfunction. The first line agents include epinephrine and other catecholamines with significant beta-1 adrenergic agonist activity. The activation of beta adrenergic receptors increases intracellular cyclic adenosine-monophosphate

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(cAMP) concentration via the adenyl cyclase (AC) pathway and leads to increased cytoplasmic calcium concentration[6]. In cardiomyocytes, this results in activation of voltage-gated calcium channels, increases the rate of depolarization and automaticity in pacemaker cells and thus HR (positive

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chronotropy). Calcium ions also bind to troponin, and enhance muscle contraction (positive inotropy). Epinephrine, similar to norepinephrine, is a hormone released by adrenal medulla and a

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neurotransmitter in the sympathetic nervous system. Epinephrine is a potent alpha-1 and beta-1/beta-2 agonist which is frequently used in patients with post-bypass LCOS. In one randomized study, epinephrine at 0.1mcg/kg/min caused significant increase in MAP without changes in SVR[23], suggesting the effect was due to increased beta-related inotropy rather than alpha-related

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vasoconstriction. Epinephrine can however significantly increase the myocardial work and oxygen demand. As the proto-typical fight-or-flight stress hormone, it has significant effect on most organs in addition to the heart due to its relative non-selectivity for adrenergic receptors. It can cause bronchial

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dilation via beta-2 receptor activation. Its effect on vascular tone depends on the relative ratio of alpha1 to beta-2 receptors in the particular vascular bed and drug concentration. Its major metabolic effect is

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the mobilization of glucose storage via glycogenolysis and lipolysis. Other less potent positive inotropic catecholamines include dobutamine and dopamine. Dobutamine is a synthetic analogue of isopreterenol with predominantly beta-1 agonist effect. The combination of increased CO and HR (beta-1) and secondary vasodilation has led to the term “ino-dilator.” Recall Ohm’s law, increased CO in the setting of severe vasodilation may result in a drop in perfusion pressure. In practice, the use of ino-dilators often requires the concomitant use of vasoconstrictors, such as norepinephrine. Both observational and randomized studies have consistently shown that dobutamine

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increases CI, stroke volume index, and HR, accompanied by reduction in SVR and PVR[24–28]. HR increase with dobutamine is dose-dependent. At doses that produce similar increase in CI, dobutamine causes significantly more tachycardia than epinephrine, suggesting that HR increase may be the primary

flow and maintains intestinal oxygenation and lactate extraction[29].

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mechanism of CO augmentation[24,26]. Unlike alpha agonists, dobutamine infusion increases splanchnic

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Dopamine has agonist activity not only on the adrenergic receptors (beta-1 and alpha-1) but also on its own endogenous receptors. The cardiovascular action of exogenous dopamine is determined by the

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plasma concentration of the drug and its relative affinity to the various receptors. At low dose (<3mcg/kg/min) dopamine causes renal and mesenteric arteriole vasodilation. However, a recent metaanalysis review of the available data failed to find any positive renal protective effect of dopamine in CPB[30]. Intermediate dose of dopamine (2.5-5mcg/kg/min) predominantly activates the beta-1

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receptors resulting in positive chronotropic and inotropic effect. In one study, dopamine at 7mcg/kg/min dose produced same degree of CI augmentation as that of epinephrine at 0.1mcg/kg/min[31]. However, at doses greater than 5 mcg/kg/min, alpha-1 receptor activation and

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vasoconstriction becomes significant and as well as increases in HR[32,33]. One study found that, while dopamine (6.2mcg/kg/min) and dobutamine (6.7mcg/kg/min) produced similar CI and HR increase,

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there was significant off-loading of the heart with dobutamine with lower LV and right ventricle (RV) filling pressures and SVR[34]. A randomized study in high risk patients with mitral stenosis showed that dobutamine is more efficacious than dopamine in weaning[25]. Dopexamine is synthetic analog of dopamine, with beta-1, beta-2 and dopamine receptor agonist effects but little alpha activity. It is not available in North America.

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Milrinone is a positive inotropic agent not structurally related to catecholamines. It is an inhibitor of type-3 phosphodiesterase (PDE-3) and prevents cAMP and cGMP degradation by PDE-3[35]. Because cAMP is the common signaling molecule in adrenergic receptor activation, PDE-3 inhibitors work

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synergistically with the catecholamine agents. In patients with LCOS and suboptimal response to

conventional catecholamines, milrinone is a good choice. In three randomized trials with high risk

patients with pre-existing low LVEF, milrinone increased post-bypass CI, decreased the need for other

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inotropes, and was more successful in weaning from CPB than placebo[36–38]. In a large randomized trial, involving 120 patients, milrinone (0.5mg/kg bolus followed by 0.5mcg/kg/min infusion) and

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dobutamine (10-20mcg/kg/min infusion) were similarly effective in treating post-bypass LCOS[27]. However, dobutamine group had higher incidence of atrial fibrillation, which may be dose related, while milrinone group had lower PAOP[27,28]. One observational study using multivariable logistic analysis appears to suggest an increased risk of post-surgical AF with milrinone[39], which is in disagreement

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with the previously mentioned randomized study comparing milrinone and dobutamine[27]. PDE-3 inhibitors are also ino-dilators because they induce protein kinase-A activation of sarcoplasmic calcium pumps that removes cytoplasmic calcium in vascular smooth muscle. Milrinone has a much longer half-

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life, 30-60 minutes, than catecholamines, and its hypotensive effect can be profound and lingers even after discontinuation. The dosing of milrinone is 50mcg/kg, typically administered as a load while on CPB,

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followed by infusion 0.1-0.75mcg/kg/hr. Some anaesthetists choose to reduce or forego the loading dose to avoid excessive vasodilation. Enoximone is another PDE-3 inhibitor, but is not currently available in North America. The first clinically available PDE-3 inhibitor was amrinone, but it has fallen out of favor due the side effect of thrombocytopenia.

Levosimendan is a novel agent, termed “calcium-sensitizer,” that enhances the sensitivity of cardiomyocytes to intracellular calcium without increaseing calcium concentration. Unlike

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catecholamines and PDE-3 inhibitors, which increase myocardial oxygen consumption and the risk of tachyarrhythmia, levosimendan was originally thought to exert its positive inotropic effect by binding and stabilizing the calcium-troponin complex to enhance muscle excitation-contraction[40]. However

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recent evidence suggests that levosimendan may also inhibit PDE-3 and enhance contractility via the cAMP-dependent pathway[40]. Additionally, it activates ATP-dependent potassium channels and causes relaxation of vascular smooth muscle cells and exerts anti-ischemic effect in cardiomyocytes[40]. A

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number of prospective, randomized trials investigating its utility in CPB have been published in the past decade, most of which were reviewed in a recent meta-analysis[41]. In the largest trial involving patients

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with normal LVEF, intraoperative administration of levosimendan was found to decrease the need for rescue inotrope, the use of intra-aortic balloon pump, and the incidence of postoperative heart failure compared to placebo[42]. Two randomized studies found that, in those with reduced LVEF, preoperative levosimendan increased the chance of successful primary weaning from CPB[43,44]. Head-to-head

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comparison with dobutamine in patients with post-bypass LCOS showed that levosimendan was as effective in improving hemodynamics, but results were limited by small sample sizes and difference in dosing[45,46]. Levosimendan’s clinical effects are most similar to milrinone; however, two small studies

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comparing the two agents yielded inconclusive results[47,48]. Meta-analsysis by Harrison et al. concluded that perioperative use of levosimendan in patients with reduced LVEF has benefit in reducing

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postoperative mortality, RRT, atrial fibrillation and myocardial injury[41]. The dosing regimens for levosimendan varied among the studies with bolus doses ranging from 10-24mcg/kg followed by infusion at rates from 0.05-0.2mcg/kg/min for typically 24 hours, though some omitted the bolus dose altogether. Unilke catecholamines and milrinone, one metabolite of levosimendan (representing 6% of the dose) is pharmacologically active with a long elimination half-life providing a prolonged therapeutic effect of more than a week. Levosimendan is not currently available in North America outside of an ongoing multi-center trial.

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IV.C. LV outflow tract obstruction (LVOTO)

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Another cause of hemodynamic instability during weaning from CPB is LVOTO. LVOTO can be present in patients with hypertrophic cardiomyopathy, also known as “idiopathic hypertrophic subaortic stenosis,” and may be sufficiently severe to warrant surgical intervention. However, LVOTO can first appear

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intraoperatively most commonly after mitral valve surgery. The combination of systolic anterior motion (SAM) of the mitral valve leaflet, LV hypertrophy, and contact between the mitral leaflet and the septum

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during systole can lead to dynamic flow obstruction. The incidence of SAM after mitral valve surgeries is at least 4-6.6%[49,50]. Pre-repair echocardiographic findings of a redundant anterior leaflet, and anterior malpositioning of the coaptation point (anterior/posterior leaflet length ratio <1.3, and coaptation point to septum distance <2.5cm) can be used to identify those at increased risk of post-

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repair SAM[51].

Dynamic LVOTO post-bypass is the result of increased LV contractility, reduced diastolic volume and

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abnormal mitral leaflet mechanics. Medical management targeting these underlying mechanisms is usually successful. The hyperdynamic LV can be the result of improved cardiac function after repair

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and/or inotrope use. Tachycardia—shortened diastolic time—exacerbates LV under-filling. The reduced LV internal diameter potentiates the likelihood of SAM and leaflet-septum contact during systole. Management includes volume resuscitation to increase LV size, the use of negative inotropic and chronotropic agents such as beta-blockers, and an increase in anaesthetic depth. Hypotension in the setting of SAM is due to obstruction and not LV failure, so the use of a positive inotrope is counterproductive. Rather, phenylephrine is useful because it maintains systemic pressure to avoid myocardium ischemia and may induce reflex bradycardia. TEE is required to make the diagnosis of SAM

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and assess the treatment response. Rarely, SAM is so severe that a return to CPB for surgical intervention is needed[49].

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IV.D. RV dysfunction

During weaning from CPB, some patients may suffer from RV dysfunction. There are a number of

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culprits. Due to its crescent shape and anterior anatomy, hypothermia of the RV is challenging to

maintain with usual cooling techniques. Gas emboli tend to enter the more anteriorly positioned right

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coronary artery and cause acute RV ischemia. Post-bypass atelectasis and ventilation-perfusion mismatch can lead to an acute increase in PVR. Lastly, protamine administered to reverse anticoagulation can cause pulmonary vasoconstriction rarely precipitating RHF requiring emergent return to CPB. Patients with pre-existing PH and right heart dysfunction are more likely to experience

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persistent RV dysfunction post-bypass. The incidence of RHF after LVAD implantation—defined as the need for extended inotrope support (> 14 days) or rescue RVAD—is between 13-32%[52–54].

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RHF is common in patients on ECMO support as it is often initiated for right heart decompensation in the setting of severe lung disease. The RV, compared to LV, is less muscular, more compliant, with a

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lower EF and is normally exposed to the pulmonary vascular bed with one fifth of the systemic resistance. With chronic PH, the RV becomes hypertrophic to compensate for higher afterload. Unlike the LV, coronary perfusion of RV normally occurs throughout the cardiac cycle due to the favorable pressure gradient in the coronary arteries and the endocardium, but this normal perfusion pattern is interrupted when the RV systolic pressure approaches systemic pressure, and RV ischemia may occur with relatively mild systemic hypotension. Echocardiographic evidence of RV dysfunction include RV dilation, decreased free wall movement, decreased tricuspid annular plane systolic excursion (<2 cm),

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worsening tricuspid regurgitation and septal dyskinesia. The septum flattens, even bows leftward (Dsign), and is pathognomonic for RHF. The principle of ventricular interdependence dictates that LV filling is maintained by an adequate RV output, and RHF leads to decreased CO and systemic hypotension

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which causes further RV ischemia and sustains the undesirable cycle. Hemodynamically RHF is usually characterized by the combination of tachycardia, low CO, systemic hypotension, and elevated CVP. While an acute increase in pulmonary artery (PA) pressure may exacerbate RV dysfunction,

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“pseudonormalization” (i.e. decrease) of PA pressure is a late sign of RHF. Hemodynamic measurements, echocardiographic findings and laboratory evidence of organ dysfunction have been investigated as risk

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factors and prognostic tools, however these are based on single center experiences and have not been validated by others[55]. The management of RV dysfunction is especially challenging and usually falls into four categories: optimize preload, minimize afterload, enhance inotropy and maintain perfusion by

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avoiding systemic hypotension[56].

Accurate assessment of RV volume and function status is based on direct visualization (intraoperatively), echocardiography, and the CVP trend. The motion and behavior of the RV free wall during filling and

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contracting phases can be directly observed. TEE can visualize any dyskinetic septum movement and signs of volume overload. Transient manipulation of venous return with patient positioning can be used

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to test RV response to varying preload conditions. In the setting of volume overload, venodilation with nitrates such as nitroglycerin, may be used albeit cautiously due to the risk of systemic hypotension. Persistent volume overload may warrant the use of loop diuretic or RRT.

Avoiding additional increase in PVR is another important aspect of RV protection. This includes pulmonary toilet, minimizing airway pressures, and avoidance of hypoxia and respiratory or metabolic acidosis. This is especially important for ECMO patients in the ICU. The weaning process usually starts

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there where the ventilation strategy is optimized. ECMO flow rate is then slowly lowered to test the tolerance by the patient. The ability to maintain adequate oxygen saturation and blood pressure on

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minimal ECMO support (1 L/min) suggests the patient may be ready for separation from ECMO.

In patients with PH, pharmacological vasodilation of pulmonary vasculature may be necessary; this is most effective in those with primary PH. The underlying cause of PH—endothelial dysfunction—results

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from a pathologic imbalance between vasodilatory molecules such as NO and prostacyclins and vasoconstrictors such as endothelin receptors and thromboxanes. These molecules have been

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investigated as therapeutic targets for the treatment of PH and RHF (Table 3).

NO is a potent endogenous vasodilator due to its activation of GC and the cGMP pathway. NO is the active metabolite of medical nitrates such nitroglycerin and sodium nitroprusside, and is the basis of

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their vasodilatory effect. However, unlike intravenous nitrates which can cause significant systemic vasodilation, inhaled NO (iNO) is delivered directly to the pulmonary alveoli and vasculature, exerts its vasodilatory action locally without systemic effect because it is rapidly inactivated by binding to

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haemoglobin. In acute lung injury, iNO has the added benefit of improving ventilation-perfusion matching as it improves blood flow to ventilated alveoli. In lambs, iNO has been shown to decrease PVR

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at dosage up to 80 parts-per-million (ppm), but the effect plateaus significantly above 20ppm[57]. iNO is only approved in the U.S. for the treatment of neonatal hypoxic respiratory failure, but is frequently used for pulmonary vasodilation in both critical care and surgical settings, especially in heart transplantation, lung transplantation, and VAD implantation[58]. The starting concentration of iNO is usually between 10-20ppm. As a free radical, NO is further oxidized to nitrogen dioxide, NO2, which can cause pulmonary irritation and edema. At higher doses, NO binding of haemoglobin can generate significant level of methemoglobin. For these reasons, the levels NO and NO2 need to be closely

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measure by a calibrated delivery system, and fresh gas flow with ventilators needs to be sufficiently high to avoid NO2 buildup. Furthermore, postoperative weaning of iNO should be done gradually to avoid

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rebound PH and acute RHF from abrupt withdrawal.

Prostacyclin analogs are a class of medication with potent vasodilatory and anti-platelet aggregation activities. Prostacyclin (PGI2) and prostaglandin E2 (PGE2) are produced in endothelial cells by

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cyclooxygenase. They activate AC, increase intracellular cAMP which lead to vascular smooth muscle relaxation and inhibit platelet aggregation. Prostacyclin analogs include epoprostenol (intravenous and

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inhaled), treprostinil (IV, subcutaneous and inhaled) and iloprost (inhaled). Chronic intravenous epoprostenol has been shown in a randomized controlled trial to have symptomatic and survival benefits in patients with primary PH[59]. Furthermore, inhaled prostacyclin has been investigated as a pulmonary vasodilator in cardiac surgery. Inhaled PGI2 increased the success of weaning from CPB in

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patients with severe mitral stenosis and PH[60]. It is as effective as iNO in decreasing PA pressures and increasing CI in patients after heart transplantation[61]. The delivery of iNO through proprietary systems is simple and easily adjustable, whereas the delivery of PGI2 requires a nebulizer and pump, with

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complex dosing. Nonetheless, due to the cost of iNO, some centers have had success in transitioning postoperative patients on iNO to inhaled prostacyclin. Unlike iNO, systemic hypotension can occur with

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inhaled prostacyclin due to slower elimination. Those patients who are on chronic stable intravenous prostacyclin therapy should continue therapy in the perioperative or peri-procedural setting without interruption.

In addition to prostacyclins, two other classes of agents are frequently used in chronic management of primary PH—endothelin receptor antagonists and type 5 PDE (PDE-5) inhibitors. The initiation of these oral agents should be cautious and reserved for those patients with stable pulmonary arterial

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hypertension[62]. Endothelins are a class of potent vasoconstrictor molecules that activate PLC pathway to increase intracellular calcium in vascular smooth muscle cells that result in contraction and hypertrophy, and play an important role in PH. Three oral agents that block endothelin receptors have

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been approved—bosentan, macitentan, and ambrisentan—as a part of advance therapy for PH patients. All of them have the risk of hepatotoxicity and can cause peripheral edema. PDE-5 degrades cGMP thereby limits vasodilation induced by NO-dependent GC pathway. Approved PDE-5 inhibitors—

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sildenafil, tadalafil and vardenafil—promote pulmonary vasodilation and are used as stand-alone

therapy or as a part of combination therapy for PH[62]. Systemic hypotension and flush are common

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side effects, and their use is cautioned when the patient is on nitrate therapy. Patients who are on these chronic therapies may need to be transitioned to prostacyclin or iNO therapy during in the perioperative setting.

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Finally, positive inotropic agents mentioned in section IV.B.—dobutamine, milrinone and levosimendan—can enhance RV inotropy and reduce PVR and afterload. However, all of these intravenous agents, unlike iNO, also cause significant systemic hypotension and possible RV ischemia.

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Recently, nebulized milrinone has been investigated as a pulmonary vasodilator, as a less expensive alternative to iNO. In a randomized study, inhaled milrinone is as effective as its intravenous counterpart

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in reducing PAP while preserving systemic arterial pressure and SVR[63]. As mentioned earlier, vasoconstrictors are often necessary to counteract the systemic hypotension associated with the use of ino-dilator such as milrinone and dobutamine. The choice of vasoconstrictor agent is of some debate as catecholamines such as norepinephrine may increase PVR as well as SVR. In low doses, vasopressin appears to have less effect on PVR. One small study in off-pump coronary bypass surgery showed that vasopressin compared to norepinephrine—used to restore milrinone-induced systemic hypotension— caused a small but favorable decrease in PVR/SVR ratio[64].

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V. Summary

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Successful weaning from CPB or ECMO poses a significant challenge to the cardiothoracic surgeons and the anaesthetists. The withdrawal of MCS places strain on the patient’s native cardiopulmonary systems, and hemodynamic instability due to failed weaning attempt can be injurious. Diagnosing the cause of

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instability should be based on preoperative risk factors, perioperative course, echocardiographic

examination and clinician assessment. Pharmacological treatment should be directed at the underlying

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pathophysiology while remain mindful of the therapeutic and side effect profiles of each agent. While prolonged ECMO support may lead to other morbidities, keeping the patient on ECMO or transitioning one who has failed weaning from CPB to ECMO may be appropriate by allowing time for

VI. Practice points

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cardiopulmonary recovery.

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1. Preoperative cardiopulmonary function and clinical history before the initiation of CPB and/or ECMO have predictive value in the ease of weaning.

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2. Echocardiography is invaluable in the assessment of cardiac function and the diagnosis of problems during weaning from CPB and ECMO. 3. Common problems during weaning from CPB and ECMO include vasodilation, LV dysfunction, LVOTO and RV dysfunction. Multiple problems may co-exist. 4. Vasoconstrictors are used to treat systemic vasodilation but may cause tissue malperfusion and ischemia.

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6. Positive inotropic agents are useful in the treatment of LCOS but may cause arrhythmia and increase myocardial oxygen demand. 7. LVOTO is usually managed medically, involving volume resuscitation, HR control and avoidance of

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positive inotropic agents.

8. The management of RV dysfunction includes optimization of RV preload, decreasing RV afterload with pulmonary vasodilators, inotropic support, and maintaining RV perfusion by avoiding systemic

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hypotension.

9. Multiple agents may be used either working synergistically or to compensate for another’s deleterious

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side effects.

VI. Research agenda

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1. Development and trials of novel agents for the treatment of VS, LCOS and RHF. 2. Validation of prognostic tools to predict RHF and development of new therapeutic strategies. 3. Improvement in MCS technology and the management of patients on extended ECMO to decrease

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associated morbidities.

Conflict of Interest None

Acknowledgement

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Table 1. Potential problems during weaning from CPB or ECMO Problem Characteristics Pharmacological treatment Systemic vasodilation CI: normal to high Vasoconstrictors (adrenergic) LVEF: normal to high - Phenylephrine (10-100mcg/min) CVP: low - Norepinephrine (0.02-0.2mcg/kg/min) PAOP: low Vasoconstrictors (other) - Vasopressin (0.01-0.04mcg/kg/min) - Methylene blue (2mg/kg over 30-60min) LV dysfunction CI: low Positive inotropes (adrenergic) LVEF: low - Epinephrine (0.02-0.2mcg/kg/min) CVP: normal to high - Dobutamine (2-20mcg/kg/min) PAOP: high - Dopamine (2-20mcg/kg/min) Positive inotropes (PDE-3 inhibitors) - Milrinone (0.1-0.75mcg/kg/min) Calcium sensitizer - Levosimendan (0.05-0.2mcg/kg/min) LVOT obstruction CI: low Volume resuscitation LVEF: high Beta adrenergic antagonists CVP: low - Esmolol (50-300mcg/kg/min) Vasoconstrictor PAOP: low - Phenylephrine Anaesthesia Analgesia RV dysfunction CI: low Preload reduction LVEF: high Pulmonary vasodilators CVP: high - iNO (10-20ppm) PAOP: variable - Epoprostenol (inhaled nebulizer 2-50ng/kg/min) - Milrinone Positive inotropes - Dobutamine - Milrinone - Levosimendan

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Table 2. Routine checks and preparation before weaning from CPB Parameter Target goal Treatment Temperature > 36 degree C Warming Heart rate 70 – 100 bpm Epicardial pacing, atropine, inotrope Heart rhythm Sinus (preferred) Defibrillation, cardioversion, lidocaine, magnesium, amiodarone Ventilation Airway suction, recruitment, resume ventilation Electrolytes K: 3.5 – 5 mEq Ultrafiltration, diuresis iCa > 1.0 mEq Ca repletion Acid-Base pH > 7.3 Sodium bicarbonate

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Table 3. Pulmonary hypertension therapies Class Mechanism Nitric oxide cGMP dependent vasodilation

Sildenafil Tadalafil Vardenafil

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Endothelin antagonists Blocks endothelin induced PLC dependent vasoconstriction PDE-3 inhibitors cAMP dependent vasodilation PDE-5 inhibitors cGMP dependent vasodilation

Epoprostenol (IV, Inh) Treprostinil (IV, SC, Inh) Iloprost (Inh) Bosentan Macitentan Ambrisentan Milrinone

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cAMP dependent vasodilation

Side effects Rebound PH Reversal of right-to-left shunt Pulmonary edema Flushing Headache Hypotension Hepatotoxicity Peripheral edema Hypotension

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Prostacyclin

Agents iNO

Hypotension Vision change Hearing loss Priapism