coronary sinus). these delivery methods are referred to antegrade and retrograde, respectively. cardioplegia solution protects the heart by arresting (i.e. stopping) the heart, thereby decreasing its metabolic demand. there are multiple types of cardioplegia solutions, but most work by inhibiting fast sodium currents in the heart, thereby preventing conduction of the action potential. other types of solutions act by inhibiting calcium's actions on myocytes. technique pre-operative planning cpb requires significant forethought before surgery. in particular, the cannulation, cooling, and cardio-protective strategies must be coordinated between the surgeon, anesthesiologist, perfusionist, and nursing staff. cannulation strategy the cannulation strategy varies on several operation-specific and patient-specific details. the typical arterial cannulation involves the placement of a single cannulation within distal ascending aorta. the most simple form on involves placement of a single cannula (known as a dual-stage cannula) passed through the right atrium and into the inferior vena cava. in some operations, such as those involving the tricuspid or mitral valve, two cannula are used—one is passed through the inferior vena cava and one through the superior vena cava. this is known as bi-caval cannulation. intra-operative technique a cpb circuit must be primed with fluid and all air expunged from the arterial line/cannula before connection to the patient. the circuit is primed with a crystalloid solution and sometimes blood products are also added. prior to cannulation (typically after opening the pericardium when using central cannulation), heparin or another anticoagulant is administered until the activated clotting time is above 480 seconds. the arterial cannulation site is inspected for calcification or other disease. preoperative imaging or an ultrasound probe may be used to help identify aortic calcifications that could potentially become dislodged and cause an occlusion or stroke. once the cannulation site has been deemed safe, two concentric, diamond-shaped pursestring sutures are placed in the distal ascending aorta. a stab incision with a scalpel is made within the pursestrings and the arterial cannula is passed through the incision. it is important the cannula is passed perpendicular to the aorta to avoid creating an aortic dissection. the pursestrings sutures are cinched around the cannula using a tourniquet and secured to the cannula. at this point, the perfusionist advances the arterial line of the cpb circuit and the surgeon connects the arterial line coming from the patient to the arterial line coming from the cpb machine. care must be taken to ensure no air is in the circuit when the two are connected, or else the patient could develop an air embolism. other sites for arterial cannulation include the axillary artery, brachiocephalic artery, or femoral artery. aside from the differences in location, venous cannulation is performed similarly to arterial cannulation. since calcification of the venous system is less common, the inspection or use of an ultrasound for calcification at the cannulation sites is unnecessary. also, because the venous system is under much less pressure than the arterial system, only a single suture is required to hold the cannula in place. if only a single cannula is to be used (dual-stage cannulation), it is passed through the right atrial appendage, through the tricuspid valve, and into the inferior vena cava. if two cannula are required (single-stage cannulation), the first one is typically passed through the superior vena cava and the second through the inferior vena cava. the femoral vein may also be cannulated in select patients. if the heart must be stopped for the operation, cardioplegia cannulas are also required. antegrade cardioplegia (forward flowing, through the heart's arteries), retrograde cardioplegia (backwards flowing, through the heart's veins), or both types may be used depending on the operation and surgeon preference. for antegrade cardioplegia, a small incision is made in the aorta proximal to the arterial cannulation site (between the heart and arterial cannulation site) and the cannula is placed through this to deliver cardioplegia to the coronary arteries. for retrograde cardioplegia, an incision is made on the posterior (back) surface of the heart through the right ventricle. the cannula is placed in this incision, passed through the tricuspid valve, and into the coronary sinus. the cardioplegia lines are connected to the cpb machine. at this point, the patient is ready to go on bypass. blood from the venous cannula(s) enters the cpb machine by gravity where it is oxygenated and cooled (if necessary) before returning to the body through the arterial cannula. cardioplegia can now be administered to stop the heart, and a cross-clamp is placed across the aorta between the arterial cannula and cardioplegia cannula to prevent the arterial blood from flowing backwards into the heart. once the patient is ready to come off of bypass support, the cross-clamp and cannulas are removed and protamine sulfate is administered to reverse the anticoagulative effects of heparin. history a heart lung machine used in london's middlesex hospital in 1958. science museum, london (2008) cardiopulmonary bypass machine used at the university of michigan in the 1960s. brukhonenko's autojektor the austrian-german physiologist maximilian von frey constructed an early prototype of a heart-lung machine in 1885 at carl ludwig's physiological institute of the university of leipzig. however, such machines were not feasible before the discovery of heparin in 1916, which prevents blood coagulation. the soviet scientist sergei brukhonenko developed a heart-lung machine for total body perfusion in 1926 named the autojektor, which was used in experiments with canines, some of which were showcased in the 1940 film experiments in the revival of organisms. a team of scientists at the university of birmingham (including eric charles, a chemical engineer) were among the pioneers of this technology. dr. clarence dennis led the team at the university of minnesota medical center that on april 5, 1951, conducted the first human operation involving open cardiotomy with temporary mechanical takeover of both heart and lung functions. the patient did not survive due to an unexpected complex congenital heart defect. one member of the team was dr. russell m. nelson, who later became president of the church of jesus christ of latter-day saints and who performed the first open heart surgery in utah. the first successful mechanical support of left ventricular function was performed on july 3, 1952, by forest dewey dodrill using a machine co-developed with general motors, the dodrill-gmr. the machine was later used to support right ventricular function. the first successful open heart procedure on a human utilizing the heart lung machine was performed by john gibbon and frank f. allbritten, jr. on may 6, 1953, at thomas jefferson university hospital in philadelphia. they repaired an atrial septal defect in an 18-year-old woman. gibbon's machine was further developed into a reliable instrument by a surgical team led by john w. kirklin at the mayo clinic in rochester, minnesota in the mid-1950s. the oxygenator was first conceptualized in the 17th century by robert hooke and developed into practical extracorporeal oxygenators by french and german experimental physiologists in the 19th century. bubble oxygenators have no intervening barrier between blood and oxygen, these are called 'direct contact' oxygenators. membrane oxygenators introduce a gas-permeable membrane between blood and oxygen that decreases the blood trauma of direct-contact oxygenators. much work since the 1960s focused on overcoming the gas exchange handicap of the membrane barrier, leading to the development of high-performance microporous hollow-fibre oxygenators that eventually replaced direct-contact oxygenators in cardiac theatres. in 1983, ken litzie patented a closed emergency heart bypass system which reduced circuit and component complexity. this device improved patient survival after cardiac arrest because it could be rapidly deployed in non-surgical settings.