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Home , Cardioplegia, Cardiopulmonary bypass

Principles of David Machin BSc ACP Chris Allsager MB ChB FRCA

Key points The use of cardiopulmonary bypass (CPB) during gas exchange in the natural technology allows cardiac surgical procedures also apply to the artificial lung. However, Membrane are to be performed in a motionless, bloodless gas exchange is less efficient. Diffusional commonly used for gas exchange during surgical field. It incorporates an extracorpor- distances are greater (approximately 200 mm cardiopulmonary eal circuit to provide physiological support. in comparison with 10 mm in the human bypass (CPB). Typically, is gravity drained from alveolus) and surface area for gas exchange is Downloaded from the and to a reservoir via venous 1.7–3.5 m2 compared with 70–100 m2 in the Roller or centrifugal pumps are utilized in CPB. cannulation and tubing, and returned oxy- human lung. Gas exchange obeys Fick’s law genated to the cannulated arterial system by of diffusion: Confirm adequate patient utilizing a pump and artificial lung (oxy- ADdP

anticoagulation before http://ceaccp.oxfordjournals.org/ genator or gas-exchanger). The tubing and V gasa initiation of CPB. T cannulae are manufactured of clear polyvinyl Sol CPB is performed over a chloride, while the casing and Da pffiffiffiffiffiffiffiffiffiffi MW range of temperatures connectors consist of polycarbonate (Fig. 1). (37–15C). where the amount of gas transferred (Vgas) Cardiac with CPB can is proportional to the area (A), a diffusion promote a systemic Gas exchange constant (D) and the partial pressure differ- inflammatory response Three basic types of blood oxygenators for ence (dP) and is inversely proportional to the syndrome. CPB have been developed. Historically, oxy- membrane thickness (T). D is proportional to at University of Southampton on November 19, 2014 genators provided gas exchange by contact of the specific gas solubility (Sol) and inversely a blood film to an rich atmosphere proportional to the square root of its mole- (e.g. disc oxygenators) or by bubbling oxygen cular weight (MW). through blood (e.g. bubble oxygenators). Applying Fick’s law to the artificial lung, Modern day oxygenators provide gas a higher partial pressure difference of oxygen exchange to blood through a membrane (maximum pressure gradient of 760 mm Hg (e.g. sheet and hollow-fibre oxygenators). minus oxygen tension in blood) and to some Sheet membrane oxygenators can either be extent (maximum gradient is configured as a flat plate microporous equal to carbon dioxide tension in blood polypropylene membrane or spiral wound phase) is required to compensate for an silicone membrane. Microporous membranes increased diffusional distance and fixed, consist of 0.05–0.3 mm pores that initially reduced surface area. Despite the pressure create a direct blood gas interface until a thin gradient for carbon dioxide (CO2) being protein film quickly forms, producing considerably lower than oxygen (O2), the molecular membranes. Silicone membranes artificial lung material is more gas perme- are considered ‘true membranes’ and prevent able to CO2 than (O2); silicone membranes David Machin BSc ACP ‘plasma leakage’ into the gas phase, which is have a CO2 :O2 transmission ratio of about characteristic of microporous membranes 5:1.2 Theatres Glenfield Hospital after long periods of CPB. Plasma leakage is Oxygen transfer in modern blood oxy- Groby Road thought to occur when the micropores lose genators is described by the advancing front Leicester their hydrophobicity by the adsorption of theory. Demonstrated by studies of oxygen LE3 9Q UK protein, which leaks through the micropores transport through constantly moving Tel: 0116 256 3604 and reduces gas exchange performance.1 blood films, the large binding capacity of E-mail: [email protected] Hollow-fibre oxygenators allow high surface haemoglobin for oxygen and rapid oxygen– (for correspondence) area-to-blood volume ratios and mainly con- haemoglobin kinetics are thought to create Chris Allsager MB ChB FRCA sist of microporous polypropylene or poly- two distinct zones in the blood film. Oxygen Consultant Anaesthetist methylpentene material. diffuses through a fully oxygen saturated Glenfield Hospital Leicester The physical process of convection, dif- zone to an unsaturated front where the 3 UK fusion and chemical reactions that occur oxygen binds with unsaturated haemoglobin.

Advance Access publication August 24, 2006 doi:10.1093/bjaceaccp/mkl043 176 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 5 2006 ª The Board of Management and Trustees of the British Journal of Anaesthesia [2006]. All rights reserved. For Permissions, please email: [email protected] Principles of CPB

Aortic Cross Clamp

Arterial Filter Solution

Gas Downloaded from In Gas Exchanger Gas Out

Cardiotomy

Reservoir http://ceaccp.oxfordjournals.org/ Sucker Vent Cardioplegia Pump Pump Pump Water In Heat Exchanger Water out Venous Reservoir at University of Southampton on November 19, 2014 Systemic Blood Pump

Fig. 1 Diagrammatic representation of a ‘closed’ extracorporeal circuit for cardiopulmonary bypass.

Carbon dioxide transfer in modern oxygenators is more difficult haemolysis (plasma haemoglobin per 100 ml of pumped blood). to predict, because of factors such as dissolved CO2, plasma Roller pumps (RPs) and centrifugal pumps (CPs) are routinely bicarbonate ions and varying partial pressure of CO2 in the gas used and can accurately deliver blood over wide range of flow phase. The latter can be decreased by increasing the ventilating rates against a variable resistance. gas flow rate (sweep gas) entering the oxygenator gas phase. The RP comprises a length of PVC or silicone tubing situated against a curved metal backing plate (raceway) which is com- pressed by two rollers located on the ends of rotating arms at Blood pumps 180 to each other. The direction of compression of the tubing During CPB, constant blood flow is delivered to the patient by a by the rotating arm containing the roller permits forward blood mechanical pump. The characteristics of an ideal blood pump flow. Hence, this type of pump is described as a positive dis- should consider properties that effect blood flow, as described placement device, allowing constant delivery of blood volume by the Hagen–Poiseuille equation: despite minor variations in the outlet afterload. Blood flow depends upon the pump tubing internal diameter (see Hagen– ðPressure gradientÞ · ðTube radiusÞ4 · p Blood flow rate ¼ Poiseulle equation), rotation rate of the rollers and diameter of ðFluid viscosityÞ · ðTube lengthÞ · 8 the pump head. Put simply, CPs consist of a vaned impeller or a nest of smooth plastic cones within a plastic casing. These impellers or cones are Pressure Blood flow rate ¼ magnetically coupled (at the base) with an electric motor and, Resistance when rotated rapidly, generate a centrifugal force to the blood, Thus, the pump should be able to generate blood flow and which is received by the pump body. Centrifugal force is pressure against a degree of resistance. It should be made converted into kinetic energy, which gives flow, or potential of biocompatible materials, create no areas of blood stasis or energy, which gives pressure. An object that produces centrifu- turbulence and be able to adjust for different sizes of extra- gal force (CF) can be defined as corporeal tubing. These mechanical pumps have low priming volumes, are easily controlled and produce a low index of CF ¼ mass · radius · angular velocity

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In a clinical setting, oxygen consumption. The potassium channel opener, nicorandil, may offer advantages over potassium-based cardioplegia by CF ¼ Mass of blood · radius of pump head providing cardiac arrest near its resting membrane potential, · speed of revolutions ðRPMÞ allowing balanced trans-membrane ion gradients and minimal Unlike RPs, CPs are totally non-occlusive and are afterload energy requirements.5 dependant. Any significant change in resistance/pressure at the Non-cardioplegic techniques include the use of moderate outlet or inlet of the pump will alter blood flow rate. The non- systemic (i.e. core temperature of 30–32C) with occlusive feature of the CP prevents generation of excessive short periods of aortic cross-clamping and ventricular fibril- pressure in the extracorporeal circuit, thus preventing circuit lation (VF). A variation of this technique involves hypo- rupture. thermic systemic combined with prolonged VF, enabling continuous coronary perfusion. Unfortunately, this Downloaded from Myocardial protection greatly increases myocardial oxygen consumption compared with the empty beating heart; it also reduces subendocardial To provide a dry, motionless, operative area, a cross-clamp is perfusion.6 Ischaemic preconditioning for myocardial protec- placed across the ascending above the coronary ostia tion is also practiced by introducing brief periods and proximal to the aortic , thus isolating the coronary of myocardial ischaemia to tolerate a longer ischaemic http://ceaccp.oxfordjournals.org/ circulation and preventing blood entering the chambers of challenge. the heart. Therefore, techniques of myocardial protection are used to preserve myocardial function and prevent cell death. Cardioplegic techniques for myocardial protection involve the Temperature management during CPB delivery of cardioplegic solution to the myocardium to provide CPB is performed under systemic hypothermia (typically a diastolic electromechanical arrest. This is administered by an nasopharyngeal temperature of 25–32C) or normothermic anterograde approach via the aortic root or direct coronary conditions. More challenging operations may require deep ostium access, or by a retrograde manner if severe coronary hypothermia (15–22C) to allow periods of low blood flow or occlusions exist. The latter may not provide adequate deep hypothermic circulatory arrest. Systemic hypothermia has at University of Southampton on November 19, 2014 right-heart protection; thus, the delivery of both anterograde remained a cornerstone of cardiac surgical practice, with a great and retrograde cardioplegia may ensure adequate distribution deal of evidence demonstrating that it decreases myocardial and subsequent improved myocardial protect. Intermittent oxygen consumption. This ensures protection and increased cardioplegia delivery (i.e. every 15–30 min) allows a relatively tolerance for ischaemia of vital organs and allows periods of low bloodless surgical view during more challenging operative blood flow during CPB. At a biochemical level, temperature periods. Continuous administration would improve for myocar- changes the reaction rates and metabolic processes by a factor dial protection but this is not always practical. known as the Q10 effect, which defines the amount of increase or Potassium is the main agent used to induce cardiac arrest; in decrease in these processes relative to a 10C difference. Total 1 a concentration of approximately 20 mmol litre it causes a body oxygen consumption is said to have a Q10 factor of reduction in myocardial membrane potential. Fast inward approximately 2.6 in adults and 3.65 in infants.7 However, sodium channels are inactivated preventing the upstroke of because of many of the detrimental processes associated with myocardial cell action potentials, causing the myocardium to hypothermia (e.g. impaired myocardial cell membrane function, 4 become unexcitable in diastolic arrest. Cardioplegia can be possible excessive postoperative bleeding), normothermic CPB is administered as a cold crystalloid cardioplegia, cold blood practiced by some to provide a more physiological cardioplegia or warm blood cardioplegia. Blood cardioplegia is state. It is also hypothesized that electromechanical work is the thought to offer the advantage of delivering oxygen at the cellular main determinant of myocardial oxygen requirement rather level via its haemoglobin content, but it may be less efficient than cooling of the heart.5 Hence, a chemically induced during cold delivery because of the left shift of the oxygen- mechanical arrested heart, without added hypothermia, is dissociation curve. Blood cardioplegia also provides other benefits expected to reduce myocardial metabolic requirements to such including hydrogen ion buffering, free-radical scavenging, reduced a degree that it can be matched by regular doses of blood myocardial oedema and improved micro-vascular flow. cardioplegia. Various ratios of blood to cardioplegic solution can be administered (e.g. 1 : 1, 2 : 1, 4 : 1) or even neat potassium (micro- Acid–base management plegia). The addition of glutamate and aspartate to cardioplegic solutions may promote oxidative metabolism in energy-depleted Management of the acid–base status throughout the hypo- . The use of esmolol and nicorandil as cardiac electro- thermic CPB period remains controversial. Arterial blood gas mechanical arrest agents has also been considered as possible parameters are either corrected for temperature and pH is kept alternatives to potassium. The negative inotropic and chrono- constant (i.e. pH-stat) or blood gas levels are uncorrected tropic effects of esmolol result in a reduction in myocardial (measured at 37C) and alkalosis is permitted during cooling

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(i.e. alpha-stat). pH-stat blood gas management increases CO2 blood flow requirements without excessive resistance or pressure content during cooling and, as cerebral blood flow is dependent generation. The CPB circuit is typically primed with a onPCO2 , cerebral blood vessels dilate. Autoregulation, which crystalloid solution with electrolyte composition and osmolarity normally keeps cerebral blood flow constant at arterial pressures similar to plasma and a colloid solution to provide a degree of 50–150 mm Hg, is lost during pH-stat and cerebral blood of plasma colloidal oncotic pressure, which is reduced as a flow becomes pressure-dependent. Alpha-stat blood gas manage- repercussion of haemodilution in CPB. Other prime additives ment seems more appropriate as it maintains autoregulation, may include (diuresis, oedema reduction, possibly free- offers better control of cerebral blood flow and demand, radical scavenging); sodium bicarbonate (buffers the prime); and limits cerebral microemboli load. However, the pressure- ; and blood, if required. CPB blood flow, estimated dependent characteristics of pH-stat may improve cooling and haematocrit on CPB and the amount of blood required in the oxygen delivery to the brain.8 prime are calculated: Downloaded from CPB blood flow rate ¼ Body surface area ðBSAÞ · Cardiac index ðCIÞ‚ Filtration ðlitre min1Þðm2Þðlitre m2 min1Þ Recycling of suctioned blood from the surgical field is where BSA is calculated by DuBois formula/DuBois BSA nomogram; accomplished by a reservoir incorporating a screen CI is 2.4–2.8 (dependant upon age) at 37C, 2.1 at 32C, 1.8 at 28C, 1.2 and depth filter to reduce fat emboli, fibrin and surgical http://ceaccp.oxfordjournals.org/ at 25C, 0.6 at 15C. contamination. Screen filters comprise a woven mesh material PBV · Hct such as polypropylene, with a defined pore size to determine its Estimated haematocrit on CPB ¼ ‚ filtration ability. Depth filters incorporate packing materials TCV such as Dacron wool or polyurethane foam that have no definite where PBV is the patient blood volume; Hct is the patient pore size; thus, filtration depends on the thickness, tightness and haematocrit; TCV is the total circulatory volume, that is PBV þ tortuous nature of the packing. Generation of gaseous (e.g. drug circuit prime volume þ estimated cardioplegic solution volume. injection and venous air) and particulate (e.g. circuit material ðTarget Hct · TCVÞðHct · PBVÞ debris) emboli exiting the oxygenator is associated with vital Blood required in prime ¼ ‚ Hct of RBCs organ injury, for example cognitive dysfunction. An arterial at University of Southampton on November 19, 2014 screen filter is often used to limit sources of embolic load to the where Target Hct is the required haematocrit on initiation of CPB patient. Air emboli retention within the wetted filter is (typically above 20% in adults and 28% in children); TCV is the accomplished by surface-active forces, which maintains fluid in total circulatory volume; PBV is patient blood volume; Hct is the pores and prevents displacement of fluid by gas through the patient haematocrit; Hct of RBCs is haematocrit of donor blood. pores. However, excessive pressure across the filter medium can Before initiation of CPB, the patient is adequately antico- allow the passage of air through the pores; this is termed the agulated with heparin (300–400 iu kg1) to achieve an activated ‘bubble point pressure’. Bacterial filtration of the gas flow line to clotting time (ACT) generally above 480 s (celite ACT above the oxygenator and the use of pre-bypass filters to reduce 750 s when aprotinin is used) to maximize inhibition of thrombin extracorporeal circuit debris are often practiced. There is a generation. The placement of arterial and venous cannulae to current trend to utilize leucocyte depleting filters, as activated perform CPB is generally via a , to the leucocytes are considered to have a pivotal role in the inflamm- and right or directly/indirectly to the atory response to CPB and post-ischaemic injury. The applica- superior and inferior . Alternative cannulation sites tion of this technique during all or part of CPB (i.e. before aortic include the femoral vessels, , left ventricular apex cross-clamp removal, during blood cardioplegia delivery or (e.g. redo procedures and aortic ), and both ascending 9 both) has demonstrated some clinical benefits. and descending aorta (e.g. interrupted arch). Venous cannula Haemofilters (haemoconcentrators or ultrafilters) are utilized size is important, as blood flow is determined by the Hagen– in CPB circuitry to remove excess fluid and electrolytes, attenuate Poiseuille equation. To achieve sufficient venous drainage for inflammatory mediators and raise haematocrit. These devices effective CPB, the cannula radius is the predominant factor (a mainly consist of a hollow-fibre semipermeable membrane to small change in dimension can have a drastic effect on venous allow the passage of water and electrolytes from the blood to a drainage); fluid viscosity and tubing length remain relatively filtrate compartment. Conventional ultrafiltration (haemoconcen- fixed. Arterial cannulae sizing is less significant as the blood can tration) and zero balance ultrafiltration (filtrate replaced with be pumped at relatively high pressures oxygen (generally 160– equal crystalloid volume) can be performed during CPB; modified 180 mm Hg). However, maintenance of blood flow at higher ultrafiltration can be initiated at the termination of CPB. pressures with smaller diameter arterial cannulae may result in turbulent flow, as predicted by the Reynolds number, which is Conduct of CPB determined by the density, velocity and viscosity of blood for a Components selected for the extracorporeal circuit are deter- given temperature. Correct positioning of the arterial cannula is mined to minimize haemodilution, while being able to achieve verified by arterial line pressure measurement within the

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extracorporeal circuit. After cannulae insertion, CPB is com- Table 1 Suggested target blood chemistry values for termination of CPB menced by releasing the venous line clamp and increasing the pH 7.35–7.45 blood pump until calculated blood flow is achieved. Mainten- PaO2 20–30 kPa ance of adequate venous drainage into the reservoir is essential PaCO2 4.6–5.5 kPa Sv >65% to provide CPB support and prevent patient . The O2 Base excess (arterial) −2 to þ2 application of pulsatile blood flow during CPB may increase or 1 Naþ (plasma) 135–144 mmol litre preserve arterial blood flow to organs such as the kidney, liver, gut Cl (plasma) 95–105 mmol litre1 and brain, and reduce systemic vascular resistance. However, the Caþþ (plasma) 2.1–2.6 mmol litre1 (adjusted for albumin) Mgþ (plasma) 0.7–1.0 mmol litre1 generation of an arterial waveform to provide substantial 1 Kþ (plasma) 3.3–5.3 mmol litre ‘physiological’ blood flow is a significant a technical challenge. Glucose 3.3–6.0 mmol litre1 Adequacy of blood flow and oxygen requirements requires Haematocrit >25% (adults); >28% (children) Downloaded from frequent, if not continuous (i.e. in-line monitoring) arterial and gas monitoring, in addition to haematological and biochemical analysis. Effective blood flow during CPB can be pressure and blood flow during hypothermia can facilitate in monitored by whole body oxygen consumption (VO2), accord- reducing this problem. ing to the Fick principle: Weaning from CPB is considered when surgical intervention http://ceaccp.oxfordjournals.org/ has been completed. The patient should be fully warm with VO2 ¼ðCaO2 CvO2Þ · CO physiological biochemical and haematological values (Table 1) and an appropriate ECG. After confirmation of mechanical where VO2 ¼ oxygen consumption, (CaO2CvO2) ¼ arterio- ventilatory support, the venous line is clamped and volume is venous oxygen content difference and CO¼cardiac output. infused from the CPB circuit until a desired filling pressure is Thus, with the additional knowledge of the level of oxygen obtained. Patient heparinization can be reversed with protamine extraction (arteriovenous oxygen content difference) and sulphate after stabilization and discontinuation of the extra- haemodilution (total haemoglobin) during CPB, the patient’s corporeal circuit. requirements can be accommodated. To enable VO2 to be a at University of Southampton on November 19, 2014 reliable indicator of blood flow adequacy, the age, size and Reducing consequences of CPB temperature of the patient need to be considered. VO2 to body weight ratio in the infant is about twice that of the adult CPB and induce a systemic inflammatory (approximately 8 : 4 ml kg1 min1). The use of in-line mixed response and cause disturbances of the inflammatory and venous oxygen saturation monitoring during CPB allows quick fibrinolytic system. Pharmacological agents are used to assessment of sufficient oxygen delivery, but should be inter- reduce these consequences. Such agents include aprotinin; preted with caution. Certain patient conditions, such as anti-fibrinolytics; ; and novel approaches with anatomical or physiological shunts, and abnormal haemoglobin angiotensin-converting enzyme inhibitors, exogenous anti- types, may under or overestimate oxygen delivery and uptake. oxidants, monoclonal antibodies and phosphodiesterase inhib- Other parameters assessed during CPB include oxygenation, itors. Surface coated and miniaturized extracorporeal circuits arterial perfusion pressure, venous pressure, temperature, are being continually developed to potentially improve bio- 11 ECG, urine output and periodic assessment of the antico- compatibility. Isolation of cardiotomy suctioned blood and agulant status (ACT > 480 s to prevent extracorporeal circuit utilization of cell salvage devices to reduce activated blood ). components and particulate emboli are of recent interest. During CPB with the aorta cross-clamped and the heart in an arrested state, gradual distension and potentially irreversible Acknowledgement damage to the heart can occur. This is because of bronchial and The authors acknowledge the assistance of Miss Aimee Hurst in coronary vessels (e.g. myocardial sinusoids, arterio-sinusoidal, the preparation of the figure. arterio-luminal vessels) draining into the heart, which can 10 contribute to 1–2% of the cardiac output. These circulations, References including the presence of non-coronary circulations (e.g. connections between mediastinal and coronary vessels), can 1. Tamari Y, Tortolani AJ, Lee-Sensiba KJ. Bloodless testing for micro- result in a blood-flooded operative field and cause cardioplegic porous membrane oxygenator failure study. Int J Artif Organs 1991; 14: 154–60 ‘wash-out’ with subsequent recurrent cardiac electrical activity. 2. Taylor KM2. Membrane oxygenation. Cardiopulmonary Bypass. London: The improper placement or inappropriate fixation of the venous Chapman and Hall Ltd, 1986; 177–210 cannula also has a significant influence on these problems. The 3. Hill AV. The diffusion of oxygen and lactic acid through tissues. use of a vent cannula placed in the left , left atrium, Proc R Soc London B Biol Sci 1929; 104: 39–96 or aortic root can prevent over-distension 4. Hearse DJ, Braimbridge MV, Jynge P. Protection of the Ischaemic of the heart and its consequences. Likewise, reducing perfusion Myocardium: Cardioplegia.. New York: Raven Press, 1981

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5. Vinten-Johansen J, Ronson RS, Thourani VH, Wechsler AS. Surgical 8. Scallan MJH. Cerebral injury during paediatric heart surgery. Perfusion myocardial protection.. In: Gravlee GP, Davis RF, Kurusz M, Utley JR. 2004; 19: 221–8 eds. Cardiopulmonary Bypass: Principles and Practice.. Philadelphia: 9. Matheis G, Scholz M, Henrich D. Timing of leukocyte filtration during Lippincott Williams & Wilkins, 2000; 214–64 cardiopulmonary bypass. Perfusion 2001; 16: 31–7 6. Hottenrott CE, Buckberg GD. Studies of the effects of ventricular 10. Nunn JF. Distribution of pulmonary ventilation and perfusion. Nunn’s fibrillation on the adequacy of regional myocardial flow: effects of Applied Respiratory Physiology. 4th Edn. London: Butterworth-Heinmann, ventricular distention. J Thorac Cardiovasc Surg 1974; 68: 626–33 1993; 156–97 7. Greeley WJ, Kern FH, Ungerleider RM. The effect of hypothermic 11. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced cardiopulmonary bypass and total circulatory arrest on cerebral meta- inflammation: pathophysiology and treatment. Eur J Cardiothorac Surg bolism in neonates, infants, and children. J Thorac Cardiovasc Surg 1991; 2002; 21: 232–44 101: 783–94 Please see multiple choice questions 6–8. Downloaded from http://ceaccp.oxfordjournals.org/ at University of Southampton on November 19, 2014

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