Anesthetic Management for Cardiopulmonary Bypass: Update for 2014.

Seminars in Cardiothoracic and Vascular Anesthesia http://scv.sagepub.com/

Anesthetic Management for Cardiopulmonary Bypass: Update for 2014 Allison Bechtel and Julie Huffmyer SEMIN CARDIOTHORAC VASC ANESTH published online 10 April 2014 DOI: 10.1177/1089253214529607 The online version of this article can be found at: http://scv.sagepub.com/content/early/2014/04/09/1089253214529607

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SCVXXX10.1177/1089253214529607Seminars in Cardiothoracic and Vascular AnesthesiaBechtel and Huffmyer

Review

Anesthetic Management for Cardiopulmonary Bypass: Update for 2014

Seminars in Cardiothoracic and Vascular Anesthesia 1–16 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1089253214529607 scv.sagepub.com

Allison Bechtel, MD1 and Julie Huffmyer, MD2

Abstract Cardiopulmonary bypass has revolutionized the practice of cardiac surgery and allows safe conduct of increasingly complex cardiac surgery. A brief review of the bypass circuit is undertaken in this review. A more thorough review of the anesthetic management is accomplished including choice of anesthetic medications and their effects. The inflammatory response to cardiopulmonary bypass is reviewed along with interventions that may help ameliorate the inflammation. Keywords cardiac anesthesia, cardiopulmonary bypass, coronary artery bypass surgery, inflammation, ischemic-reperfusion injury

Introduction Cardiopulmonary Bypass While a review of the mechanistic components of cardiopulmonary bypass (CPB) is beyond the scope of this specific review and is further discussed in another review of this current journal issue, it is important to have some basic understanding of the process of CPB. The CPB circuit is designed to take on the work of the human heart and lungs to accomplish the following functions: divert blood from the patient in order to provide optimal surgical conditions, oxygenate and remove carbon dioxide from the blood, cool and rewarm the patient’s blood and body where appropriate, and return blood to the patient. Venous blood is drained from the right side of the patient’s heart to the venous reservoir, which is a large container that serves as the “mixing chamber” for blood, fluids, and drugs that are added to the circuit. Blood is drained from the patient mainly as a result of gravity or a siphon effect where the difference in central venous pressure, height from patient on the operation room table to the venous reservoir (which is conventionally very low to the ground), and any resistance in the venous circuit determines the efficiency of drainage. From the venous reservoir the blood travels directly to the oxygenator and heat exchanger where oxygenation, removal of carbon dioxide, and warming or cooling of the blood occurs. Blood is then passed through the arterial filter and returned to the patient via the arterial side of the circuit. Additional vents decompress the left ventricle and in-line filters remove air and debris. Cannulae in the aortic root and coronary sinus supply cardioplegia solution to arrest the heart during surgery. There are safety mechanisms built into the CPB circuit such as bubble detectors, pressure monitors, and oxygen

fail safe monitors. None of these supplant the vital need for qualified expert perfusionists to manage the bypass circuit in addition to anesthesiologists skilled and trained in the management of patients with cardiac disease undergoing cardiac surgery.

Anesthetic Management Despite the support from CPB, the anesthesiologist plays a central role in bringing the entire cardiac surgical team together. Anesthesiologists trained in the care of patients undergoing cardiac surgery help individualize the anesthetic management while on bypass, and importantly direct and facilitate weaning from bypass. This article will review conduct and anesthetic implications of CPB organized into the prebypass and bypass periods and then provide a more in-depth review and update of some anesthetic management decisions including modulation of the stress response and acute lung injury as a complication related to CPB. Postbypass anesthetic management and considerations will not be reviewed.

Prebypass Period General Concerns. Preoperative preparation and evaluation, monitoring, induction, and maintenance of anesthesia for patients requiring CPB for heart surgery remains a vital 1

Emory University, Atlanta, GA, USA University of Virginia, Charlottesville, VA, USA

2

Corresponding Author: Julie Huffmyer, University of Virginia, PO Box 800710, Charlottesville, VA 22908-0710, USA. Email: [email protected]


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Seminars in Cardiothoracic and Vascular Anesthesia

Table 1. Prebypass Checklist. Anesthesia medications •• Volatile anesthetics, IV anesthetics, analgesia, paralysis Monitoring •• TEE •• Arterial blood pressure Anticoagulation •• Heparin or other agent •• Assure adequate anticoagulation: ACT 250 with heparin coated circuit (Ovrum E), otherwise 350 to 400 seconds of heparin concentration monitoring >2 units/mL41-44 Arterial cannulation •• Blood pressure management during placement •• Test the line, evidence of dissection Venous cannulation •• SVC/IVC obstruction •• Inspect head and neck •• Venous drainage

and incredibly important aspect of anesthetic management but will not be reviewed in this article. Planning for maintenance of anesthetic depth, neuromuscular relaxation, and prevention of awareness during CPB is important during the prebypass period (Table 1). Paralysis is vital to prevent shivering during cooling and rewarming, which will increase myocardial oxygen consumption. Movement by the patient if not adequately paralyzed can cause disruption or dislodgement of life-sustaining cannulae for CPB. In the time prior to initiation of bypass as well as the maintenance of bypass and separation periods, episodes of transient or prolonged hypotension due to either surgical necessity or patient hemodynamic instability may place patients at risk for awareness. Processed EEG as in use of the bispectral index (BIS) during anesthesia for cardiac surgery has been shown to help prevent awareness and guide use of anesthetic medications and agents.1,2 Hypothermia in addition to related changes in physiologic function such as protein binding, liver and kidney perfusion, and metabolic rate may decrease anesthetic requirements; hence, BIS levels have been shown to be lower in patients during hypothermia during CPB.3 Puri and colleagues studied 30 patients monitored with BIS during cardiac surgery and those whose BIS values were known and used to titrate anesthetic medications had significantly less hypertension and tachycardia and had a nonsignificant reduction in time to recovery of consciousness.4 BIS values also were significantly higher in the blinded group at times that are prone to awareness: the commencement and termination of CPB.4 Another group evaluated 40 patients undergoing coronary artery bypass graft (CABG) with CPB who were anesthetized with propofol and remifentanil infusions, one group targeting the propofol infusion to BIS levels of 40 to 50.5 The BIS targeted group allowed a 30%

reduction in propofol infusion rates without affecting the stress response to surgery.5 A very recent substudy of cardiothoracic patients in the BAG-RECALL trial found that significantly fewer patients in the BIS-guided group developed postoperative delirium as compared to standard end tidal volatile anesthetic monitoring.6 Thus, evidence suggests use of the BIS to help not only reduce awareness in an at-risk population but also to possible decrease delirium and attenuate rapid changes in hemodynamics through providing a stable anesthetic course. Use of near-infrared spectroscopy (NIRS) as a noninvasive monitor for cerebral oxygenation during cardiac surgery and CPB has been suggested in addition to an algorithm to treat cerebral oxygen desaturation and reduce neurologic complications.7,8 Harilall and colleagues randomized 40 patients for CABG surgery with CPB to NIRS with protocol versus no NIRS.9 They found significantly higher levels of S100β, a marker of neurological injury as well as significantly increased desaturation time in the control group.9 Interventions undertaken in response to cerebral oxygen desaturation by NIRS include increasing blood pressure, assuring adequate hemoglobin levels, increasing oxygen content of the blood, and increasing carbon dioxide tension to increase cerebral blood flow. A recent study evaluated the use of norepinephrine and phenylephrine as vasoconstrictors to treat hypotension on CPB.10 These investigators found significant reduction in frontal lobe oxygenation in diabetic patients with the use of norepinephrine and a nonsignificant trend toward reduction in oxygenation with phenylephrine in the same group of patients.10 A major goal of anesthesia for cardiac surgery aims at reducing the normal neurohumoral response to surgical stress. There are several options for induction and maintenance of general anesthesia in the cardiac surgery patient that are able to accomplish this goal. Opiates. Historically high-dose opiate techniques combined with amnestic agents such as benzodiazepines were chosen to provide stable anesthetic and analgesic effects and the least deleterious effects on hemodynamics. Another technique involves the combination of low-dose opioids and short-acting hypnotic drugs for “fast-track” cardiac anesthesia care with a goal for extubation within a specific time period and decreased length of stay in the intensive care unit (ICU) and hospital. A recent Cochrane review11 found that a low-dose opioid technique combined with time-directed extubation protocols for fast-track cardiac surgery patients has a comparable risk of complications including myocardial infarction, stroke, acute renal injury, sepsis, and major bleeding and mortality as compared to high-dose opioid-based general anesthesia. The authors concluded that in low and moderate risk patients, fast track interventions are safe and effective for earlier


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Bechtel and Huffmyer extubation and decreased ICU length of stay.11 Remifentanil may be an ideal drug for fast-track cardiac anesthesia given that it preserves hemodynamic stability, has rapid onset and offset times despite extended infusion times due to its low context sensitive half-time, and is able to successfully attenuate the stress response to surgical stimuli as a strong analgesic. The benefits from remifentanil anesthesia include decreased cardiac troponin release, earlier time to extubation, decreased hospital length of stay.12 Remifentanil appears to be useful for cardiac preconditioning with high doses of remifentanil prior to sternotomy leading to decreased cardiac injury in patients undergoing onpump CABG surgery.13 An earlier study of fentanyl and remifentanil demonstrated no difference in time to extubation but an improved blunting of hypertensive responses and cortisol excretion in the remifentanil group but more episodes of hypotension.14 In a more recent study, patients administered remifentanil as compared to fentanyl for CABG surgery had attenuation of the exaggerated inflammatory response and a decreased ICU length of stay.15 One noted side effect of high-dose remifentanil infusion or bolus doses is hypotension and increased use of inotropes, but this is an acknowledged side effect and the dose can be adjusted accordingly since low-dose remifentanil infusion without bolus administration appears to preserve hemodynamics even in patients with poor cardiovascular function.12 Postoperative analgesia must be addressed if remifentanil is chosen for maintenance. Anesthetic Induction Agents/Adjuncts: Propofol, Etomidate, and Ketamine. Propofol is a common anesthetic agent used for induction and maintenance in cardiac surgery. Hemodynamic consequences associated with use of propofol for anesthetic induction include transient vasodilation, myocardial depression, and a reflex tachycardia, but these effects can be ameliorated or even abolished with careful titration, use of smaller total induction doses, and a balanced technique. In an early study evaluating the effects of propofol for patients undergoing CPB, high-dose propofol infusion (200 µg/kg/min) decreased mean arterial pressure and cardiac index while causing an increase in heart rate.16 Myocardial blood flow and myocardial oxygen consumption were decreased by 26% and 31%, respectively.16 Myocardial lactate production was seen in one patient reflecting production of myocardial ischemia.16 High-dose propofol infusion during cardiac surgery resulted in lower levels of plasma markers for cerebral injury compared to low-dose propofol regimen.17 This appears to be a dosedependent brain protective effect of propofol due its antiinflammatory and antioxidant properties.17 Other evidence indicates that propofol has beneficial effects such as antioxidant, antianxiolytic, and immune system modulating effects.18 Etomidate is a commonly used anesthetic induction medication in patients with poor cardiovascular reserve

but it has been shown to cause suppression of adrenal function even after a single dose.19,20 In cardiac surgery patients etomidate has also been associated with reduction in adrenal function for 24 hours but this has not translated into an increase in vasoconstrictor requirements.21 Ketamine may possess beneficial anti-inflammatory effects for patients undergoing cardiac surgery with CPB. Patients randomized to ketamine-propofol-midazolam as compared to sufentanil-propofol-midazolam for cardiac surgery had significantly lower levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and significantly higher levels of the anti-inflammatory cytokine IL-10 after aortic unclamping.22 A 2012 meta-analysis of 684 patients, including 8 studies using CPB as well as noncardiac surgery studies, demonstrated that administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response.23 Volatile Anesthetics. In general, volatile anesthetic agents used via vaporizer on the bypass circuit provide reduction in systemic vascular resistance and blood pressure as well as anesthetic to the patient. The decrease in blood pressure associated with all the currently used volatile anesthetics is a result of vasodilation and depression of myocardial contractility. One recent study evaluated with microcirculatory changes associated with sevoflurane, isoflurane, and desflurane for patients undergoing cardiac surgery with CPB and found that sevoflurane had a negative effect on the microcirculation, isoflurane decreased vascular density but increased flow and desflurane produced the most stable effects on the microcirculation.24 These changes only persisted at most for the first 24 hours after surgery and were not associated with changes in ICU length of stay.24 Volatile anesthetics possess some cardioprotective properties such as preconditioning and postconditioning effects that attenuate apoptosis and necrosis and help decrease myocardial dysfunction after ischemia and reperfusion.25,26 In addition there may be activation of protective enzymes that also protect the heart.25,26 Vasodilatory, anti-inflammatory, and antioxidant effects have also been ascribed to the use of volatile anesthetics and may play a role in the protection of the myocardium.27-29 Sevoflurane at 4 volume % (or 2 MAC) significantly decreased the postoperative release of brain natriuretic peptide, a marker of myocardial contractile dysfunction and showed pronounced translocation of protein kinase C δ and ε (a measure of the occurrence of effective preconditioning at the cellular level).30 A meta-analysis of 38 randomized trials from 1991 to 2012, with studies mainly done in CABG surgery utilizing CPB showed that volatile anesthetic agents were associated with reduction in mortality as compared to total intravenous anesthetic (TIVA), which was defined as being “not volatile” with mortality of 1.3% in volatile anesthetic group as compared to 2.6% in the TIVA group, yielding an odds ratio of 0.51, confidence interval of 0.33 to 0.81. In


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this same meta-analysis use of sevoflurane or desflurane alone were individually associated with reduced mortality as compared to TIVA.31 Neuraxial Anesthesia. Benefits of thoracic epidural anesthesia (TEA) for pain control during and after cardiac surgery include a sympathetic block with stable heart rate and decreased myocardial consumption, coronary artery dilation, and increased arrhythmia threshold. In this age of minimally invasive surgery, TEA may become a beneficial technique for stable hemodynamics and fast-track extubation and hospital discharge.32,33 The combination of TEA with general anesthesia may lead to a decrease in acute renal injury, postoperative ventilation, and the composite endpoints of myocardial infarction and death.34 Spinal anesthesia has also been evaluated and considered in cardiac surgery patients. High-dose intrathecal bupivicaine (37.5 mg) was combined with general anesthesia as compared to sham spinal anesthesia with skin local anesthetic and general anesthesia resulted in less beta adrenergic receptor dysfunction and lower stress response during CABG surgery.35 In a meta-analysis from 2011,36 use of TEA was shown to significantly reduce supraventricular tachyarrhythmias and respiratory complications, but the authors report this based on a fairly large number of studies spanning 30 years during which anesthetic agents and technical considerations advanced dramatically. In addition, one of the main concerns in providing TEA is the risk of epidural hematoma, given that full anticoagulation must be achieved in order to maintain CPB. In this same metaanalysis,36 no cases of epidural hematoma were reported. More recently, a 2012 risk assessment of TEA for cardiac surgery37 revealed very low risk for epidural hematoma. The authors conclude that risk of an epidural hematoma is similar in a patient undergoing cardiac surgery and general surgery. Another 2012 study revealed no complications related to neuraxial anesthesia in a series of 714 pediatric and adult patients undergoing cardiac surgery with CPB requiring full heparinization for congenital heart disease.38 Therefore, the updated risk calculation reveals that it is not unreasonable to provide TEA for cardiac surgery patients provided that an appropriate protocol is in place to safely manage these patients with particular attention to their coagulation profiles and preoperative and postoperative antiplatelet therapies.37 Cannulation Sites and Options. Choice of cannulation sites for both the venous and arterial systems is largely determined by the surgical plan and whether the patient has had previous heart surgery that may make it difficult technically to gain access to the heart and great vessels for cannulation. Central cannulation consists of one aortic cannula in the ascending aorta for the arterial line and venous drainage from the right atrium. Axillary arterial cannulation or femoral arterial and venous cannulation may be

employed in emergency situations, in case of repeat sternotomy, or in procedures that involve the ascending aorta and arch.39 TEE can be used to help visualize vessels, guidewires, and cannulae and help guide successful placement especially in the setting of peripheral cannulation for minimally invasive cardiac surgeries.40 Arterial Cannulation. Arterial cannulation is completed first as a safety mechanism. If a vascular disaster occurs after arterial cannulation, volume resuscitation can proceed through the arterial cannula or in extreme situations, “sucker bypass” may be employed whereby a drop-in suction catheter in the chest becomes the venous line that diverts blood to the reservoir and arterial return can begin via the aortic cannula. Heparin is given for anticoagulation prior to aortic cannulation (see Table 1). During aortic cannula insertion, systolic blood pressure is reduced temporarily to 80 to 90 mm Hg in order to reduce sheer stress on the aorta and prevent aortic dissection. Other complications associated with aortic cannula placement and positioning include embolization of air and atheromatous/ calcific material, accidental/inadvertent aortic arch vessel cannulation, and vascular injury. In cases of highly calcified, porcelain aortas or high atheroma burden, prior to placement of the aortic cannula or to plan alternative methods of cannulation, epiaortic ultrasound scanning may be employed and has been found to be helpful in identification of potential cannulation sites/avoidance of disruption of atheromatous plaques.45,46 Venous Cannulation. Venous cannulation of the right side of the heart for drainage to the bypass circuit can be accomplished in a variety of ways. A single “multi-stage” venous cannula inserted into the right atrial appendage via a single atriotomy incision is useful for procedures on a closed heart such as coronary artery bypass grafting or aortic valve replacement. Bicaval cannulation is accomplished with 2 separate cannulae placed into the superior vena cava and inferior vena cava. Bicaval cannulation provides complete isolation of the right side of the heart such that it can be operated on or through such as in mitral and tricuspid valve surgery. Return of blood to the venous reservoir may be impaired by impingement of the venous cannulae; thus, it is important for the anesthesiologist to check the level of blood in the venous reservoir at the start of CPB and intermittently throughout bypass. It is also important to do a brief physical exam to assure adequate venous drainage of the head, by looking for signs of venous engorgement such as swelling of the head, neck, and tongue, conjunctival and facial edema. IVC engorgement is more difficult to evaluate and may only be noticed by a fall in venous reservoir volume. If femoral venous cannulation is used, it may not provide enough drainage of blood from the heart in order to empty the right ventricle and thus partial bypass may only


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Bechtel and Huffmyer be undertaken. This causes blood to remain circulating through the right heart and the pulmonary vasculature, necessitating continuation of mechanical ventilation and oxygenation. If ventilation is discontinued, shunt physiology may occur. Thus, if femoral venous cannulation is planned, an alternative method of venous drainage may be required once full mediastinal access is achieved or partial bypass may be used with continued mechanical ventilation and oxygenation. Making certain that the femoral venous cannula is inserted into the right atrium, with the tip near the SVC under TEE guidance as well as providing lowvacuum-assisted drainage on CPB can help improve the venous drainage. Other Cannulae in the Heart. The bronchial, thebesian, and systemic to pulmonary collateral networks drain into the left side of the heart. This can cause the left ventricle to be injured due to distention and increased wall tension during the period of bypass. Venting is required to remove this blood and avoid distention. A left ventricular vent is placed via the left superior pulmonary vein, in addition to the dual-functioning aortic root vent/antegrade cardioplegia cannula. Antegrade cardioplegia is delivered into the aortic root through a small cannula and retrograde cardioplegia is delivered into a coronary sinus catheter for areas of the heart that are silently ischemic or unable to be reached by antegrade cardioplegia.

Initiation of Bypass Once the patient has been adequately prepared for the onset of CPB and the prebypass checklist conditions are met, the perfusionist unclamps the venous line, allowing blood to fill the venous reservoir while returning oxygenated blood from the arterial line to the patient’s aortic cannula. This process occurs fairly quickly, and full bypass flow is said to occur once all systemic venous blood is drained from the patient to the venous reservoir. The heart is still contracting, but with full CPB flow, there is a mean arterial blood pressure visible on the arterial line, and pulsatility decreases significantly. Once full flow is assured, mechanical ventilation and oxygenation may be discontinued (Table 2). Other methods of ventilation will be reviewed in relation to prevention of respiratory dysfunction later in this article.

Bypass Period What is the ideal flow on CPB? What is the ideal blood pressure on CPB? These represent age-old questions, and the debate continues as to which is more important. CPB flow is effectively the output of the pump and is akin to cardiac output, which is then divided by body surface area and cardiac index is calculated. Flow during CPB is a

Table 2. Bypass Period Checklist. Venous outflow •• What is blood level in venous reservoir? •• Evidence of SVC obstruction Arterial return •• Appropriate oxygenation of arterial return blood •• Signs of arterial dissection •• Hypotension on bypass? Hemodilution? •• Signs of unilateral overperfusion? Full bypass •• Assessment of pressure and flow on CPB Discontinue mechanical ventilation •• Consider continuation of low tidal volume ventilation Discontinue fluids and drugs from anesthesia •• Any medications required to CPB •• Continued need for anesthetic and neuromuscular paralysis

balance between providing oxygen delivery to the tissues and assuring surgical visualization by providing as bloodless field as possible. The most common goal is to flow at the lowest level that provides good surgical conditions yet does not result in end organ oxygen delivery impairment. Pump flow and pressure are related through arterial impedance, which refers to a combination of hemodilution, temperature, and cross-sectional area of the arterial bed. Mean Arterial Pressure. Clinicians who advocate for lower MAPs on bypass (50-60 mm Hg) suggest that there is less trauma to blood elements, reduction of blood in the surgical field, improved myocardial protection through reduced collateral coronary blood flow, and reduced embolic load to the brain.47 In patients who are chronically hypertensive, data indicate that the lower limit of autoregulation and thus the safe lower limit for MAP during CPB may be higher than the conventional 50 to 60 mm Hg.48,49 Potential advantages of using higher MAP on bypass include enhanced tissue perfusion in patient with history of hypertension and diabetes, improved collateral blood flow to tissue beds at risk for ischemia, and higher MAP allows for higher pump flow rates on CPB.47 CPB Pump Flow. Pump flow is determined by several variables including the patient’s body surface area, degree of hypothermia, acid–base balance, oxygen consumption, oxygen content of the blood, and depth of anesthesia. The flow rate most commonly used during CPB is that approximating a normal cardiac index for an anesthetized normothermic patient with a normal hematocrit level, 2.2 to 2.5 L/min/m2.50 When patients are perfused with hypothermic bypass and lower hematocrit in the range of 22%, lower pump flows are possible, in the range of a cardiac index of 1.2 L/min/m2.51 Perfusionists and anesthesiologists monitor mixed venous oxygen saturation (SvO2) as a guide to


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trend perfusion of end organ tissue beds. SvO2 of 70% is the target but does not guarantee optimal tissue perfusion to some beds such as muscle and fat, which are effectively removed from the circulation when on bypass.52 Osawa and colleagues performed an animal study to evaluate the safe levels for hematocrit and mixed venous oxygen saturation on CPB and found hematocrit level >12% and SvO2 >46% to be “safe” for CPB.53 In a study of patients undergoing CPB, Ranucci and colleagues identified the lowest hematocrit of 26% associated with increased renal impairment outcomes that allows an oxygen delivery of 262 mL/ min/m2.54

Preparation for Separation From Bypass Once the cardiac surgical procedure is complete, preparation for the process of separation from bypass begins. This is a multistep process and is a reverse of the prebypass phase, beginning with rewarming of the patient and culminating in separation from bypass, reversal of anticoagulation, and removal of bypass cannulae. There is potential for awareness under anesthesia and shivering as well as diaphoresis during this phase of bypass and measures such as recommended in the prebypass phase should be undertaken here to prevent awareness. Table 3 provides a checklist of events that should occur in order to prepare for separation from CPB. Rewarming. During the rewarming phase, the patient is gradually warmed by increasing the temperature of the arterial return blood via the heat exchanger of the bypass machine. Rewarming represents a potentially problematic phase of the bypass period as there is temptation to rewarm quickly, which requires high temperatures of the return blood or perfusate. Cerebral hyperthermia may cause increased free radical production, enlargement of any new cerebral ischemic penumbral zones, oxygen supply and demand mismatch in the brain, intracellular acidosis, and increased excitatory amino acid neurotransmitters, which can lead to neurologic injury and cognitive dysfunction in the postoperative period.55 The brain is predisposed to developing hyperthermia given that it receives a greater amount of overly warmed blood and is located near the inflow cannula in the proximal aorta. In addition, the nasal temperature may underestimate the actual cerebral temperature by 1°C to 2°C.56 An appropriate strategy to manage temperature prior to coming off bypass involves monitoring temperature in the nasopharynx, tympanic membrane, and arterial inflow line. In patients who are at increased risk for neurological injury or cognitive dysfunction, the goal should be mild hypothermia (34 to 35°C), followed by slowly rewarming the patient to no more than 37°C in order to prevent cerebral hyperthermia.56 A goal temperature for separation from bypass is 35.5°C to 36°C so as to prevent overwarming of the brain.

Table 3. Separation From Bypass Checklist. Rewarming •• What is patient temperature? •• Readminister anesthetic drugs and paralytics Electrolytes/acid–base balance •• Potassium, calcium •• Hematocrit •• pH, metabolic or respiratory acidosis •• SVO2 Heart rhythm •• Defibrillation •• Pacing necessary? •• Arterial blood pressure •• Is vasoplegia present? Deairing •• Look for air on TEE •• Be wary of air-induced right ventricular dysfunction •• Mechanical ventilation •• Recruitment of lungs •• Treat atelectasis •• Resume ventilation and oxygenation prior to working the heart Vasoactive medications and inotropes •• Evaluate need for medications prior to working the heart •• Make sure medications are reaching the patient, via central access •• Work the heart •• Reduce support from CPB, allow more blood flow through the heart •• Remember to ventilate first TEE/hemodynamic evaluation •• As CPB is weaned, evaluate TEE for heart function, regional wall motion •• Valvular function Potential need for mechanical support •• Will patient sustain self off CPB? •• Possible options to consider: IABP, VAD, ECMO

Arterial Blood Pressure. Once aortic cross clamp is removed, the coronary arteries are once again perfused in an antegrade fashion with blood from the aortic cannula. Consequent to rewarming and removal of the cross-clamp, some patients have a significant reduction in MAP as measured by a radial artery blood pressure monitor. This reduction in peripheral arterial pressure is a result of presumed vasodilation and often there is a radial-central aortic blood pressure discrepancy, such that monitors of central blood pressure reveal a significantly higher MAP than the radial catheter.57 Vasodilation is usually a transient problem during separation from bypass and the early postbypass period, but a measure of central aortic blood pressure (either palpation of the ascending aorta, aortic blood pressure monitoring via the aortic root cannula, or femoral arterial line) may be needed to help guide therapeutic decisions.58


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Bechtel and Huffmyer Heart Rhythm. Ventricular fibrillation after removal of the cross-clamp and rewarming is common and it may spontaneously convert, but prolonged ventricular fibrillation should be treated aggressively as subendocardial perfusion suffers, myocardial oxygen consumption increases and the left ventricle may become distended, which risks injury in the face of reduction in oxygen supply. Biphasic waveform defibrillation is accomplished with internal paddles at energies of 10 Joules with increases of 5 Joules for each cumulative defibrillation attempt.59 Acid–base balance and electrolytes should be evaluated and abnormalities treated. Lidocaine and amiodarone also aid with successful defibrillation. Junctional bradycardia is a common first rhythm after the cross-clamp is removed and is usually inadequate to maintain perfusion and cardiac output in the face of weaning from CPB. Current methods of pacing include atrial pacing, ventricular pacing, atrioventricular pacing, and biventricular pacing. The BiPACS trial is a randomized, controlled study that evaluated biventricular pacing for patients undergoing open-heart surgery. The results of this study revealed that BiV pacing increased cardiac output by 13% versus patients without pacing while patients who only had atrial pacing at the same heart rate did not have an increased cardiac output immediately after discontinuation from CPB.60 De-Airing. Air emboli can have significant negative effects while weaning from CPB, after separation from bypass, and in the postoperative period including neurological deficits, ventricular dysfunction, and arrhythmias. There are several methods for de-airing including Trendelenburg position, partial ascending aortic side clamping, CO2 insufflation, left heart vents, and the Lund technique. The Lund technique involves the following steps.61 Opening of the pleural spaces and lung collapse takes place after initiation of CPB. Prior to weaning from CPB, the aortic root is suctioned with complete collapse prior to removal of the cross-clamp. LV preload is increased to allow blood to move through the right heart and lungs and out the LV vent until no air is seen in the left heart. The patient is ventilated and the heart is allowed to eject with continued de-airing maneuvers. This technique is a faster and safer method that is easily reproducible with significantly less gas emboli on TEE and microemboli on transcranial Doppler.61 Intracardiac air, which reflects as highly echogenic on TEE, commonly collects in the right and left superior pulmonary veins, left ventricular apex, left atrium, left atrial appendage, pulmonary artery, and right coronary sinus of Valsalva. Once blood flow is restored to the lungs, air bubbles most commonly migrate to the right coronary artery and innominate artery. Evidence of air embolism may include right coronary ischemia and right ventricular dysfunction, which is treated with increased perfusion pressures and hemodynamic support.62

Restoration of Mechanical Ventilation and Oxygenation. Once the heart is ejecting and the surgical procedure is completed during the bypass period, if ventilation has been discontinued, mechanical ventilation and oxygenation must begin. Conventionally, the lungs are not ventilated during the period of CPB since the CPB machine takes over the respiratory/gas exchange function and lack of ventilation reduces movement in the surgical field and improves surgical visualization. There is suggestion that this apnea not only promotes atelectasis but also activation of enzymes in the pulmonary circulation that is correlated with postoperative lung dysfunction.63 Methods of providing some ventilation to the lungs have been proposed including intermittent continuous positive airway pressure (CPAP), low frequency/low tidal volume ventilation, ventilation with some pulmonary artery perfusion in order to match perfusion and ventilation. Studies of these methods to provide ventilation with and without perfusion have shown some improvement in the inflammatory response and compliance of the lungs,64,65 time to extubation and extravascular lung water but no overall outcome difference.66 A small randomized study of isolated valve surgery patients recently reported that the patients who were managed with beating heart, on CPB surgery and low tidal volume ventilation throughout had lower levels of inflammatory and oxidative stress markers such as malondialdehyde, lactic acid, and myeloperoxidase.67 While some studies have looked at inflammatory markers, a more recent meta-analysis of trials evaluated the outcomes of different methods of ventilation management during CPB.68 Use of continuous positive airway pressure (CPAP) from 5 to 15 mm Hg with range of FIO2 from 0.21 to 1.0 during CPB showed an improvement in oxygenation and decrease of shunt fraction immediately after CPB weaning but may interfere with surgical exposure.68 Vital capacity maneuvers 1 to 3 times with a pressure of 35 to 40 cm H2O at the end of the CPB period also improved the oxygenation in the early post-CPB period.68 Despite early improvements in oxygenation, neither CPAP nor vital capacity maneuvers had sustainable effects on oxygenation or lung function into the ICU time period.68 In this same meta-analysis, continuation of low tidal volume ventilation during the CPB period was not associated with any improvement in clinically relevant respiratory or oxygenation parameters.68 In 2 other trials,69,70 investigators reported earlier extubation in patients treated with CPAP on CPB and earlier extubation in patients receiving vital capacity maneuvers possibly due to increased surfactant release. Finally, the studies that looked at ventilation during CPB failed to show an improvement in oxygenation indices, AaDO2, and the length of hospital stay.68 Vasopressors and Inotropes. Calcium is administered after the aortic cross-clamp has been removed and while


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Table 4. Hemodynamics and Decision-Making Post-Bypass. Arterial BP

Pulmonary Artery Pressure

Cardiac Index

↓

↓

Normal

↓

↑

↓

↓

Normal

↑

↓

↑

↓

TEE Findings

Condition

Left and right ventricles Hypovolemia small and underfilled; good ventricular function Regional wall motion Left ventricular abnormalities, global ischemia, failure, hypokinesis of LV, dilated dysfunction LV Heart may be underfilled, Vasodilation; no resistance to ejection; vasoplegia increased contractility RV distention with small underfilled LV; reduced excursion of RV free wall; tricuspid regurgitation

weaning from CPB to improve cardiac contractility and systemic perfusion through vasoconstriction.71 Negative effects of calcium administration include increased ischemic injury, decreased diastolic compliance and relaxation, and decreased systolic function during reperfusion with corresponding stunned myocardium.72 Indications for calcium administration include hypocalcemia and hyperkalemia in order to improve cardiac conduction and contractility.73 Vasopressors and inotropes are started during bypass weaning to improve blood pressure and contractility, respectively. A variety of drugs can be used to assist in weaning a patient from bypass. An action plan including vasopressors is reviewed along with arterial blood pressures, pulmonary artery pressures, cardiac index, TEE findings, and common conditions that occur in weaning or after bypass in Table 4. There are several newer drugs including natriuretic peptides (nesiritide) and calcium-sensitizing agents (levosimendan) that may be useful in cardiac surgery patients. Levosimendan is an inodilator that functions by increasing inotropy through sensitization of troponin to intracellular calcium without c-AMP and it has properties of a phosphodiesterase inhibitor that increases peripheral and coronary vasodilation. This drug may be useful in cardiac surgery patients since levosimendan therapy leads to decreased myocardial damage and improved cardiac function with increased tissue perfusion as well as earlier time to hospital discharge.74 A recent meta-analysis showed reduced postoperative mortality in patients who were given levosimendan as compared to those treated in the control arm.75 In a nonsurgical meta-analysis, levosimendan was associated with improvements in hemodynamic status and reduction in mortality as compared to

Right ventricular failure or dysfunction

Action Plan Administer fluid volume bolus Support LV: milrinone, epinephrine, dobutamine, device (IABP, LVAD, ECMO) Add Vasoconstrictor: vasopressin, norepinephrine, phenylephrine, dopamine, methylene blue Support RV function: milrinone, epinephrine, dobutamine, inhaled prostacyclin or inhaled nitric oxide

dobutamine.76 Lomivorotov and colleagues77 studied high risk, low ejection fraction patients undergoing CABG who were randomized to levosimendan or intra-aortic balloon pump (IABP) therapy. They found that patients treated with levosimendan had lower postoperative troponin levels as well as improved hemodynamics as compared to patients with IABP.77 Nesiritide is a natriuretic peptide with rapid onset and short duration that increases cardiac index and decreases pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), mean arterial pressure (MAP), and systemic vascular resistance (SVR). In patients with pulmonary hypertension and decreased ejection fraction, nesiritide may lead to improved postoperative renal function, decreased hospital length of stay and decreased mortality.78 One of the challenges during separation from CPB and in the post-CPB phase, particularly after prolonged bypass time, is vasoplegic syndrome. Vasoplegic syndrome is characterized by severe, vasopressor-resistant vasodilation due to activation of nitric oxide synthase, vascular smooth muscle ATP-sensitive potassium channels, and relative deficiency of vasopressin. First-line therapy includes adequate fluid resuscitation and vasopressor drugs such as phenylephrine, norepinephrine, epinephrine, dopamine, and vasopressin. Methylene blue acts as a competitive inhibitor of nitric oxide and has been used as a rescue drug.79 Vasopressin, in the setting of euvolemia, can be useful for improving vascular tone while separating from CPB especially since metabolic acidosis does not impair the function of vasopressin receptors.80 If during the weaning from bypass period despite all preparation to separate from bypass including vasopressors, inotropes, electrical therapies such as pacing,


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Bechtel and Huffmyer treatment of electrolyte abnormalities, it becomes evident that the native heart is not functioning well enough to separate from bypass or life-sustaining blood pressure and function is absent, mechanical support may be warranted. An intra-aortic balloon pump or counterpulsation (IABP) or a ventricular assist device (VAD) should be discussed and implemented as necessary. In the past, studies have shown a high mortality rate in patients who receive an IABP intra- or postoperatively, between 21% to 73% associated with rare but serious complications from IABP placement including limb ischemia, vascular injury, bleeding, infection, and stroke.81 However, a recent meta-analysis82 showed that prophylactic IABP for high-risk patients undergoing CABG surgery leads to decreased postoperative low cardiac output syndrome and risk of death. Preoperative IABP in patients undergoing cardiac surgery leads to decreased length of stay in the hospital and ICU.82 This meta-analysis also revealed a low complication rate of 7.4%.82 In patients with failure to wean from CPB due to respiratory and/or cardiac failure, extracorporeal membrane oxygenation (ECMO) may be considered as a bridge to recovery of heart and lung function.83 However, it is important to risk stratify potential ECMO candidates. Prediction of weaning from ECMO and survival to hospital discharge appears to be related to a rapid decrease in inflammatory mediators within 2 days of ECMO initiation.84

Separation From Bypass Separation from CPB is the process of decreasing venous return to the venous reservoir and increasing the volume to the patient’s heart. Successful weaning from CPB concludes with the removal of cardioplegia and venous and arterial cannulae. TEE is a valuable monitor that can be used to evaluate cardiac function, valve prosthesis function and to look for other complications. Eltzschig and colleagues report that TEE changed the cardiac surgery procedure in 9% of surgeries.85 There are several phrases used to describe difficulty in weaning from CPB including postbypass inotropic support, which includes the use of dopamine, dobutamine, or epinephrine for greater than 12 hours in the ICU and low cardiac output syndrome, defined as the use of an IABP or inotropic medications (dopamine, dobutamine, milrinone, or epinephrine) to maintain systolic blood pressure greater than 90 mm Hg and cardiac output greater than or equal to 2.2 L/min/m2.86 The important elements of successful weaning from CPB include systolic blood pressure as a marker of tissue/end-organ perfusion pressure, filling pressures including central venous pressure, diastolic pulmonary artery pressure, pulmonary capillary wedge pressure, and pharmacological intervention (Table 4). Weaning from bypass occurs after the steps above are completed and anesthesiologist, surgeon, and perfusionist

are prepared to support patient hemodynamics. Initially, the perfusionist allows blood volume to remain in the heart and circulate to the lungs and left side of the heart by partially clamping the venous line to fill up to the goal PA pressure or CVP. The patient’s hemodynamics and heart function in the chest and on TEE are reassessed frequently paying particular attention to the right ventricle as the heart receives more volume. When the PA pressures reach an adequate level, the perfusionist reduces pump flow, usually at 0.5 to 1 L/min in a gradual fashion. While the patient is weaning from bypass, the anesthesia team titrates appropriate vasoactive infusions and inotropic agents to maintain adequate SVR and contractility. When the patient is on minimal support from the bypass machine (usually 500 mL to 1 L/min/m2) with stable hemodynamics and the surgeon, anesthesiologist, and perfusionist all agree, separation from CPB is achieved. After separation from bypass, surgical attention is turned to removal of cannulae as well as hemostasis. Protamine is given to reverse heparin anticoagulation. A common strategy for protamine administration is 1 mg protamine per 200 units of heparin in the initial heparin bolus and in the CPB prime solution. Historically, a ratio of 1:1 (1 mg protamine per 100 units heparin) was given, but a lower protamine dose is associated with a reduction in blood loss and blood transfusions after CPB.87 Appropriate heparin–protamine matching for neutralization is important to decrease surgical bleeding and avoid protamine overdose. When anticoagulation was managed with a heparin–protamine titration system, Hemochron RxDx, patients received a lower protamine dose and had less postoperative blood loss.88 Stress Response to CPB. Cardiac surgery with CPB induces a systemic inflammatory response syndrome characterized by CPB induces a systemic inflammatory response syndrome associated with release of cytokines interleukin (IL)-2, IL-12, and interferon-γ.89 The early phase of this inflammatory response occurs as a result of exposure of blood elements to the CPB circuitry and induces both cellular and humoral responses. Intrinsic and extrinsic coagulation systems, complement system and leukocyte activations occur liberating thrombin, complement proteins and cytokines such as interleukins and tumor necrosis factor.89 The late phase of the inflammatory response to CPB includes ischemia reperfusion injury and endotoxemia.90,91 Exaggerated and prolonged activation of immune system after cardiac surgery leads to increased postoperative complications, morbidity, mortality, and prolonged ICU and hospital length of stay.92,93 Steroid Use in Cardiac Surgery. The benefits of prophylactic low-dose steroid use in cardiac surgery patients may include hemodynamic stability, decreased vasopressor/ inotrope requirements, earlier extubation, decreased


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hospital length of stay, and improved quality of recovery with minimal complications.94 The Dexamethasone for Cardiac Surgery (DECS) study was unable to show a reduction in the 30-day incidence of major adverse events with a single high dose of IV dexamethasone (1 mg/kg of body weight, with 100 mg maximum dose), but did find a benefit of dexamethasone prophylaxis to decrease postoperative infections, respiratory failure, and delirium.95 A recent best evidence topic in cardiac surgery evaluated the use of steroids to decrease postoperative atrial fibrillation.96 The authors concluded that a single dose of corticosteroid (50-210 mg of dexamethasone equivalent or 200-1000 mg/day hydrocortisone) reduces the risk of postoperative atrial fibrillation without any increased risk of complications.96 The Steroids in Cardiac Surgery (SIRS) study has completed enrollment of 7500 patients and will help inform decision making for mortality and other possible benefits associated with use of methylprednisolone 250 mg on induction of anesthesia and with commencement of CPB. In the smaller SIRS pilot study, this same dosing of methylprednisolone was effective to reduce bleeding, improve hemodynamic stability, reduce duration of mechanical ventilation and length of ICU stay.97 Aside from its anti-inflammatory effects of reducing IL-6 and increasing IL-10, methylprednisolone has been shown to increase endothelin-1, which indicates endothelial cell activation in patients undergoing CPB. Endothelial dysfunction is purported to be one of the primary causes of postoperative lung failure.98 Depending on the outcome of the large-scale SIRS trial, prophylaxis with steroids in the form of dexamethasone to decrease the inflammatory response is not indicated. Lung Management Strategies on Bypass. Impaired pulmonary function is a well-documented and fairly common complication, occurring in about 25% of patients after CPB for cardiac surgery99; in the most severe cases acute respiratory distress syndrome results and contributes to significant postoperative morbidity and mortality.100,101 Etiologies for this impaired lung function have been studied and the problem is likely multifactorial, but the inflammatory response to CPB, reviewed above, has been strongly implicated.102 Traditionally, once full flow has been assured on bypass, mechanical ventilation has been discontinued. The inflammatory milieu created by use of CPB impacts pulmonary function after heart surgery, although surgery without use of CPB has not entirely reduced postoperative lung dysfunction.103-105 Several management strategies during the CPB period are reviewed below that seek to attenuate the inflammatory response and thus acute lung injury. Heparin-coated circuits purportedly mimic the normal physiologic endothelial surface of the vasculature, thus

reducing complement activation and the overall inflammatory reaction as evidenced by reductions in interleukin levels, complement levels, and oxygen free radical levels.106-109 Measures of pulmonary function have improved with heparin-coated circuits but this has not lead to clinically meaningful reduction in mechanical ventilation requirement or ICU length of stay.106,110,111 Researchers from Norway studied their patient population of nearly 6000 patients undergoing CABG with use of heparin-coated CPB circuits in addition to a reduction in systemic heparin dosing to achieve ACT 250 seconds (for the lower limit) with the theory that reduction in systemic heparin dose would reduce bleeding and need for blood transfusions, which also have an impact on acute lung injury. In their protocol, median time to extubation was 1.7 hours, only 7.2% of patients required blood transfusion, the stroke rate was 1%, and perioperative myocardial infarction rate was 1.2%.112 Miniaturized CPB circuits, also known as minimized extracorporeal circuits (ECC) with a crystalloid prime volume of 800 mL as compared to 2000 mL for standard circuits, have been postulated to minimize foreign body–blood contact, are heparinized, reduce the inflammatory response, ameliorate the reduction in end organ function, including the pulmonary system, as well as reduce hemodilution and need for transfusion.113-115 Sakwa and colleagues studied 199 patients undergoing CABG and found that patients whose CPB period was managed with a miniaturized circuit had significantly higher hematocrit, platelet count, received fewer red blood cell transfusions, had reduced chest tube drainage, and had a shorter time to extubation.114 During the period of CPB, leukocytes become activated and have been implicated in ischemia reperfusion injury of multiple organ beds, including and heart and lung. Leukocyte depletion filters are used to reduce the leukocytes that become trapped within the pulmonary capillaries after CPB and have been shown to decrease heart and lung reperfusion injury.116 Some studies have shown improvement in oxygenation, lower extravascular lung water, and a reduction in postoperative mechanical ventilation117 but no longer term outcome differences.118 A recent meta-analysis of several small studies from 1993 to 2005 has not confirmed the reduction in pulmonary complication related to use of leukocyte filters.119 Additionally, the process of leukocyte reduction by these filters may activate white blood cells even further.120 At the time of commencement of CPB, there is mixing of the patient’s blood with the acellular CPB prime that causes immediate hemodilution. While some level of hemodilution may be helpful to facilitate tissue perfusion, hematocrit levels below 23% have been associated with increased interstitial edema and dysfunction of end organs


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Bechtel and Huffmyer such as brain, heart, and lungs.121 Methods to reduce hemodilution and improve the oncotic pressure may help reduce this interstitial edema. Use of blood cardioplegia and hemofiltration may accomplish this as well as retrograde autologous priming (RAP) of the CPB circuit. RAP involves removal of some of the crystalloid CPB circuit prime with the patient’s own circulating blood after venous and arterial cannulae have been inserted for bypass. A study by Hwang and colleagues showed that patients who underwent RAP prior to bypass had significantly higher hematocrit as well as cerebral oxygenation saturation levels during the bypass period.122 This statistically significant increase in hematocrit did not extend into the postoperative period although a trend toward increase in hematocrit persisted.122 Ultrafiltration during the CPB period allows removal of priming volume (acellular crystalloid) and theoretically helps reduce postoperative weight gain, edema, and totally body water. This should result in improvement in extravascular lung water and overall oxygenation and pulmonary function. Aside from removal of fluid, a type of ultrafiltration, zero balance ultrafiltration (ZBUF) may help ameliorate lung injury by removal of destructive and inflammatory cytokines and toxins such as IL-6, IL-8.123-126 Studies have also shown improvement in platelet function and reduction in postoperative blood loss as a result of ultrafiltration methods.127 Modified ultrafiltration (MUF) is ultrafiltration that occurs after the majority of the cardiac surgery has taken place, near the end of the CPB time period for a short period of time. Torina and colleagues used MUF for 15 minutes at the end of CPB for a group of CABG patients and demonstrated reduction in chest tube drainage, red blood cell transfusions, higher hematocrit but either no reduction or an increase in inflammatory markers such as IL-6, P-selectin, intracellular adhesion molecule, and soluble tumor necrosis factor.128 Oxygenation and hemodynamics were not different from patients treated in standard fashion without MUF.128 Normovolemic MUF has also recently been shown to reduce the levels of pro-inflammatory lipopolysaccharide-binding protein and terminal complement complex as well as been associated with reduction in blood loss and postoperative lactate concentrations after high risk cardiac surgery.129 Another method to reduce extravascular lung water as a result of increased capillary permeability and decreased colloid osmotic pressure is use of colloid or hypertonic fluids. Lomivorotov and colleagues randomized patients undergoing CPB to receive hypertonic saline/hydroxylethyl starch versus 0.9% sodium chloride for 30 minutes after anesthesia induction.130 They found reduction in extravascular lung water index, improved arterial oxygenation, reduced alveolar-arterial oxygen difference, and increased cardiac output in the hypertonic saline/hydroxylethyl starch group that persisted to 4 hours post-CPB.130

Cardiotomy suction provides collection of pericardial blood from the surgical field into the CPB circuit but this is activated by tissue plasminogen activator as well as has procoagulant properties. The transfusion of cardiotomy suction blood induces an inflammatory response and leads to reduction in hemostasis and impaired lung function postoperatively.131,132 Several actions may reduce this activation of the inflammatory response due to use of cardiotomy suction blood. Reducing the contact time between the shed cardiotomy blood with the pericardium and then to retransfusion as well as minimizing the entry or contact of air with the shed blood may help attenuate the inflammatory response.133 Topical antifibrinolytic agents introduced into the surgical field may also improve the accelerated fibrinolysis and increase hemostasis.134 A recent study by Nakahira and colleagues evaluated the use of open venous reservoir CPB circuits with and without cardiotomy suction as well as a completely closed circuit (with no cardiotomy suction).135 These authors found activation of coagulofibrinolysis only in the group with cardiotomy suction. The group with the open venous reservoir, but no cardiotomy suction, despite the blood–air interface, had similar thrombin generation as the completely closed circuit group. Thus, use of perioperative cell-salvage systems may not only help conserve blood but also may reduce the inflammatory response associated with CPB and in turn attenuate acute lung injury.135

Conclusion Cardiopulmonary bypass has revolutionized the practice of cardiac surgery and allows safe conduct of increasingly complex cardiac surgery. Anesthesiologists trained in the care of cardiac surgery patients allow safe and expert care of patients during cardiopulmonary bypass. Choice of anesthetic drugs for induction and maintenance of anesthesia have the potential to impact the outcome of patients undergoing cardiac surgery with cardiopulmonary bypass. Bypass management techniques such as ultrafiltration and use of heparin-coated circuits as well as medications administered like steroids may modulate immune response and affect inflammation. More large, randomized controlled trials are necessary to definitively guide practice. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.


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