1. Cardiopulmonary bypass & hypothermic circulatory arrest
Nishith Patel
Waikato Cardiothoracic Unit

2. CARDIOPULMONARY BYPASS & HYPOTHERMIC CIRCULATORY ARREST
Welcome to the Cardiopulmonary Bypass Module of this MSc in Translational Cardiovascular Medicine
Nishith Patel BSc(Hons), PhD, FRCS (C-Th)
NIHR Academic Clinical Lecturer & Speciality Registrar in Cardiothoracic Surgery
Imperial College London

3. Overview History of Cardiopulmonary Bypass (CPB) Principles of CPB
Goals of CPB
Complications of CPB
Hypothermic Circulatory Arrest
We will briefly look at the history and evolution of cardiopulmonary bypass.
This will be followed by the key principles governing CPB.
After this we will look at the goals of CPB and how monitor the adequacy of perfusion.
We will then look at the complications of cardiopulmonary and the role translational research plays in understanding and preventing these complications.

4. HISTORY OF CARDIOPULMONARY BYPASS

5. 60th Anniversary of 1st Successful Open Heart Operation with CPB
6th May 1953 – 1st Successful Open Heart Operation with Heart-Machine (or formally known as the Cardiopulmonary Bypass Machine).
By Dr. John Gibbon Jr at the Jefferson University Medical Centre
18 year old woman
Large Atrial Septal Defect
Total CPB time: 26 mins
2013 marks the 60th anniversary of the 1st successful open heart operation performed with cardiopulmonary bypass.
Open heart surgery was possible only because of the development of cardiopulmonary bypass
This first procedure was performed on 6th May 1953 by Dr. John Gibbon Jr of the Jefferson Medical Centre in the US.
He operated on an 18 year woman with a large atrial septal defect (in lay terms…. A hole in the heart) and took just 26 mins to complete the procedure.
Dr. John Gibbon

6. Need for Heart-Lung Machine
In 1950’s it became obvious that there was a need for a heart-lung machine to deal with the majority of congenital malformations and valvular heart lesions (“open-heart” or “intra-cardiac” operations)
Key requirements of a heart lung machine:
Pumping blood around the body: A method of pumping blood without destroying red blood cells
Oxygenating blood: A method to oxygenate blood and and dissipate carbon dioxide
Prevent blood clotting: Safe method of anticoagulation that could be reversed at the end of the operation
By the 1950’s it had become obvious to the medical community that a heart-lung machine was essential to treat intra-cardiac pathology.
And the key requirements of any such machine would be:
To effectively pump blood around the body – so it needed a pump
To oxygenate blood – so it needed an oxygenator that could oxygenate haemoglobin but also remove the carbon dioxide
To prevent blood clotting – blood clots as soon as it leaves the circulation. So a method by which blood could be anticoagulated was required in addition to a method by which this anticoagulation could be reversed. This was fulfilled by the administration of intravenous heparin which is an anticoagulant and can be reversed by Protamine.

7. Pre-1953 Mainly closed operations & experiments
Most patients with intra-cardiac pathology developed either disabling heart failure or died prematurely
1930: Dr. Churchil (mentor to Dr. Gibbon) removed a large embolus from a young mother’s pulmonary artery
Patient died
Dr Gibbon: “It was then that I found myself thinking how we could have helped her if we only had had some way of taking out the blue venous blood, getting oxygen into it while carbon dioxide escaped, and then putting the blood back into the arterial system.”
1935 – maintained a cat’s circulation on CPB while closing the pulmonary artery
– Teamed with IBM to develop first clinical CPB machine
Prior to 1953 all heart operations were either closed procedures such as ligation of a patent ductus arteriosus or experiments in animals .
Therefore most patients with intra-cardiac pathology, such as rheumatic mitral valve disease, developed disabling heart failure and died prematurely.
In 1930 Dr. Gibbon was working as a resident in the firm of his mentor, Dr. Churchill. They operated on a young mother with a large embolus in one of the main branch pulmonary arteries. They attempted to remove this clot at which they were successful at but at the cost of excessive bleeding and haemodynamic compromise. The patient died soon after the procedure.
This clinical experience was the inspiration for Dr. Gibbon to develop the cardiopulmonary bypass machine.
He initially trialed his CPB machine in a cat and was successful at maintaining the cat’s circulation whilst operating on the pulmonary artery.
He subsequently collaborated with the IT giant, IBM to develop the first clinical CPB machine.

8. This was the first Gibbon-IBM heart lung machine.
The Gibbon-IBM heart-lung machine model II. The oxygenator screens are on the top at the left.

9. PRINCIPLES OF CARDIOPULMONARY BYPASS

10. Principle of CPB Venous blood (Deoxygenated) Reservoir Pumped
Gravity (Siphonage)
Reservoir
Pumped
Oxygenated
Temperature regulated
Filtered
Returned to the body via an arterial cannula
The key principle of Cardiopulmonary Bypass is that following anticoagulation with heparin, deoxygenated venous blood is removed from the circulation by gravity, which is also known as siphonage. This blood accumulates in a venous reservoir and is then pumped to an oxygenator where the blood is oxygenated, its temperature regulated and the blood filtered for microemboli. The blood is then reinfused into the patient via an arterial cannula.

11. This is a real life clinical cardiopulmonary bypass machine.

12. This is a schematic of a complete cardiopulmonary bypass circuit
This is a schematic of a complete cardiopulmonary bypass circuit. You do not need to learn this whole circuit but it here to demonstrate to you that this is quite a complex circuit.

13. This is a simplified schematic of a cardiopulmonary bypass circuit
This is a simplified schematic of a cardiopulmonary bypass circuit. The key components of this circuit are:
Cannulation to obtain venous blood, in this picture this is from the right atrium
The blood then accumulates in a venous reservoir.
The blood is then pumped
To the heat exchanger and oxygenator where blood is temperature regulated and oxygenated.
The blood then passes through a microfilter to remove any microemboli
After which it is returned to the patient through a major artery, most commonly the distal ascending aorta as is shown in the schematic.

14. Venous CannuLation
Venous drainage achieved by following cannulation strategies:
Cavoatrial: 2-stage single venous cannula inserted via right atrial appendage. Distal tip rests in IVC.
Bi-caval – SVC and IVC cannulated separately
We wlll now look at these different components in more detail.
Venous drainage is achieved in most patients by one of 2 cannulation strategies:
1.Cavo atrial: this makes use of a 2-stage venous cannula which is inserted into the right atrium. The tip of the cannula sits in the inferior vena cava. It is called a 2 stage cannula as it has 2 areas with holes where blood is drained. The first area is at its tip and therefore allows drainage of blood from the IVC and therefore the lower half of the body. The other area of holes sits in the right atrium and therefore allows drainage of blood coming from the Superior vena cava.
2. The second strategy is bi-caval cannulation. This is when both the SVC and the IVC are cannulated individually. This strategy is only used when the right or left atria need to be opened, e.g. during replacement of the tricuspid or mitral valves.
In cases where we are unable to access the atria or vena cavae, we sometimes have to cannulate the femoral vein to obtain venous drainage, although this is uncommon.
A. Cavoatrial
B.Bicaval

15. Venous Drainage
Venous blood drained into reservoir via cannula by the process of gravity or siphonage.
Venous reservoir kept below the level of the heart.
Amount of venous blood drained dependent on CVP, size of cannulae, height of table, air in tubing
Vacuum assisted drainage also available but rarely used
Once venous cannulation has been achieved, blood is drained into a low pressure, high capacitance reservoir by the process of siphonage. This is the same process by which petrol is removed (or stolen) from a car. The venous reservoir is kept below the level of the heart to aid this process.
The amount of venous blood drained is dependent on the central venous pressure, size of the cannulae, height of the table and air in the tubing.
In rare circumstances, when venous drainage is inadequate, vacuum assisted drainage is also available but is rarely used.

16. Pumping Blood
Next the blood is passed through a pumping device. The development of the pump was one of major rate limiting steps in the evolution of CPB as blood had to be pumped back to the body with destroying all the cells.
Currently one of 2 pumps are used: either a centrifugal pump or a roller pump.

17. Heat Exchanger Controls body temperature
Function in combination with external heater-cooler
Temperature controlled water is pumped into the water phase of the heat exchanger which is separate from the blood phase by a highly conductive material
Chosen temperature dependent on type of procedure
Hypothermia preferred for most cardiac operations
The blood then passes through a heat exchanger where the temperature of the blood is regulated. This functions in combination with an external heater-cooler which pumps temperature controlled water into the water phase of the exchanger.
The chosen temperature is dependent on the type of procedure although in most parts of the world, hypothermia (ie a blood temperature of less than 35 degrees) is preferred. Hypothermia has been shown to reduce oxygen consumption of organs and thereby protect them during CPB. However, the benefits of normothermia have recently been demonstrated by research from Bristol.

18. Membrane Oxygenator
Next, the blood passes through an oxygenator, which is a membrane oxygenator. This imitates the natural lung by providing a thin membrane of either microporous polypropylene or silicone rubber between the gas and blood phases
Plasma filled pores prevent gas from entering blood but allows exchange of Oxygen and CO2
Blood is spread as thin film over a large area with high differential gas pressures between compartments
Areas of turbulence enhance diffusion of oxygen within blood
The development of the oxygenator was one of the major rate limiting steps in the evolution of CPB. In the initial development years during the 1940’s and 1950’s many different types of oxygenators were evaluated including monkey lung!

19. Arterial Microfilter
Flow of blood through CPB machine can generate microemboli
These can lodge in cerebral vessels and cause cognitive defects or even strokes
The microfilter removes particles <40μm
The blood then passes through a microfilter which removes particles less than 40 um. This is important as microemboli formed during the process of CPB and pump can lodge in the brain and cause strokes.

20. Arterial Return
Cannulation of Ascending Aorta
Oxygenated blood returned via arterial cannula placed in a major arterial vessel:
Ascending Aorta
Femoral Artery
Axillary artery
Finally the blood is returned to the patient via an arterial cannula. Most commonly this is placed in the distal ascending aorta. Arterial cannulae can also be placed in the femoral artery or axillary artery.

21. Priming CPB circuit/tubing must be primed to avoid air emboli.
Priming solution consists of:
1.5 – 2.0 L
0.9% Normal Saline or Hartmanns Solution
Drugs, e.g. mannitol
Prime solution:
Reduces blood viscosity and therefore improves flow
Causes haemodilutional anaemia which reduces oxygen delivery
As I’m sure you can imagine, the CPB circuit contains a lot of tubing made of polyvinyl silicone or latex. This tubing is sterile but contains air and therefore needs to primed with some form of fluid prior to the start of surgery to avoid infusing large amounts of air into the patient. In adult patients, priming solution consists of 1.5 – 2.0L of a crystalloid solution, such 0.9% saline or hartmanns solution and other drugs, e.g. mannitol which is a diuretic.
In addition to removing air, the initial priming solution that is infused into the patient reduces blood viscosity and thereby improves flow. However, a prime load of 1.5 – 2.0 L of crystalloid solution also causes anaemia by haemodilution and this is associated with reductions in oxgen delivery and organ injury.

22. Anticoagulation “Over” anti-coagulation to prevent clots in the system
IV Heparin injected prior to the start of CPB
300 – 400 U/kg body wt
Derived from porcine intestinal mucosa or bovine lung
Heparin binds to and activates Antithrombin III which inhibits Thrombin (and therefore clot formation)
Degree of anticoagulation measured by Activated Clotting Time (ACT)
ACT >480 secs to initiate CPB
Effects of heparin reversed at the end of CPB by the administration of Protamine
To prevent blood clotting as it is exposed to foreign surfaces, patients are anticoagulated using intravenous heparin. In fact they are “over anticoagulated” prior to the start of bypass. Modern heparin is derived from porcine intestinal mucosa or more commonly bovine lung. It acts by binding to and activating antithrombin III which then inhibits thrombin and thereby prevents clot formation.
The degree of anticoagulation is monitored by measuring the Activated Clotting Time. This is measured in theatre and should be above 480 secs for cardiopulmonary bypass to be initiated.
Following the termination of bypass, the effects of heparin are reversed by the administration of protamine.

23. Heparin
This is a simplified schematic of the coagulation cascade which demonstrates the action of heparin on antithrombin III which subsequently prevents clot formation by inhibiting thrombin.

24. GOALS OF CARDIOPULMONARY BYPASS
We will now briefly consider the goals of cardiopulmonary bypass and how we assess the adequacy of perfusion during bypass.

25. Motionless & Bloodless Field
The first goal of cardiopulmonary bypass is to provide and maintain a motionless and bloodless field. This is done by draining the heart of all blood. A motionless field is achieved by arresting the heart using high potassium cardioplegia solution.

26. Maintain Oxygen Delivery
DO2 = CaO2 × Flow
(1.39 × Hb × SaO2) + (0.003 × PaO2)
Preop RBC transfusion
Minimising haemodilution
Avoiding systemic hypoxia
CPB flow rates
The second goal is to maintain oxygen delivery to all tissues and organs in the body. Oxygen delivery is a product of arterial oxygen content and blood flow. Arterial oxygen content is mainly affected by the haemoglobin concentration and oxygen partial pressures. These can be optimised by transfusing anaemic patients with red blood cells prior to surgery, minimising haemodilution and maintaining adequate oxygenation.
Key:
DO2 = Oxygen Delivery (ml/min)
CaO2 = Arterial Oxygen Content (ml/100 ml)
Flow (L/min)
Key:
Hb = haemoglobin (g/L)
SaO2 = arterial oxygen saturation (%)
PaO2 = Arterial Oxygen pressures (mmHg)

27. CPB Flow Rate
CPB Flow Rate
(L/min)
Body Surface Area
(m2)
Cardiac Index
(L/min/m2) X =
Cardiac Index varies depending on age and temperature.
In an adult, CI is:
2.4 at 370C
2.1 at 320C
1.8 at 280C
1.2 at 250C
0.6 at 150C
CPB flow rate is a product of body surface area and cardiac index. It varies depending on age and temperature. So at lower temperatures cardiac index and therefore CPB flow rates are much lower. This is because oxygen consumption of tissues reduces at lower body temperatures and therefore their requirement for oxygen also reduces. This is the reason that most surgical units around the world prefer hypothermic bypass (temperatures between 32 and 35 degrees) as it is thought to protect organs.

28. Maintain Adequate Perfusion
Adequacy of perfusion assessed by measuring whole body oxygen consumption
VO2 = (CaO2 – CvO2) × CO
VO2 = Oxygen consumption, (CaO2 – CvO2) = arteriovenous oxygen content, CO = Cardiac output (which = CPB flow)
Additional measures of the adequacy of perfusion:
ScvO2 = Central venous oxygen saturations, Value >65%
Serum Lactate = Increasing lactate indicates anaerobic metabolism
The adequacy of perfusion is assessed by several means. Firstly it is assessed by measuring oxygen consumption. All the variables in the oxygen consumption equation can be directly measured during cardiopulmonary bypass.
Additional measures include central venous oxygen saturation, which is a surrogate marker of oxygen consumption. A value above 65% indicates adequate perfusion.
Serum lactate is another marker. Increasing lactate concentrations indicates anaerobic metabolism and therefore inadequate perfusion.

29. COMPLICATIONS OF CARDIOPULMONARY BYPASS
Despite its many benefits, Cardiopulmonary bypass is associated with several complications. We will consider these briefly,

30. Foreign Surfaces, Non-pulsatile flow, Microemboli, Haemodilution, Shear Stress, Ischaemia-reperfusion
Inflammation, Coagulopathy, Platelet activation and dysfunction, Endothelial cell injury and activation
Organ Injury: Heart, Kidneys, Brain, Lung
Greater injury in patients with preoperative organ dysfunction, e.g. elderly, diabetic patients, smokers
INITIATORS
EFFECTORS
The initiators of injury are exposure of the patients blood to the foreign surfaces, non-pulsatile CPB flow, microemboli, haemodilution which not only dilutes red cell but also clotting factors and platelets. Shear stress of passing through tubing and pumps. And finally ischaemia reperfusion injury.
All of this leads to inflammation, coagulopathy, platelet and endothelial cell activation and dysfunction. And these mechanisms result in organ injury. As our organs have considerable reserve to withstand insults, this organ injury is only really manifest in patients with preoperative organ dysfunction, such as the elderly, diabetic patients and smokers.
OUTCOMES

31. HYPOTHERMIC CIRCULATORY ARREST
Cardiopulmonary bypass has developed and evolved due to translational biomedical research. Acute kidney injury, Acute lung injury, Low Cardiac Output Syndrome and Systemic Inflammatory Response Syndrome remain important problems in specific patient populations undergoing cardiac surgery. Translational research represents the methodology through which these problems can be investigated and overcome.

32. Definition of hypothermia
Yan TD et al. Ann Cardiothorac Surg 2013;2:

33. PURPOSE OF HCA HCA developed by Randall Griepp in 1970s. Purpose:
Provide a bloodless operating field
Reduce the brains metabolic demand, thereby prevent cell death – MAIN FOCUS = BRAIN
‘Safe’ surgical time period – lengthens the period of ischaemia tolerated

34. USES OF HCA Aortic arch surgery Type A Aortic Dissection
Pulmonary thromboendarterectomy
Resection of IVC tumour

35. ACHIEVING ECS
Yan TD et al. Ann Cardiothorac Surg 2013;2:

36. SAFE DURATION OF HCA
Yan TD et al. Ann Cardiothorac Surg 2013;2:

37. Ghosh S, Falter F, Cook DJ. Cardiopulmonary Bypass (2009).

38. TEMPERATURE VARIATION

39. MULTIMODAL STRATEGY TO BRAIN PROTECTION

40. Antegrade cerebral perfusion

41. DELITERIOUS EFFECTS OF HCA
Neurological
Cardiovascular
Respiratory
Metabolic
Haematology/Coagulation
Gastrointestinal

42. Summary
The development of CPB was essential to perform open heart operations
Key principle: removes deoxygenated venous blood, oxygenates the blood, then pumps this back into the body via a major artery
Goals of CPB: bloodless field, oxygen delivery
Adequacy of perfusion assessed by several factors
CPB causes organ injury
In Summary, the development of cardiopulmonary bypass was essential for surgeons to perform open heart operations so as to treat intra-cardiac pathology.
The key principle of Cardiopulmonary bypass is to remove deoxygenated venous blood, oxygenate the blood, and then pump it back to the patient via a major artery. The goals of CPB include maintaining a blood less field and preserving whole body oxygen delivery. The adequacy of perfusion is assessed by oxygen consumption and other variables such as lactate.
Cardiopulmonary bypass however does cause organ injury and this presents the opportunity to conduct translational biomedical research the goal of protecting organ function and preventing organ injury.

43. Further reading
Cohn, L. Cardiac surgery in the adult. 4th Ed. Chapter 12: Extracorporeal circulation.
Kouchoukos, NT et al. Kirlkin/Barratt-Boyes Cardiac Surgery. 3rd Ed. Volume 1. Chapter 2: Hypothermia, Circulatory arrest, and cardiopulmonary bypass.