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Hypothermia, Circulatory Arrest, and Cardiopulmonary Bypass
Section I
Hypothermic Circulatory Arrest
Historical Note
In 1950, Bigelow and colleagues, in their publications on experimental hypothermia produced by surface cooling, introduced the concept that whole-body hypothermia might be useful in cardiac surgery. They subsequently reported cooling dogs to 20°C by surface cooling, with recovery after 15 minutes of circulatory arrest. In 1951, Boerema and colleagues reported experimental studies indicating that when animals were cooled by a femoral-femoral shunt through a cooling coil, up to 15 minutes of circulatory arrest (produced by inflow stasis) were tolerated without apparent ill effect. Using surface cooling, Lewis and Taufic reported successful repair of an atrial septal defect in a 5-year-old girl in 1953, and in the same year, Swan and colleagues reported successful results in a series of patients treated using the same technique. In 1958, Sealy and colleagues reported successful clinical cases in which hypothermia was combined with cardiopulmonary bypass (CPB). In 1959, Drew and colleagues reported experimental studies in which CPB (using the subject's own lungs as the oxygenator) was used to cool and rewarm the subject, and operations were done during circulatory arrest at 15°C.
In 1960, Guiot and colleagues and Weiss and colleagues reported use of hypothermia and circulatory arrest for cardiac surgery in humans. In 1961, Kirklin and colleagues at Mayo Clinic reported results of operation with hypothermic circulatory arrest in 52 patients, using Drew's technique in 23 and a pump-oxygenator in 29. In 1963, Horiuchi and colleagues from Tohoku University reported using surface cooling to 25°C and circulatory arrest during repair of ventricular septal defect in 18 infants younger than 1 year of age, with 16 survivors. Dillard and colleagues modified this technique to permit surface cooling to hypothermic temperatures of 17°C to 20°C and extension of circulatory arrest to 60 minutes. In 1967, they reported successful repair of total anomalous pulmonary venous connection in four infants by this method of surface cooling and rewarming. Similar experiences with this and other congenital malformations were reported by Hikasa and colleagues and Wakusawa and colleagues.
In 1970, Barratt-Boyes and colleagues in New Zealand reported repair of a variety of malformations during hypothermic circulatory arrest in 34 infants weighing less than 10 kg using surface cooling to 22°C to 27°C, followed by a brief period of CPB to reduce the temperature further, as well as rewarming with CPB. In 1973, using only CPB for cooling (core cooling), Hamilton and colleagues reported operations with hypothermic circulatory arrest in 18 infants. These experiences and subsequent modifications in technique opened the way for safer intracardiac surgery in neonates and infants.
Use of hypothermic circulatory arrest in combination with CPB in adults was first reported by Barnard and Schrire in 1963. Two patients with aneurysms of the ascending aorta and aortic arch underwent replacement of the involved aortic segments using hypothermia to an esophageal temperature of approximately 10°C and short intervals of circulatory arrest. One survived. In 1964, Borst and colleagues reported successful repair of an arteriovenous fistula involving the aortic arch using a period of hypothermic circulatory arrest. In 1969, Lillehei and colleagues reported use of partial CPB, hypothermia, and circulatory arrest for managing ruptured mycotic aneurysms, ruptured left ventricles, and other complicated cardiac pathology. The first series of patients with aneurysms of the aortic arch that were successfully resected during an interval of hypothermic circulatory arrest was reported by Griepp and colleagues in 1975.
Hypotheses
A basic hypothesis underlying use of circulatory arrest for cardiac and aortic surgery is that there is a safe duration of this state, the length of which is inversely related to temperature of the organism during the arrest period. A safe period of circulatory arrest is characterized by absence of detectable functional or structural organ derangements in the early or late postoperative period. Structural derangements without apparent functional correlates are of concern, particularly in the central nervous system, because of an implied loss of neurologic reserve that may be important to the individual later in life.
Temperature of the organism is not easily defined or described. In normal humans, temperature gradients between areas of the body at rest are small, so a single representation of inner body temperature is generally acceptable. When hypothermia is produced by surface cooling, internal temperature gradients are relatively small, although skin and muscles become cooler than inner organs, and rectal temperature is substantially lower than nasopharyngeal temperature. During cooling by hypothermic perfusion with CPB (core cooling), the relationship of rectal to nasopharyngeal temperature is reversed, and regional differences in temperature are considerable, although they can be lessened by prolonging the period of cooling. Thus, when the latter technique is used wholly or in part to induce hypothermia, the specific site of temperature measurement, as well as the limitations in interpretation of the measurements themselves, must be noted.
Another hypothesis is that hypothermia, without itself producing damage, reduces metabolic activity to the extent that available energy stores in the various organs maintain cell viability throughout the ischemic period of circulatory arrest and thus allow normal structure and function to return after reperfusion. The magnitude of reduction of oxygen consumption is hypothesized to directly relate to safe duration of circulatory arrest.
Oxygen Consumption During Hypothermia
Oxygen consumption ( 
) is considered a measure of metabolic activity, so the magnitude of its decrease by hypothermia (in the anesthetized subject in whom shivering is prevented) is an index of the degree of reduction of metabolic activity. Use of 
as such a marker is reasonable because for all practical purposes, tissue and cellular stores of oxygen do not exist. The body is dependent on circulation to bring oxygen to tissues in amounts determined by their metabolic needs.
Relationship between Oxygen Consumption and Body Temperature
Energy requirements of the body, reflected in part by 
, are reduced during hypothermia, reflecting dependence of the rate of biochemical reactions on temperature. Quantitative interrelations have been expressed mathematically in various ways ( Box 2-1 ). Some have used a linear model . Others, including Harris and colleagues, have used a model based on the Arrhenius equation, which states that the logarithm of the rate of a chemical reaction is inversely proportional to the reciprocal of the absolute temperature. The nomogram describing this relationship is S-shaped (similar to the oxygen dissociation curve) such that at high temperatures, the reaction rate ceases increasing with temperature (reaches an asymptote).
Box 2-1
Kinetics of Oxygen Consumption
The relationship of oxygen consumption ( 
) to perfusion flow rate ( 
) and temperature (T) is not linear; that is, a unit increase in 
or T does not increment 
a constant amount. A number of formal mathematical models (see Box 6-5 in Chapter 6 ) have been proposed that relate, in particular, metabolic activity and T based on fundamental thermodynamics. These models provide a good starting point for examining 
data for other empirical relations, such as with blood flow.
Arrhenius Equation
The Arrhenius equation relates reaction rate k to temperature T , the universal gas constant R , activation energy E a , and a constant related to molecular collision as:
where e is the base of the natural logarithms. If logarithms are taken of both sides of this equation, one obtains the following:
Constants A , R , and E a are coalesced ( a, b ) to obtain a log-inverse equation:
Therefore, one can examine the correlation of the logarithm of oxygen consumption and inverse temperature to see if the data are consistent with this relation.
van't Hoff Law (Q 10 )
Another relation is expressed in the van't Hoff law, which is generally formulated in terms of change in metabolic rate ( k ) per 10°C change in temperature (Q 10 ):
If T 1 − T 2 is 10°, then Q 10 is simply the ratio of k 1 to k 2 (metabolic rates at each temperature). This relation can be derived from the parameter b in the Arrhenius equation.
Hyperbolic Equation
Metabolic rate (reflected in 
) and 
should be independent until blood flow becomes limiting. This suggests a hyperbolic relation between the two variables:
where c is the asymptotic (limit of 
) value of 
as 
becomes large (metabolic rate independent of flow).
Empirical Relations
Actual data may be better characterized by (1) a linear relation (rare), (2) a log-linear (exponential) relation, (3) a log-log relation, (4) an inverse-log relation, or a more complex relation. Many of these models can be fitted to data using linear regression (see Box 6-5 in Chapter 6 ) by logarithmic or inverse transformations of scale. Others require iterative nonlinear optimization methods to obtain parametric estimates (see Box 6-14 in Chapter 6 ).
At physiologic temperatures, biochemical systems operate only on the upswing of the curve. Thus—particularly when the range of temperatures is relatively small—this relationship finds numeric expression in the van't Hoff law, which relates the logarithm of a chemical reaction rate directly to temperature. Conveniently, according to this equation, the reaction rate increases by two to three times for an increase in temperature of 10°C. Chemists use the symbol Q 10 for this multiple.
Because oxygen uptake is the expression of all oxidative reactions, both direct and indirect, the logarithm of 
might be expected to be directly proportional to temperature. In general, this appears to be so. Whether the observed decline in 
during clinical hypothermia can be accounted for entirely on this physicochemical basis is doubtful, however (see “ Oxygen Consumption during Hypothermia in Tissue Slices and Isolated Organs ” later in this section).
Total Body Oxygen Consumption after Surface Cooling
When hypothermia is induced by cooling the surface of anesthetized humans or experimental animals, cooling is rather uniform throughout the body, and temperatures of internal organs and regions differ by less than 2°C. Therefore, values for whole-body 
at various body temperatures are probably useful, and the relative magnitude of reduction can be assumed to be similar throughout the body.
Good data in this area are available from the animal experiments of Bigelow and colleagues, Ross, and Penrod. Data for surface cooling in humans are sparse, although Harris estimated Q 10 to lie between 1.9 and 4.2 in 10 surface-cooled infants. The experimental data were reanalyzed using (1) a linear equation, (2) the Arrhenius equation, and (3) the van't Hoff law. The van't Hoff law best fits this combined set of data ( Fig. 2-1 ) and is considered the most appropriate model for this purpose. This model also best fits the relation between temperature and cerebral oxygen consumption during CPB in humans.
Kent and Peirce studied 
in experimental animals during hypothermia produced by combined surface and core cooling. Their data are similar to those obtained from surface cooling alone.
Oxygen Consumption during Hypothermia in Tissue Slices and Isolated Organs
Data from the studies described could lead to an underestimation of true oxygen demand, because only areas in which perfusion of the microcirculation continues can participate in oxygen consumption (tissue and cellular stores of oxygen being trivial). In theory at least, a considerable part of the reduction in oxygen consumption from surface cooling could be from shutting down the microcirculation of portions of the body or from arteriovenous shunting. New technologies, particularly magnetic resonance imaging (MRI), may resolve some of these questions.
Studies of tissue slices at various temperatures show that oxygen consumption is in fact reduced by hypothermia. These studies and those of isolated organs suggest that Q 10 , although differing from tissue to tissue, is on average about 2 (for references and a table of Q 10 values, see Harris and colleagues ). Measurement of human whole-body 
before and after heating, rather than cooling, indicates a Q 10 in this same range (≈1.9). Vasodilatation caused by heating presumably ensures access of oxygen to the tissues, and this Q 10 probably represents true tissue oxygen requirement. A Q 10 greater than 1.9 associated with cooling may therefore indicate that oxygen delivery has been compromised by inadequate flow rate. Fuhrman and colleagues have spent many years investigating this possibility. They showed that, in general, there was a close agreement between resting 
at 37°C and tissue slice respiration. However, rats cooled by immersion to 18°C exhibited a 33% lower 
than would be expected from studies of tissue slice respiration at this temperature. The discrepancy was not accounted for either by inhomogeneities in whole-body temperature or by known changes in Q 10 exhibited by some tissues (in part related to altered function at reduced temperatures). The precise mechanism remains unknown. It could be due to arteriovenous shunting or to shutting down of perfusion to some areas of the body. Microvascular physiologists have referred to the latter as a decrease in effective capillary density . This may result not only from reduced cardiac output and vasoconstriction but also from changes in blood viscosity, geometry, and compliance of red blood cells, plasma “skimming,” and clumping of formed blood elements.
Some studies of tissue slices and isolated perfused organs show a relative reduction of oxygen consumption at any degree of hypothermia that is greater than in those of the body as a whole ( Table 2-1 ). This may be related to known species differences in tissue respiration, suboptimal conditions for tissue respiration in the studies with tissue slices, or increased 
during whole-body perfusion caused, for example, by catecholamine release.
Table 2-1
) | Tissue Slices (Rats) b | Isolated In Situ Organs (Dogs) c (Cooling Coil Shunt) | Isolated In Situ Organs (Dogs) d (Surface Cooling) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Organ | 37°C | 25°C | %  Reduction |
37°C | 25°C | %  Reduction |
37°C | 25°C | %  Reduction |
| Brain | 1.98 ± 0.31 | 0.73 ± 0.139 | 63 | 5.16 ± 0.90 | 3.54 ± 0.90 | 31 | 4.31 ± 0.64 | 1.46 ± 0.30 | 66 |
| Kidney | 3.87 e | 1.63 e | 58 | 5.58 ± 1.98 | 0.96 ± 0.36 | 83 | — | — | — |
| Muscle | 0.76 | 0.36 | 53 | 0.90 ± 0.30 | 0.30 ± 0.12 | 67 | — | — | — |
a Expressed as mL · h −1 · g −1 wet weight ± SD. Data have been rearranged and recalculated to allow comparisons.
c Data from Holobut and colleagues.
A striking and important fact from whole-body, tissue, and organ studies is that 
is not reduced to near zero at temperatures close to 0°C. Metabolic activity is therefore continuing, and the time limits of safe circulatory arrest must be finite. Furthermore, this continuing metabolic activity causes a tendency for organs and systems to rewarm during the arrest period. Donald and Kerr showed in dog brains cooled to 1°C to 2°C that an increase in temperature occurred during a 30-minute period of circulatory arrest and that this was in part related to the gradient between brain and room temperature and in part to continuing metabolic activity in the brain.
Other Phenomena During Hypothermia and Circulatory Arrest
No-Reflow Phenomenon
It is only a hypothesis that a numeric relationship exists between 
and safe circulatory arrest time at any given temperature. In fact, existence of a necessary and close relationship between the two over a wide range of temperatures would be surprising in view of other phenomena that occur during circulatory arrest. One of these is regional vascular occlusion in the brain and probably in all organs and tissues, leading to the no-reflow phenomenon. This is an obstructive lesion of the microcirculation that prevents local reperfusion and leads to additional damage after the general circulation of blood has been reestablished.
The no-reflow phenomenon could theoretically damage the brain after hypothermic circulatory arrest. However, Norwood and colleagues have shown experimentally that this phenomenon develops as a result of severe hypoxia or anoxia, not because of circulatory arrest per se. They have also shown that hypothermia to 20°C prevents the no-reflow phenomenon from 90 minutes of anoxia produced by continuing perfusion at an arterial Pa o 2 of about 10 mmHg. Thus, this phenomenon may represent, at least in part, hypoxic endothelial cell injury, with altered expression of endothelial relaxing and constricting factors. In experimental studies, hypoxia followed by reoxygenation results in an almost twofold increase in release by endothelial cells of endothelin-1, the most powerful vasoconstrictor yet identified. Other experimental studies have shown that this response can be blunted when ischemia is induced under hypothermic conditions, so hypothermia may provide protection against hypoxic endothelial cell injury. Hypoxia may also promote a procoagulant response in endothelial cells that can result in intravascular microthrombosis. Edema, as well as neutrophil and platelet plugging, may also contribute to the impaired perfusion that occurs following ischemia, despite what appears to be adequate restoration of blood flow.
Changes in Plasma Volume
Chen and colleagues demonstrated progressive hemoconcentration and decrease in plasma volume during surface cooling of infants to 25°C, an observation supporting their own and previous experimental studies. This may represent sequestration of plasma in portions of the vascular bed and plasma leakage into the interstitial fluid compartment.
Damaging Effects of Circulatory Arrest During Hypothermia
It is generally agreed that the brain has the shortest safe circulatory arrest time of any organ or region of the body, although occasionally the kidney seems to be damaged by a period of circulatory arrest when the brain is not. Although other organs and regions can be severely damaged by long periods of circulatory arrest, their safe arrest times are generally longer than that of the brain.
Brain Function and Structure: Risk Factors for Damage
The possibly damaging effects of circulatory arrest on the brain, as well as the risk factors related to it in patients undergoing cardiac operations during hypothermic circulatory arrest, are incompletely understood. The conduct of cooling and rewarming by CPB and the damaging effects of CPB itself likely contribute to or interact with the injury produced by circulatory arrest per se.
Duration of total arrest of cerebral blood flow is clearly a determinant of the amount of brain damage, but the safe duration of circulatory arrest to the brain (the duration within which irreversible structural or functional damage does not occur) is affected by a few known risk factors and no doubt by other risk factors that are as yet poorly understood. Furthermore, in patients undergoing cardiac surgery, brain damage that occurs in the setting of hypothermic circulatory arrest is rarely diffuse. In adults, it is usually manifested by specific intellectual or motor deficits, whereas in neonates, infants, and small children it is more likely to be manifested by seizures or choreoathetoid movements. This may be related to the phenomenon of selective neuronal vulnerability, a heightened sensitivity of specific neuron groups to ischemic injury. This sensitivity has been correlated with the concentration of specific membrane receptors whose density in specific areas varies with age. Concentration of these receptors is transiently high in the basal ganglia in the neonatal period, which may relate to the appearance of choreoathetosis as a result of ischemic injury in the very young.
Risk factors for irreversible structural and functional brain damage from circulatory arrest, in addition to duration of the arrest, include mean and regional brain temperature during circulatory arrest, rate of cooling and rewarming, cerebral blood flow and distribution during cooling, arterial blood pressure during cooling and reperfusion, electrical activity before arrest, biochemical milieu and catecholamine levels during cooling and circulatory arrest, absence of pharmacologic interventions before and after cessation of cerebral blood flow, and total management of reperfusion.
Temperature and Duration
Most clinical studies of the relationship of temperature to safety of a given circulatory arrest time are flawed by lack of information about the temperature of the brain itself and by the variety of sites of measurement of temperature (tympanic membrane, nasopharynx, rectum, midesophagus, bladder, extremity skin) used to estimate safety. There is little consistent correlation between some of these sites, although temperature of the tympanic membrane and nasopharynx most closely resembles mean temperature of the brain. For this reason, these sites should be used whenever possible.
Animal experiments and clinical experiences indicate that when the brain is cooled to 15°C to 20°C, circulatory arrest of 30 minutes or less is tolerated without development of evident structural or functional damage. During such a period, adenosine triphosphate (ATP) concentrations decline to 35% of initial values but return rapidly to normal during reperfusion. Evidence that circulatory arrest of 45 minutes at these temperatures is safe is less secure.
Considerable information supports the inference that circulatory arrest of 60 minutes or more at temperatures of 15°C to 18°C is associated with irreversible structural or functional damage, although it may be tolerated without evident damage by some subjects under some circumstances. In experimental studies by Folkerth and colleagues and Fisk and colleagues, histologic evidence of anoxic brain damage was found in all animals subjected to hypothermic circulatory arrest for 45 to 60 minutes, although some animals survived without evident functional abnormality. Half (2 of 4) of the animals studied by Kramer and colleagues showed no recovery of ATP when subjected to 60 minutes of hypothermic circulatory arrest.
Some clinical studies have found few problems associated with 60 minutes or more of hypothermic circulatory arrest. Particularly striking is the experience of Coselli and colleagues, who found no clinical evidence of brain damage attributed to hypothermic circulatory arrest (mean nasopharyngeal temperature 16.9°C; range, 10.1°C-24.1°C) in 56 patients with arrest times ranging from 14 to 109 minutes (median 36 minutes). Comprehensive neuropsychometric studies were not undertaken. Hemiparesis or hemiplegia attributed to cerebral edema developed in 3 of 51 surviving patients (6%; CL 3%-11%). In contrast, Gega and colleagues, in a subsequent study of 394 patients undergoing aortic arch replacement, reported 8 strokes (13%; CL 8.6%-18%) among 61 patients in whom the duration of hypothermic circulatory arrest exceeded 40 minutes. Only 10 strokes (3.3%; CL 2.3%-4.3%) occurred among the remaining 333 patients with shorter intervals of circulatory arrest.
Temporary neurologic dysfunction (postoperative confusion, agitation, delirium, obtundation, or transient parkinsonism without localizing signs) can occur in up to 20% of survivors of operations on the thoracic aorta in which hypothermic circulatory arrest is used. Incremental risk factors associated with developing this complication are duration of hypothermic circulatory arrest and increasing patient age. Prevalence of temporary neurologic dysfunction increases substantially among patients in whom duration of circulatory arrest exceeds 60 minutes ( Fig. 2-2 ). Although postoperative delirium is not permanent, it can be an important complication. Among a group of patients undergoing pulmonary thromboendarterectomy, circulatory arrest times of greater than 50 minutes were a powerful risk factor for its occurrence.
Some evidence supports the concept that continuous perfusion of the brain for 60 or more minutes at low temperature also produces neurologic sequelae in a few patients (see “ Evidence of Gross Neurologic Damage ”). However, cold (10°C-15°C) continuous perfusion of brains already at 15°C resulted in no intellectual or other deficit in trained rhesus monkeys.
Characteristics of the Cooling Process
Uneven cooling of the brain is probably a risk factor for brain damage, although evidence is largely indirect. Almond and colleagues conducted experiments in dogs undergoing hypothermic circulatory arrest for 30 minutes. Results were interpreted to indicate structural and functional brain damage when cooling by CPB was done with the perfusate 20°C colder than the patient. These investigators believed that this did not occur when the blood was only 4°C to 6°C cooler than the subject. However, the damage might have been related to the short period of cooling required with the very cold blood, producing uneven brain cooling, as suggested by the work of Zingg and Kantor. The longer period of cooling required with the blood only 4°C to 6°C colder than the subject probably produced more uniform cooling. In their patients, Stewart and colleagues noted a considerably higher prevalence of major neurologic events after circulatory arrest when core cooling by CPB alone was used, compared with surface cooling first to 28°C, followed by core cooling ( Table 2-2 ). A reasonable presumption is that the more rapid core cooling resulted in uneven cooling of the brain. In another study in neonates and infants, rapid core cooling was associated with more evidence of neurologic deficits after hypothermic circulatory arrest than more prolonged core cooling. Again, a reasonable presumption is that prolonged core cooling results in more uniform cooling of the brain.
Table 2-2
Major Neurologic Events after Hypothermic Circulatory Arrest
Data from Stewart and colleagues.
| Method | No. of Patients | Circulatory Arrest (min) | Major Neurologic Events a | ||
|---|---|---|---|---|---|
| No. | % | CL | |||
| Surface cooling to 28°C, then core cooling | 80 | 42.5 ± 13.6 | 0 | 0 | 0-2 |
| Core cooling only | 138 | 42.8 ± 15.4 | 8 | 6 | 4-9 |
| T otal | 218 b | ||||
| P | .03 | ||||
a Excludes seizures followed by uneventful convalescence.
b Repair of ventricular septal defect, tetralogy of Fallot, transposition of the great arteries, and atrioventricular septal defects. Mean temperature ± standard deviation during arrest for both groups was 19.7 ± 1.76°C.
Cerebral Blood Flow during Cooling and Rewarming
The relationship of cerebral blood flow during cooling (before establishing hypothermic circulatory arrest) to safety of the arrest period has received little investigation. The earlier literature suggested that reduced arterial blood pressure during CPB without circulatory arrest contributes to postoperative neurologic dysfunction, presumably because the hypotension resulted in reduced cerebral blood flow, but this possibility now appears less certain (see “ Cerebral Blood Flow ” under Distribution of Blood Flow in Section II ).
More recently, when cerebral blood flow was measured during operations involving hypothermic circulatory arrest in children, Greeley and colleagues observed that patients with increased oxygen extraction before circulatory arrest may be particularly vulnerable to cerebral injury. In a subsequent study, they demonstrated that during cooling, a parallel reduction in cerebral oxygen consumption and cerebral blood flow occurred. However, in three of four patients who were subsequently found to have sustained neurologic injury, oxygen extraction before the period of circulatory arrest was increased, suggesting that cerebral blood flow during this period was inadequate to sustain metabolic requirements. Other studies in children have confirmed the observation that cerebral blood flow generally decreases with temperature during cooling, and that coupling with cerebral metabolism is maintained even at low temperatures when ventilation is managed according to the alpha-stat strategy.
Information is available about the magnitude and effect of cerebral blood flow during rewarming. Experimental studies have found that cerebral blood flow is reduced during rewarming after circulatory arrest ( Fig. 2-3 ). With or without circulatory arrest, this phenomenon occurs in humans during cardiac surgery and may affect outcome. In infants, cerebral blood flow is reduced during rewarming immediately after hypothermic circulatory arrest and after achieving normothermia. Based on measurements of jugular venous oxygen saturation, oxygen delivery appears to be adequate during this period of reduced flow. In a study of 255 adult patients undergoing elective coronary artery bypass grafting (CABG) with or without associated cardiac valve replacement, Croughwell and colleagues observed a decline in postoperative cognitive function in 38%. The severity of decline was related to greater arteriovenous oxygen content difference between radial artery and jugular venous blood (Cav o 2 ) during rewarming. This increase in oxygen extraction was associated with a low jugular venous oxygen saturation and low cerebral blood flow.
Biochemical Milieu
Only incomplete information is available in the area of biochemical milieu. It is uncertain whether some variables are actual risk factors or surrogates for the real risk factor. Arterial blood pH and P co 2 during cooling may have important direct effects on brain tissue at the beginning of the period of circulatory arrest, and thereby on outcome, but they also influence cerebral blood flow, and perhaps its distribution, during cooling (see Controlled Variables in Section II ). Any effect they may have on neurologic outcome, which is uncertain, could be through either mechanism.
Brunberg and colleagues and Anderson and colleagues suggested that increased tissue glucose, such as is usually present at the beginning of the arrest period, may lead to excessive glycolysis and acidosis during the arrest period, possibly resulting in tissue damage from lactic acid accumulation. This possibility makes it imprudent to use glucose solutions for priming the pump-oxygenator and for intravenous infusion when a period of circulatory arrest is contemplated.
Based on the work of Choi and of Olney and colleagues, evidence has accumulated indicating that the neuroexcitatory amino acids—particularly glutamate, the major transmitter mediating synaptic excitation in the mammalian central nervous system—have potent neurotoxic activity during conditions of depleted cellular energy (e.g., hypoxia, ischemia) when the synaptic reuptake of these amino acids, a highly energy-dependent process, is compromised. Resulting overaccumulation of glutamate leads to excessive excitation of the glutamate receptors, leading to an increase in intracellular calcium and eventual neuronal cell injury and death. This process has been observed in experimental animals after 2 hours of circulatory arrest. Neuronal necrosis is selective and corresponds closely to distribution of excitatory amino acid receptors. The hippocampus, cerebellum, and basal ganglia, which have high concentrations of glutamate receptors, are characteristically most vulnerable to this injury, implying excitation as an underlying mechanism.
Apoptosis, or programmed cell death, has been demonstrated experimentally in the neocortex of piglets following hypothermic circulatory arrest for 90 minutes at 19°C. Damaged neurons were observed between 8 and 72 hours after reperfusion. Caspase 3 and caspase 8, the principal cysteine proteases involved in apoptosis, were substantially elevated in these animals compared to control animals (no CPB or CPB without circulatory arrest). ATP levels were similar to those of control animals. Glutamate excitotoxicity secondary to hypothermic circulatory arrest has been shown to mediate neuronal apoptosis as well as necrosis.
Fessatidis and colleagues’ experimental studies using histopathologic techniques demonstrated that the cerebellum is the most vulnerable area of the brain to prolonged periods (>70 minutes) of hypothermic (15°C) circulatory arrest.
Electroencephalogram Before Arrest
Electroencephalographic (EEG) criteria for safe circulatory arrest are conflicting. In a study by Coselli and colleagues, the longest recorded durations of safe circulatory arrest in adults were in situations in which a full formal EEG had recorded electrocerebral silence (no electrical activity of cerebral origin at maximal gain, 2 µV · mm −1 ) for 3 minutes before the arrest. Mean nasopharyngeal temperature at this point was 16.9°C (range, 10.1°C-23.1°C).
In a subsequent study by Stecker and colleagues of 109 adult patients undergoing hypothermic circulatory arrest, electrocerebral silence was achieved at a mean nasopharyngeal temperature of 17.8°C (range, 12.5°C-27.2°C). Using a standardized protocol, this required cooling for a mean of 27.5 minutes (range, 12-50 minutes). Distributions of times to cool to various EEG events are shown in Fig. 2-4 . The time to cool to electrocerebral silence was prolonged by high hemoglobin concentration, low arterial partial pressure of carbon dioxide, and slow cooling rates. Only 60% of patients demonstrated electrocerebral silence by either a nasopharyngeal temperature of 18°C or a cooling time of 30 minutes. Although cooling to an end point such as electrocerebral silence provides a more reproducible effect of hypothermia on the nervous system than cooling to a specific temperature (e.g., 12.5°C, which was sufficient to produce electrocerebral silence in all patients in this study), the optimal temperature for circulatory arrest could not be determined.
Others have found that in infants and children cooled to a nasopharyngeal temperature of 18.5°C, the EEG was characterized by continuous phasic activity. During cooling, however, there was a gradual disappearance of fast components and an increase in slow components. Occasionally, repetitive rapid discharges occurred. Such reports indicate that when circulatory arrest is established, electrocerebral silence develops after an interval that is inversely related to nasopharyngeal temperature at the beginning of the arrest period ( Fig. 2-5 ). However, Reilly and colleagues reported persistent EEG activity during circulatory arrest, perhaps reflecting activity in the white matter and cerebellum. This is of interest because of the occasional postoperative occurrence of choreoathetoid movements in humans and high-stepping gaits in experimental animals. These abnormalities may be due in part to uneven brain cooling secondary to regional differences in flow.
When CPB is resumed after circulatory arrest in infants, EEG activity is absent initially and then gradually returns as rewarming proceeds. In general, after 20 to 30 minutes of rewarming, the EEG has returned approximately to its control condition. This latent period between resumption of whole-body perfusion for rewarming and time of return of reasonably normal EEG activity is believed by Weiss and colleagues to be related to the important metabolic (oxygen) debt that develops during the arrest period. This in turn is influenced by brain temperature during arrest and by duration of the arrest. They observed that when circulatory arrest lasted less than 40 minutes, EEG activity always reappeared within less than 20 minutes, whereas longer periods of circulatory arrest were followed by longer and more varied latent periods.
In adults, Stecker and colleagues observed that lower nasopharyngeal temperatures at the time of circulatory arrest resulted in a slower return to continuous activity. Prolonged time to recovery of continuous EEG activity and higher temperature at which the EEG first became continuous were associated with increased risk of neurologic injury. Patients who sustained postoperative neurologic injury also had a longer period of circulatory arrest (52 ± 21 minutes) than patients who did not (37 ± 12 minutes) ( P = .006).
Patient Age
Although it has been stated that very young patients suffer less brain damage than older patients from hypothermic circulatory arrest, there is little factual support for this concept. Relative to the general population, cognitive, language, and motor performances are importantly reduced at age 4 years in infants younger than 3 months in whom circulatory arrest has been used. In a randomized trial of 171 neonates with D-transposition of the great arteries who had open repair using either hypothermic circulatory arrest or low-flow CPB, the circulatory arrest group at age 4 years had lower motor scores and more speech abnormalities ( P = .03). They also performed worse on tests of fine motor and visuospatial skills. At 8 years, the circulatory arrest group performed worse on tests of motor function ( P = .003), speech apraxia ( P = .01), visual motor tracking ( P = .01), and phonologic awareness ( P = .0003) than children in whom low-flow CPB was used. In adults in whom circulatory arrest is used, increasing age is an important predictor of both stroke and temporary neurologic dysfunction. Temporary neurologic dysfunction is a marker for long-term functional neurologic deficit.
Effects of Brain Damage
Evidence of Gross Neurologic Damage
Choreoathetosis has occurred early postoperatively in infants and children undergoing hypothermic circulatory arrest. When it occurs, it usually develops 2 to 6 days postoperatively. As time passes, the movements usually lessen in severity. If mild, they disappear completely, but if severe, they or hypotonia may persist. Brunberg and colleagues found no correlation between circulatory arrest time or depth of cooling (between 16°C and 20°C) and development of choreoathetosis. These reports suggest that this specific complication occurs in 1% to 12% of patients and that its residual effects are permanent in some. When choreoathetosis occurs, it is often in the setting of prolonged circulatory arrest.
Choreoathetosis has been observed in infants and children subjected to hypothermic CPB without circulatory arrest. There are suggestions that this complication can result from perfusion of the brain with very cold blood for a prolonged period at relatively high flows. This is the basis for the recommendation that arterial temperature not be reduced to less than 15°C.
The cause of choreoathetosis is unclear. Deep hypothermia per se may cause neurologic injury. Egerton and colleagues reported that continuous hypothermic perfusion at 10°C to 12°C produced moderate or severe brain damage, including choreoathetosis, in 10 of 16 patients (63%; CL 46%-77%). Air or particulate embolization to the brain may be a contributing factor. When circulatory arrest is used, choreoathetosis may be related to uneven brain cooling, leading to continued metabolic activity in the white matter and cerebellum (as reported by Reilly and colleagues ), and possibly to uneven brain reperfusion related to vascular changes associated with the no-reflow phenomenon. The latter finding lends support to the rationale for using hemodilution during cooling, because absence of red cells in the perfusion used just before circulatory arrest to the brain eliminates the no-reflow phenomenon. Use of the alpha-stat strategy of acid-base balance has also been implicated as a causative factor.
Seizures have occurred in the early postoperative period in 5% to 10% of patients undergoing hypothermic circulatory arrest. Because seizures are usually transient and followed by uneventful convalescence, they have not been considered major neurologic events. However, in an analysis from the Boston Circulatory Arrest Study involving 171 children with D-transposition of the great arteries, transient postoperative clinical and EEG seizures were associated with worse neurodevelopmental outcomes at ages 1 and 2.5 years, as well as neurologic and MRI-detected abnormalities at age 1 year. At age 4 years, occurrence of perioperative seizures was associated with lower IQ scores ( P = .01) and increased risk of neurologic abnormalities (odds ratio 8.4, P = .05).
In a more recent prospective study of 178 neonates and infants less than age 6 months undergoing CPB with or without hypothermic circulatory arrest for a variety of congenital heart defects, including hypoplastic left heart syndrome and other forms of single ventricle, EEG-recorded seizures occurred in 20 patients (11.2%; CL 8.8-14.2%). Patients with duration of circulatory arrest of more than 40 minutes had more seizures (14 of 58, 24%; CL 18%-31%) than those with a duration of 40 minutes or less (4 of 59, 6.8%; CL 3.5%-12%; P = .04). Occurrence of seizures among patients with a duration of circulatory arrest of 40 minutes or less was similar among those in whom circulatory arrest was not used ( P = .38).
The comments concerning possible causes of choreoathetosis are applicable to seizures. However, it is well known that infants are highly susceptible to seizures from other causes, such as disturbances of thermoregulation and fluid balance, as well as from metabolic disorders, especially those related to glucose and calcium, and many of these factors may be operative in these patients.
Severe gross evidence of brain damage occurs uncommonly after hypothermic circulatory arrest in infants and children, including coma either dating from surgery or developing some hours later, followed by lasting impairment or death . In a study by Stewart and colleagues, 3 (1.4%; CL 0.6%-2.7%) such instances occurred among 218 young patients undergoing repair of the common types of congenital heart disease with hypothermic circulatory arrest; 5 other patients developed choreoathetosis. All these events occurred in the group of patients in whom core cooling alone was used. None occurred in patients in whom the duration of circulatory arrest was less than 45 minutes, and the probability of developing major neurologic events increased as circulatory arrest time increased beyond this ( Fig. 2-6 ).
Focal neurologic damage resulting in serious neurologic impairment (stroke) occurs in adult patients following hypothermic circulatory arrest. Ergin and colleagues demonstrated that this form of injury is related to older age ( P < .0001) particularly beyond 60 years, presence of clot or atheroma in the aortic arch ( P < .0001), as well as longer duration of hypothermic circulatory arrest ( P < .0001). In the series of adult patients reported by Gega and colleagues in whom hypothermic circulatory arrest was used as the sole means of brain preservation, prevalence of stroke was 13.1% (8 of 61; CL 8.6%-19.1%) among patients in whom the duration of circulatory arrest exceeded 40 minutes. Computed tomographic (CT) scans demonstrated that 62% of these strokes were embolic in origin and 38% were related to hypoperfusion.
Postoperative Intellectual Capacity
The effect of hypothermic circulatory arrest on late postoperative intellectual capacity and behavior in infants and children has been difficult to study. Problems in testing infants preoperatively so that each may serve as his or her own control contribute to the difficulty. Associated congenital developmental disorders, possible adverse effects before operation of severe congenital heart disease, and effects of other perioperative events complicate interpretation of the data.
Results of psychomotor testing in 146 children undergoing cardiac surgery during hypothermic circulatory arrest early in the experience with this technique, obtained by combining the three largest reported series, are summarized in Table 2-3 . Late postoperatively, 23 of the 146 (16%; CL 13%-19%) had an IQ of 80 or less, more than 1 standard deviation below the test mean. In approximately half these patients, preoperative events were considered likely to account for the low scores. In the remainder, an occasional child suffered an adverse perioperative event, but the low scores were unexplained in nine (6.2%; CL 4.1%-9.0%) patients.
Table 2-3
Results of Intelligence Testing Some Years after Surgery Performed in Infancy Using Hypothermic Circulatory Arrest
| IQ < 80 | |||||
|---|---|---|---|---|---|
| Investigators | No. of Patients Tested | “Explained” by: | |||
| Preoperative Events | Postoperative Events | Unexplained | Total (%) | ||
| Stevenson et al. | 36 | 3 | 0 | 1 | 4 (11) |
| Dickinson and Sambrooks | 38 | 3 | 1 | 3 | 7 (18) |
| Clarkson et al. | 72 | 6 | 1 | 5 | 12 (16) |
| T otal | 146 | 12 (8%; CL 6%-11%) | 2 (14%; CL 0.5%-3.2%) | 9 (6.2%; CL 4.1%-9.0%) | 23 (16%; CL 13%-19%) |
Key: CL, 70% confidence limits; IQ, intelligence quotient.
Wells and colleagues obtained data on intellectual and psychological development in children that caused them to question the idea that 60 minutes of circulatory arrest at 18°C is safe. They found that verbal ( P = .06), quantitative ( P = .07), and general cognitive ( P = .003) IQ scores of patients with an arrest time of 50 minutes or more were lower late postoperatively than those of patients with an arrest time of less than 50 minutes.
The first randomized clinical trial comparing prevalence of brain injury after corrective heart surgery in infants with D-transposition of the great arteries using deep hypothermia, predominantly with circulatory arrest or low-flow CPB, was conducted at Boston Children's Hospital. This study demonstrated that infants in whom circulatory arrest was used had a higher prevalence of neurologic abnormalities and poorer mental function at age 1 year, and poorer expressive language and motor development at age 2.5 years. Follow-up studies of the same cohort at age 4 years showed that use of circulatory arrest is associated with worse motor coordination and planning but not with lower IQ or worse overall neurologic status. However, neither IQ nor overall neurologic status was correlated with duration of circulatory arrest. In the cohort as a whole, cognitive, language, and motor performance were reduced relative to the general population.
In summary, there is increasing evidence that intervals of hypothermic circulatory arrest of 40 minutes or more are associated with brain injury in infants, children, and adults. Early experience at the Mayo Clinic suggested that 45 minutes was the maximum safe duration even when nasopharyngeal temperature was reduced to 20°C.
Spinal Cord Function
The spinal cord is less susceptible to ischemic injury than the brain, as evidenced by absence of sensory or motor deficits of the trunk or the upper and lower extremities of infants, children, and adults who have been subjected to intervals of hypothermic circulatory arrest of up to 60 minutes. Hypothermia also provides important protection of the spinal cord during ischemic intervals produced by aortic clamping. In a clinical study of hypothermic CPB and circulatory arrest (mean interval of arrest, 38 minutes; range, 8-62 minutes) for operations on the descending thoracic and thoracoabdominal aorta in 161 patients, prevalence of paraplegia or paresis (severe injury resulting from spinal cord ischemia) remained constant and less than 3.5% for ischemic (but hypothermic) intervals of up to 138 minutes ( Fig. 2-7 ).
Renal Function and Structure
Experimental Studies
At normothermia, at least in rats, 20 minutes of circulatory arrest to the kidney produces no histochemical evidence of cell death, whereas 30 minutes produces extensive cell death in the distal portion of the proximal convoluted tubules, with scattered areas of cell death being seen at 25 minutes. Vogt and Farber identified progressive accumulation of lactic acid during ischemia as a causative factor, and rapid decrease of ATP to 20% of control values as an indicator of impending renal death.
Hypothermia prolongs the safe circulatory arrest time for the dog kidney. Ninety minutes of circulatory arrest after surface cooling to 18°C to 20°C produces no late morphologic changes in the kidney, but precise relationships among temperature, duration of circulatory arrest, and morphologic and functional renal damage are not clear. Gowing and Dexter suggest that minimal morphologic changes evolve in the rat kidney after 60 minutes of circulatory arrest at 21°C. It is apparent, however, that at any temperature, the safe circulatory arrest time for the kidney is longer than it is for the brain and shorter than it is for the liver. In addition, a scattered loss of cells through cell death probably results in no detectable loss of renal function, whereas this may not be true in the brain.
As with other organs, the question of damaging effects of hypothermia per se is not fully resolved. Ward found fewer morphologic and functional derangements of the kidney after 90 minutes of circulatory arrest at 15°C than at either lower or higher temperatures. This suggests that temperatures less than 15°C may damage the kidney.
Studies in Humans
Important oliguria beginning about 12 hours postoperatively occasionally complicates recovery of infants operated on with hypothermic circulatory arrest for less than 60 minutes. Venugopal and colleagues reported 4 deaths (3%; CL 2%-6%) from renal failure among 130 patients operated on with surface-induced hypothermic circulatory arrest. Among patients who died, renal failure was the mode of death in 14%.
The primary cause of the renal failure appears to be low cardiac output after operation. However, in at least some cases, severe oliguria develops when the hemodynamic state of the patient appears to be adequate. In view of the finding in experimental studies that morphologic and functional damage to the kidney does not occur after 60 minutes of circulatory arrest at temperatures of 18°C to 20°C ( Fig. 2-8 ), damaging effects from CPB must be implicated. In part, this may be the result of low cardiac output preceding and following the interval of circulatory arrest. In part, it may be due to damage to the kidneys by free hemoglobin and circulating toxins that appear during CPB (see Section II ). Free hemoglobin has been found in the renal tubules of some of these patients at autopsy.
In 161 adult patients undergoing resection of the distal aortic arch and descending thoracic and thoracoabdominal aorta in whom hypothermic circulatory arrest was used (mean nasopharyngeal temperature, 14.5°C; mean interval, 38 minutes; longest interval, 62 minutes), prevalence of postoperative renal failure requiring dialysis among 157 operative survivors was 2.6% (4 patients; CL 1.3%-4.6%). Among the subgroup of 18 operative survivors who had evidence of renal dysfunction preoperatively (serum creatinine level > 1.5 mg · dL −1 ), none developed renal failure that required dialysis.
Liver Function
Studies in dogs suggest that complete hepatic circulatory arrest for 45 minutes or more at 37°C is followed by serious functional derangements. The normothermic liver of humans resumes normal function after its complete isolation from the circulation for 35 to 40 minutes. With hypothermia (20°C-22°C), 60 minutes of circulatory arrest does not produce structural or functional abnormalities in the liver.
Safe Duration of Circulatory Arrest
The preceding information does not allow formulation of a table or an equation relating safe duration of circulatory arrest to various temperatures based on rigorously derived rules. Knowledge of biological systems in general indicates that if adequate information were available, relationships should be expressed as probability of no functional or structural damage (i.e., probability of safe circulatory arrest) at a given temperature, rather than as an absolute value.
Fig. 2-9, A shows three curves relating probability of safe circulatory arrest to arrest time at nasopharyngeal temperatures of 37°C, 28°C, and 18°C. These estimates are based on available information, but because of lack of data they have not been rigorously derived. To emphasize that each curve would have a degree of uncertainty even if considerable data were available, the 70% confidence limits around the continuous point estimate for 18°C are shown in Fig. 2-9, B . The preceding pages indicate that histologic changes in the central nervous system, without functional abnormalities, are the most sensitive indicators of lack of complete safety of the arrest period used. The portrayal at 18°C of essentially complete safety of 30 minutes of circulatory arrest is consistent with all available information. The portrayal of essentially complete safety of arrest of 45 minutes for at least 70% of subjects is also consistent with the facts, and the damage produced within this period is likely to be structural and without permanent functional sequelae. Most patients will have some structural evidence of damage from 60 minutes of arrest, but only about 10% to 20% will have evident functional damage, and in many of them the manifestations will be transient. It remains a vexing clinical problem that the probability of the safe period of circulatory arrest varies widely, especially because state-of-the-art medicine is not yet capable of defining specific patient genetic or phenotypic profiles that may help identify individual patient vulnerability. The attendant uncertainty is particularly problematic because perfusion strategies other than circulatory arrest are available for essentially all clinical cardiac surgical problems.
Other support systems, such as continuous CPB at normothermia or with moderate or deep hypothermia, with or without low perfusion flow rates, have their own potential for damaging one or more organ systems. It should be kept in mind that the damage uniquely caused by circulatory arrest is likely additive to the damage caused by continuous CPB, because a long period of CPB is required when circulatory arrest is used. Furthermore, the heart disease being treated has the potential for producing damage. An inaccurate repair can produce damage, and such inaccuracies are more likely to result when surgical exposure is poor. The surgical team must therefore weigh the relative risks of these and other factors in deciding whether circulatory arrest should be used for a given patient and, if it is to be used, determining its duration and temperature during the arrest period (see Section III for additional details).
Section II
Whole-Body Perfusion during Cardiopulmonary Bypass
CPB for cardiac surgery is conceptually simple, and equipment is available to accomplish it with relative ease. Most or all of the patient's systemic blood, which normally returns to the right atrium, is diverted into a device in which oxygen is supplied to the blood and carbon dioxide is removed. The newly arterialized blood is pumped from the device into the aorta. Among the complexities of CPB are that blood does not naturally (1) circulate through nonendothelially lined channels, (2) contain gaseous and particulate emboli, and (3) experience nonphysiologic shear stresses. Also, the body is unaccustomed to absence of any appreciable pulmonary blood flow and to presence of only minimally pulsatile aortic pressure. In addition to CPB, the patient undergoing cardiac surgery experiences all of the stress responses characteristic of major surgical procedures and trauma.
What is truly remarkable is that most patients survive operation and CPB and convalesce in a reasonably normal manner. For a time, however, almost every patient retains a few demonstrable stigmata from the procedure; some have major morbidity, and a few die of their response to CPB. Prevalence of these unfavorable outcomes in a group of patients is in part determined by identifiable risk factors, but determinants of their occurrence and severity in an individual patient remain incompletely defined.
When essentially all systemic venous blood returns to the pump-oxygenator instead of to the heart, the situation is termed total cardiopulmonary bypass . When some systemic venous blood returns to the right atrium and right ventricle and is pumped into the lungs, then passes back into the left atrium and is pumped by the left ventricle into the aorta, the situation is termed partial cardiopulmonary bypass . Partial CPB has long been known to be better tolerated than complete CPB. Reasons for this have not been clearly defined, but continuation of at least some pulmonary blood flow is a likely explanation. The remainder of this section is concerned with total CPB.
Historical Note
The historical aspects of CPB for cardiac surgery are not easily described, because it is almost impossible to determine who first conceived the idea of diverting the circulation of a patient to an oxygenator outside the body and pumping it back to the arterial system to allow surgery to be performed on or within the heart. References to extracorporeal gas exchange in blood go back to the last part of the 19th century. For example, Frey and Gruber worked with an oxygenator in 1885. Subsequently, scores of laboratory studies with oxygenators and pumps were reported. However, serious consideration of pump-oxygenators for cardiac surgery had to await development of modern anesthesia, modern surgical methods, and scientific developments such as discovery and use of heparin and manufacture of biocompatible plastic materials.
Without doubt, John Gibbon, with his pioneering experimental work at Massachusetts General Hospital in Boston in the late 1930s, was a major contributor to development of CPB and its advancement to the stage of successful clinical application. Gibbon's work was interrupted by World War II, but when he came to Jefferson Medical College in Philadelphia after military service, he resumed work with CPB, its pathophysiology, and the equipment required for it. Most of the medical and surgical world took little note of his work, considering it unlikely to lead to any useful purpose, but Gibbon persevered. In 1953, he performed the first successful operation in which the patient was totally supported by CPB when he repaired an atrial septal defect in a young woman using a pump-oxygenator. Unfortunately, his subsequent four patients died of a variety of problems, and he became discouraged with the method (Gibbon JH Jr: personal communication, 1955).
Meanwhile, a few others began to work with pump-oxygenators for CPB during the late 1940s. Among them were Clarence Dennis and his colleagues at the University of Minnesota. His laboratory studies led him to make what may have been the first attempt to use a pump-oxygenator for clinical cardiac surgery in 1951. Dennis and Richard Varco operated on a patient thought to have an atrial septal defect. These surgeons believed they had done a satisfactory repair, but the patient died. Autopsy showed that the lesion was in fact a partial atrioventricular septal defect, and misinterpretation of the anatomy was a major factor in the patient's death. In Stockholm, Viking Bjork and Åke Senning also worked with CPB during the late 1940s and early 1950s. In related efforts, Clarence Crafoord was an early user of this method for removal of an atrial myxoma.
After Dennis's unsuccessful effort, C. Walton Lillehei and his colleagues at the University of Minnesota began working in the laboratory with controlled cross-circulation, using another intact subject as the “oxygenator.” Their experimental studies led them to adopt the now discarded “azygos flow principle,” which presumed that only low perfusion flow rates were needed. In March 1954, they began a spectacular series of operations in 45 children with congenital heart disease using “controlled cross-circulation” with the mother or father as the oxygenator. A 53-year follow-up of the 28 hospital survivors documented only 8 late deaths, and of the remaining 20 survivors, none was limited by cardiac conditions. Although this particular technique was soon abandoned, the work of Lillehei and colleagues brought into being the modern era of open intracardiac surgery.
Experimental work at the Mayo Clinic with pump-oxygenators began in the early 1950s under the direction of John Kirklin. This led to the first use of CPB with a pump-oxygenator at the Mayo Clinic on March 22, 1955, when a ventricular septal defect was successfully repaired, and subsequently to the world's first published series of intracardiac operations performed with use of CPB and a pump-oxygenator. These procedures were performed using the Mayo-Gibbon pump-oxygenator, which was designed and constructed in the engineering shops of the Mayo Clinic. Use of a pump-oxygenator for CPB during cardiac surgery expanded rapidly, and today the method is used many times a day in hospitals in almost every country in the world.
Uniqueness of Cardiopulmonary Bypass
The patient whose arterial blood flow is temporarily provided by means of a pump-oxygenator is in an abnormal state that affects most if not all physiologic processes. Throughout evolution, blood has passed only through channels lined with endothelial cells, but during CPB, it is passed across nonendothelial foreign surfaces. As a result, and perhaps because of other factors, virtually all humoral and cellular components of the inflammatory response are acutely activated, and probably some of the more slowly reactive specific immune responses are activated as well, at least initially. The general stress response seen after surgery and trauma also occurs to a major degree.
During total CPB, a number of physiologic variables are under direct external control, in contrast to the situation in intact humans. These include total systemic blood flow (“cardiac” output); input pressure waveform; systemic venous pressure; pulmonary venous pressure; hematocrit and chemical composition of the initial perfusate; arterial oxygen, carbon dioxide, and nitrogen levels; and temperature of the perfusate and patient.
Another group of variables is determined in part by the externally controlled variables but in large part by the patient. These include systemic vascular resistance, total body oxygen consumption ( 
), mixed venous oxygen levels ( 
), lactic acidemia and pH, regional and organ blood flow, and organ function.
A third group of largely uncontrolled variables includes, to a greater or lesser degree, all components of the process of inflammation, incited in large part by the organism recognizing the foreign surfaces across which blood passes as “nonself.”
These features make the patient who has undergone CPB a unique organism, at least for a few days. Recognition of this, as well as a detailed knowledge of the post-CPB state, is necessary for delivery of optimal postoperative care (see Chapter 5 ).
Controlled Variables
Arterial Output to the Patient
Arterial output (outflow) from the pump-oxygenator to the subject is achieved by generating a large pressure gradient by a pump. The most commonly used type of arterial pump is the roller pump (originally used by DeBakey for blood transfusion ). It generates a relatively nonpulsatile flow and is simple, reliable, and relatively inexpensive. In clinical use, roller pumps are generally set to be nearly occlusive. 1 When they are occlusive, trauma to the formed elements in blood is increased; when they are too nonocclusive, they are unable to maintain the same rate of flow against the wide range of resistances (pressure differentials of 30-300 mmHg) offered by arterial cannulae and the patient's systemic vascular resistance. The tubing passing through the roller pump head is most often Tygon, a special nontoxic surgical grade of polyvinyl chloride. During hypothermia, Tygon tubing decreases in elasticity and filling volume, so stroke volume of the pump is slightly decreased. Silicone rubber tubing does not have this disadvantage and may be used in the roller pump head when hypothermia is required. Volume output of the roller pump is more certain to be that predicted when output resistance is high than when a high negative pressure is generated on the input side. When generated negative pressure on the input side exceeds about 200 mmHg, volume output of the roller pump becomes less predictable.
1 In the laboratory, this is defined as a fall of 1 inch per minute of a column of water in tubing held vertically above the roller pump. Clinically, when the pump-oxygenator is fully primed, the system is pressurized to 300 mmHg measured by an onboard manometer. The roller heads are adjusted to allow a slight pressure drop over 1 minute.
The controlled vortex (centrifugal) pump is also commonly used for cardiac surgery and for closed-chest support of patients in whom both arterial and venous cannulation are accomplished centrally or peripherally (termed cardiopulmonary support [CPS]). Flow generated by a controlled vortex pump varies with changes in resistance to flow into and out of the pump. When pressure in the output line reaches about 500 mmHg, both outflow from and inflow into the pump become zero. When pressure in the inflow line decreases to about −500 mmHg, both inflow and outflow become zero. Therefore, in contrast to the roller pump, revolutions per minute (rpm) of the controlled vortex pump cannot be used to estimate flow. Instead, a flow meter must be placed on the arterial (output) or venous (input) line. However, if the arterial line becomes completely occluded, either intentionally or by accident, flow immediately ceases, but pressure in the arterial line will rise no higher than 500 mmHg, and it is unlikely that the tubing will rupture or a junction connector will give way. Blood trauma is similar in controlled vortex and roller pumps. Although air can be entrapped within the controlled vortex pump, it, like the roller pump, can transmit air bubbles from the venous to the arterial lines. (However, air entrapped in a vortex pump breaks down into microbubbles that eventually pass out of the pump; a roller pump will pump gross air presented to it.)
Venous Input from the Patient
The venous input (inflow) into the pump-oxygenator from the patient is achieved by a negative pressure gradient from patient to machine. The negative pressure required to move blood from the patient to the pump-oxygenator is considerably less than the pressure required to move blood from the pump-oxygenator to the patient, because of the different characteristics of the venous and arterial systems of the patient and to some extent of the venous and arterial cannulae.
Sufficient negative pressure for venous input into the pump-oxygenator can be generated by:
- ▪
Creating a controlled vacuum within a venous reservoir
- ▪
Using a siphon system in which gravity creates the negative pressure
- ▪
Using a controlled vortex pump to create the negative pressure within the venous line from the patient
Vacuum-Assisted Venous Return
The ideal method for creating negative pressure for venous input into the pump-oxygenator is by a regulated and monitored vacuum pressure system coupled to the venous reservoir. The patient and machine can be at or near the same vertical level from the operating room floor, the negative pressure does not rise above the controlled level if the cannula becomes occluded, and the amount of negative pressure can be varied as needed. Most importantly, the two pressures (i.e., output pressure to the patient and input pressure from the patient) are uncoupled and can be varied independently with an arterial roller pump. If a controlled vortex pump is used, the vacuum pressure in the venous system will reduce the outflow pressure of the nonocclusive vortex pump, thus requiring higher rpm to achieve a constant flow.
Use of a hard-shelled venous reservoir in currently available oxygenators and a vacuum regulator connected to wall suction set at −40 to −60 cm H 2 O has allowed vacuum-assisted venous return (VAVR) to become widely accepted. VAVR permits use of smaller venous cannulae, smaller reservoirs, considerably shorter tubing, and low priming volume. It is of considerable value for cardiac operations performed in infants and through small incisions in children and adults (see Special Situations and Controversies in Section III ). In a study by Banbury and colleagues at Cleveland Clinic, VAVR was found to reduce priming volume from 2.0 ± 0.4 L to 1.4 ± 0.4 L ( P < .0001), increase hematocrit both on bypass and immediately postbypass ( P < .0001), and reduce use of blood products both intraoperatively and postoperatively from 39% of patients to 19% ( P = .002).
Siphon (Gravity) Drainage
A common method of generating the negative pressure gradient is through siphonage. Disadvantages of this approach include an imposed difference in the levels of patient and pump-oxygenator, the relatively narrow range of negative pressures that can be generated in the operating room by its use, and its interruption by large boluses of air in the venous line. Most importantly, the need for a reservoir increases the filling (priming) volume of the pump-oxygenator. It is, however, simple, reliable, effective, and inexpensive.
Venous Pumping
The controlled vortex pump permits direct pumping from the patient's venous system and is more effective and safer than a roller pump. The potentially large pressure gradient between the tip of the venous cannula and right atrium or venae cavae must be controlled in some way to prevent “fluttering” of their walls around the end of the cannulae. One way of accomplishing this is to use small venous cannulae to impose a considerable resistance between the pump and tip of the cannula, rather than between the tip of the cannula and the patient's venous system. This is fortuitously advantageous in percutaneous peripheral cannulation, because an 18F or 20F venous cannula of some length can be easily passed into the venous system of a normal-sized adult and provides adequate venous drainage. It also facilitates minimally invasive cardiac surgery. By contrast, 28F to 32F catheters are required when gravity drainage is used.
Gas Exchange
The device for gas exchange, the oxygenator, is a highly important component of pump-oxygenators. Not only does it regulate tension of gases in the arterial blood emerging from the pump-oxygenator, it is also the largest area of foreign surface blood comes into contact with, and therefore probably the component of the pump-oxygenator where the most blood damage occurs. This contact occurs in the boundary layer of the blood, which is made very large in the oxygenator to facilitate gas exchange. Only a small proportion of the formed and unformed blood elements comes into contact with tubing and pump surfaces.
Gas exchange occurs directly across the blood/gas interface in bubble oxygenators, rotating disk and cylinder oxygenators, and stationary vertical screen oxygenators used in the past. It occurs across a multitude of tiny pores in so-called membrane oxygenators of the hollow-fiber, microporous polypropylene and other types, in which there are still blood/gas interfaces. However, damage to the blood is less in these types of oxygenators than in bubble oxygenators. Only in the true silicone rubber membrane oxygenator of the type devised by Kolobow and colleagues, or the tightly woven microporous polymethylpentene membrane currently used for extended extracorporeal membrane oxygenation, is there no blood/gas interface. This allows CPB to be used for more than 24 hours with reasonable safety.
Because of their efficiency, hollow-fiber and true membrane oxygenators do not depend on minute ventilation (gas flow) to the oxygenator for CO 2 regulation under most circumstances. Rather, the ventilating gas flow rate and composition are regulated independently. This allows precise regulation of arterial P o 2 and P co 2 .
Arterial Oxygen Levels
With present-day oxygenators, maintaining Pa o 2 at about 250 mmHg is easily accomplished. Higher Pa o 2 is unnecessary and theoretically subjects patients to the risk of oxygen toxicity and bubble formation. Pa o 2 lower than about 85 mmHg results in a declining arterial oxygen content (Ca o 2 ) (according to the oxygen dissociation curve of blood) and a corresponding reduction of tissue and mixed venous oxygen levels. Shepard demonstrated that when arterial oxygen saturation (Sa o 2 ) fell below 65% in dogs undergoing normothermic CPB, 
fell, indicating hypoxic cell damage.
Pa o 2 is related to temperature of the patient, which is related to 
(see Fig. 2-1 ), blood flow rate ( 
), performance of the oxygenator, and, in a complex fashion, to ventilating gas flow rate and composition (see “ Gas Exchange ,” earlier). Reducing the patient's body temperature reduces 
and increases 
, resulting in increased Pa o 2 . During rewarming by perfusion from the pump-oxygenator, the increasing 
and the metabolic debt that has accumulated result in relatively low 
. ( Fig. 2-10 ). This period, then, places maximal demands on the oxygen transfer capacity of the oxygenator.
Arterial Carbon Dioxide Pressure
Arterial carbon dioxide pressure (Pa co 2 ) is controllable during CPB by varying the ratio between gas flow rate into the oxygenator ( 
, or ventilation · min −1 ) and 
through the oxygenator. This is facilitated by use of microporous or true membrane oxygenators, because 
is not the force driving blood through the oxygenator, as is the case in bubble oxygenators, and Pa o 2 is well maintained over a wide range of 
. Inline P co 2 and pH meters facilitate control of Pa co 2 and pH.
Some clinical perfusions for cardiac surgery are performed at normothermia (≈37°C) and others at various levels of hypothermia: mild (30°C-35°C), moderate (25°C-30°C), or deep (<25°C). Therefore, it is necessary to consider the strategy for controlling Pa co 2 and, indirectly, pH. The alpha-stat strategy is based on (1) using the pH measured at 37°C and uncorrected for the temperature of the patient's blood , and (2) maintaining this level at pH 7.4. That is, the ventilation of the oxygenator is maintained at the level appropriate for a body temperature of 37°C, no matter how low the temperature. This hyperventilation during hypothermia results in a decrease in Pa co 2 and an increase in pH when the values for these are corrected for the temperature of the patient's blood. Swan and Reeves and Rahn and colleagues have all emphasized that at low temperatures, neutrality exists at a higher pH than at normothermia, because of the change of the dissociation constant of water with temperature. The alpha-stat strategy results in optimal function of a number of important enzyme systems, including lactate dehydrogenase, phosphofructokinase, and sodium-potassium ATPase.
In contrast, the pH-stat strategy strives for the same values of pH and Pa co 2 , corrected to the temperature of the patient's blood, during hypothermia as at normothermia. This represents a state of respiratory acidosis and hypercarbia. Cerebral blood flow usually increases under these circumstances. This may be considered advantageous in some situations, but so-called luxury perfusion may expose the brain to a larger number of microemboli than would otherwise be the case, and therefore could be disadvantageous.
At a cellular enzyme level, the alpha-stat strategy may be preferable, but which is preferable in clinical cardiac surgery in neonates, children, and adults is the subject of continued investigation and debate. The alpha-stat strategy results in a lower Pa co 2 , which may adversely affect cerebral blood flow. This may be of particular importance for patients with cyanotic congenital heart disease (e.g., tetralogy of Fallot with pulmonary atresia) for whom low Pa co 2 may result in pulmonary vasodilatation in addition to cerebral vasoconstriction. Thus, there can be a steal of blood from the cerebral to the pulmonary vascular bed. Several studies in infants suggest that pH-stat management results in superior neurologic outcome during deep hypothermic CPB and hypothermic circulatory arrest. The pH-stat technique may depress cardiac function. However, at least in dogs, regional distribution of blood flow during normothermic and hypothermic full-flow CPB is similar with the alpha-stat and pH-stat strategies.
A recent review of 16 best-evidence published papers concluded that better results were achieved with the alpha-stat technique in adult patients and with the pH-stat technique in pediatric patients.
Heparin Levels
Before CPB is established, the patient is anticoagulated by intravenous or intracardiac injection of heparin, usually in a dose of 300 to 400 units · kg −1 body weight (sometimes expressed as 3 to 4 mg · kg −1 ). (Details of dosage of heparin and protamine, and of activated clotting time (ACT), are given later in “ Heparinization and Later Protamine Administration ” under Preparation for Cardiopulmonary Bypass in Section III ). Heparin, one of a heterogeneous group of glycosaminoglycans, has an approximate molecular weight of 3000 to 100,000. It binds to and greatly amplifies the effect of antithrombin III, which is responsible for virtually all of its anticoagulant activity. Currently, a purified form derived from porcine intestinal mucosa is commonly used, whereas the form derived from bovine lung was used more commonly in the past. Experimental and limited prospective clinical studies suggested that lung heparin may be preferable for CPB, because bovine lung heparin has a more reliable protamine neutralization response. However, current supply of heparin in the United States is 100% derived from porcine intestinal mucosa.
Heparin concentrations in plasma can be measured directly; the usual values during CPB are 3.5 to 4 units · mL −1 . Usually these measurements correlate well with ACT. One exception is the situation of antithrombin III deficiency, a state of heparin resistance. Two or three times the usual dose of heparin may be required to produce satisfactory anticoagulation (i.e., ACT of 480 seconds); if only the heparin level is measured, initiation of CPB might produce thrombosis in the pump-oxygenator system and introduce thrombus into the patient. The most common cause of antithrombin III deficiency is previous exposure to heparin in a dose-dependent fashion. If repeated ACTs indicate an unsafe level for CPB, antithrombin III supplementation must be considered. This is accomplished with either fresh frozen plasma or antithrombin III concentrate.
Although heparin used in the manner described has been clinically satisfactory, activation of the clotting cascade during CPB is not completely neutralized. At least factor XII, factor XI, and prekallikrein are activated, and high-molecular-weight kininogen is cleared. Thus, markers of fibrin formation can be detected in most patients during and early after CPB, and fibrin deposition and embolization can occur. In most patients, this subclinical coagulation does not cause the concentrations of the soluble coagulation factors to become sufficiently low during or early after CPB to cause bleeding.
Increasing the dose of heparin does not prevent this subclinical coagulation during CPB, so maintaining ACT at 300 to 350 seconds (rather than 450 seconds) results in no more subclinical plasma coagulation than does the traditional method, requires less heparin, and may be associated with less bleeding after operation. Yet a 2008 survey of 54 cardiac surgery centers in the United States and Canada indicated that the majority of institutions (71% for U.S. and 69% for Canadian sites) used a target ACT for instituting CPB of between 400 and 480 seconds.
The former use of aprotinin affected the concepts of heparinization for CPB for intracardiac surgery, because this agent prolongs both clotting time and ACT, depending on the method of measurement (see “ Fibrinolytic Cascade ” under Details of the Whole-Body Inflammatory Response later in this section). If aprotinin is used, an optimal recommendation is to administer the usual initial dose of heparin and add additional heparin to maintain the ACT above 700 seconds if the activating agent is Celite (diatomaceous earth). Kaolin is a more dependable activating agent, giving ACTs in the presence of aprotinin similar to those without aprotinin in vitro and during CPB. Therefore, a preferable method when aprotinin is used during CPB is to use kaolin as the activating agent and maintain the usual ACT at 480 seconds. Alternatively, the heparin concentration is measured at intervals and kept above 3 mg · kg −1 . Because of results of randomized trials demonstrating that aprotinin was associated with a higher risk of death after cardiac surgical procedures than other antifibrinolytic agents used to decrease the need for red blood cell transfusions, Bayer Pharmaceuticals withdrew their drug Trasylol (aprotinin) from the market in May 2008. Subsequent meta-analysis has confirmed higher morbidity and mortality associated with use of aprotinin. 2
2 The controversy surrounding aprotinin and its eventual removal from the market provides an interesting yet sobering insight into evidence-based medicine. Aprotinin was introduced for its serine proteinase inhibitory properties, which are relevant to the damaging effects of CPB discussed later in this chapter. Its profound effect on blood loss during cardiac surgery was a serendipitous pleiotropic finding, although this had been observed in cyanotic children with hematologic derangement by Urban and colleagues and others. What was considered by some an unethical number of small randomized trials repeatedly demonstrated this effect on blood loss. Nevertheless, in a thoughtful assessment, Angoustides and Fleisher pointed out that at least three essential issues remained unresolved: (1) safety in specific subsets of patients, (2) platelet protection, and (3) organ protection. For example, many studies, such as those of Koch and colleagues, have demonstrated that morbidity and mortality of cardiac surgery steadily increase with number of transfused red cell units ; yet despite the substantial decrease in transfusion requirement with aprotinin, morbidity did not proportionately decline. It was the observational study of Mangano and colleagues that focused attention on safety of aprotinin despite its efficacy. This study with numerous flaws, combined with another randomized trial and concern about the transparency of reporting of safety by the manufacturer, led to withdrawal of aprotinin from the market. In developing an evidence base, even randomized trials can be misleading when they (1) focus on efficacy without sufficient power (sample size) to identify possible safety problems; (2) do not compare against placebo, just other drugs of the same class; (3) do not take into account differential effects on different patient subsets; or (4) fail to assess known primary effects of the drug when interesting and unexpected efficacy is discovered. The result is incomplete evidence that clouds decision making.
It has been estimated that 1% to 5% of patients who receive therapeutic anticoagulation with unfractionated heparin develop antibodies, with concomitant development of thrombocytopenia defined as HIT (heparin-induced thrombocytopenia). HIT may complicate management of patients who require cardiac surgery using CPB when a large dose of heparin is required. In patients with established or suspected HIT, all heparin must be withheld and alternative forms of anticoagulation used.
Bivalirudin, a synthetic 20-amino-acid peptide analog of hirudin, has become the anticoagulant most commonly used to replace heparin in patients with HIT who require cardiac surgery. A randomized, open label, multi-institution trial comparing bivalirudin (101 patients) with heparin (49 patients) for operative procedures requiring CPB demonstrated similar procedural safety (freedom from death, Q-wave myocardial infarction, reoperation for coronary artery surgery, or stroke) between the two groups at 7 days, 30 days, and 12 weeks. Secondary end points including mortality, 24-hour blood loss, transfusion requirements, and duration of operation were similar. Avoiding blood stasis was critical for patients receiving bivalirudin. A more recent single-institution study of 115 patients receiving bivalirudin during operations requiring CPB demonstrated procedural safety (similarly defined) of 99.4% at 7 days and 30 days. Although specific dosage protocols have not been determined, Czosnowski and colleagues, in a review of available randomized trials and other clinical studies, recommended a 1-mg · kg −1 bolus followed by a 2.5-mg · kg −1 · h −1 infusion (goal: ACT > 2.5 times baseline).
Perfusate
Diluent
The diluent (which is used to prime the pump-oxygenator system, wholly or in part, and for any erythrocyte-free additions during CPB) is a balanced electrolyte solution with a near-normal pH and an ion content resembling that of plasma. There is some evidence for the concept that in both adults and young patients, it is disadvantageous to include either glucose or lactate in the priming solution (see “ Biochemical Milieu ” under Brain Function and Structure: Risk Factors for Damage in Section I ). However, priming solutions containing glucose and lactate are used in some centers.
In pump-oxygenator systems without a venous reservoir or those using VAVR, mixing of blood and prime may be partially or wholly avoided, with residual prime discarded.
Hemoglobin Concentration
At some institutions, in adult patients and even young patients, no effort is made to control hemoglobin concentration or hematocrit during CPB. Instead, the pump-oxygenator is routinely filled initially with a balanced salt solution.
In intact humans at 37°C, the normal hematocrit of 0.40 to 0.50 is optimal rheologically and for oxygen transport (assuming a normal red blood cell hemoglobin concentration). This provides sufficient oxygen delivery to maintain normal mitochondrial P o 2 levels of about 0.05 to 1.0 mmHg, and average intracellular P o 2 levels of about 5 mmHg, these being reflected in normal 
of about 40 ( 
of about 75%). When the hematocrit is abnormally high, oxygen content is high, but the increased viscosity tends to decrease microcirculatory blood flow. The rate of oxygen transport varies directly with hematocrit (because oxygen content varies directly with hematocrit, assuming normal red blood cell hemoglobin concentrations and adequate oxygenation) and inversely with blood viscosity (which is also determined primarily by hematocrit). Hypothermia increases blood viscosity; therefore, at low temperatures, a lower hematocrit is more appropriate than at 37°C.
A lower-than-normal hematocrit appears desirable during hypothermic CPB because the perfusate has a lower apparent viscosity and low shear rates and provides better perfusion of the microcirculation. Thus, a hematocrit of about 0.20 to 0.25 may be optimal during moderately and deeply hypothermic CPB, although a low hematocrit could predispose the patient to neurologic dysfunction, particularly when it exists during a period of low CPB flow and also in elderly and diabetic patients with poor cerebral regulation of blood flow. Several studies of infants suggest that a hematocrit of 0.25 is associated with better neurologic outcome than one of 0.20, but that there is no incremental improvement for hematocrit greater than 0.25 (up to 0.35). During rewarming, a higher hematocrit may be desirable because of increased oxygen demands, and the higher apparent viscosity of a higher hematocrit is appropriate during normothermia. This may be achieved by ultrafiltration (see “ Components ” under Pump-Oxygenator in Section III ) or by adding packed red blood cells if the blood volume is too low to allow this.
The need for and amount of additional blood or packed red blood cells to achieve a desired hemoglobin concentration during CPB can be determined before the start of CPB ( Box 2-2 ). If the calculated hematocrit is in the desired range, a blood-free priming solution is used. If the calculated hematocrit is lower than desired, an appropriate amount of blood (or packed red blood cells) is added.
Box 2-2
Algorithm for Calculating Patient-Machine Hematocrit
The need for and amount of additional packed red blood cells to achieve a desired hemoglobin concentration early after commencing bypass is determined by the patient's blood volume (VpB) and hemoglobin concentration prior to CPB (expressed as hematocrit, HCTp), and the volume of pump-oxygenator prime (VmB) and its hemoglobin concentration (expressed as hematocrit, HCTm). Patient blood volume is estimated as
where f is the proportion of body weight attributable to blood volume; f = 0.08 for infants and children up to 12 years of age, f = 0.065 for older patients, and wt is weight in kg. (These are average values for the proportion of body weight that is blood volume. More complex regression equations are available for more accurate estimates. )
Patient (VpRBC) and machine (VmRBC) red cell volumes are:
Then, mixed patient-machine hematocrit (HCTpm) is:
If no blood is in the prime:
These calculations may be included in a computer-prepared printout for the perfusionist, available before the patient comes to the operating room.
Banked blood preferably less than 48 hours old is preferred, but older blood is accepted for adults when necessary. Banked blood is rendered calcium-free by the anticoagulant solution (citrate-phosphate-dextrose [CPD]) and is acidotic, so additions of heparin, calcium, and buffer may be required before placing it in the pump-oxygenator, before or during CPB. However, in at least a few institutions, no calcium is added before placing the blood in the pump-oxygenator, and none is added thereafter until the patient's nasopharyngeal temperature reaches about 28°C during the rewarming process. It is important to monitor the ionized calcium level, and calcium is added if necessary. (The normal level is about 1.2 mmol · L −1 , with total calcium being about 2.5 mmol · L −1 or 10 mg · dL −1 .) This practice results in extremely low levels of ionized calcium when CPB is first established. Unduly high levels of ionized calcium could be more deleterious (see “Damage from Global Myocardial Ischemia” in Chapter 3 ). A reasonable practice would be to initially add 3 mL of calcium chloride (10%) rather than 5 mL for each unit of banked blood used, and then add no more until the ionized calcium is measured.
Albumin Concentration
Concentration of albumin in the mixed patient-machine blood volume, as well as of hemoglobin, is affected by the amount of hemodilution. Theoretically, according to the Starling law of transcapillary fluid exchange (see “ Pulmonary Venous Pressure ” later in this section), a reduction of albumin and thus of the colloidal osmotic pressure of the plasma accentuates movement of fluid out of the vascular space into the interstitial space. That this occurs is indicated by the work of Cohn and colleagues, who showed that extracellular fluid volume increases more rapidly when hemodilution is used than when it is not.
During CPB, microvascular permeability to macromolecules is increased ; some of the administered albumin leaks into the interstitial fluid and has an unfavorable effect on the relationships expressed in the Starling law. Homologous albumin may provoke an allergic response, which also increases microvascular permeability and causes leakage of albumin into the interstitial fluid.
These complex interrelations probably explain the failure of a randomized trial to find a favorable effect from adding homologous albumin to the prime in adults. It is not uncommon for cardiac surgical patients, particularly the elderly, to present with low-normal or below-normal albumin levels. Whether albumin concentration should be maintained at normal levels in some special situations such as this remains arguable.
Other colloidal solutions (dextran 40, dextran 70, hydroxyethyl starch) can also be added to the priming solution to attenuate loss of fluid from the intravascular space. However, none of them has been conclusively shown to have a beneficial effect.
Other Additives
Practices vary regarding addition of substances and drugs to the perfusate (by administering them into the priming volume of the pump-oxygenator or patient before CPB, or into the patient or pump-oxygenator during CPB), other than basic balanced salt solution and blood and its required additives.
Use of an osmotic diuretic may be advisable. Mannitol (≈0.5 g · kg −1 ), a pure osmotic diuretic, can be included as part of the prime. Mannitol also has the advantage of being an effective agent against oxygen free radicals generated during CPB. Glucose (added to the prime of the pump-oxygenator in sufficient quantity to obtain a glucose concentration of about 350 mg · dL −1 in the prime) also produces diuresis. However, its use in the priming volume and its administration during and early after CPB, employing more than moderate hypothermia, may be unwise in view of the strong suggestion that hyperglycemia during cooling and early after hypothermic circulatory arrest increases the probability of brain injury.
Administration of a potent diuretic during CPB is generally useful. Incorporating furosemide in the pump prime is practiced by many groups. It may be more advantageous to give it as a bolus in a dose of 1 to 2 mg · kg −1 at the start of rewarming, either after an interval of circulatory arrest or moderately or deeply hypothermic CPB.
The short-acting adrenergic α-receptor blocking agent phentolamine is capable of antagonizing the vasoconstriction produced by catecholamines and has been shown to produce more uniform body cooling and rewarming and improved tissue perfusion when given during CPB. A bolus of 0.2 mg · kg −1 is administered just after the start of CPB and the initiation of cooling. When circulatory arrest is used, an additional dose of 0.2 mg · kg −1 is administered with the resumption of CPB for rewarming.
Alternatively, the long-acting adrenergic α-receptor blocking agent phenoxybenzamine can be used in infants and children to produce total α-blockade for 8 to 10 hours. It is given in a dose of 1 mg · kg −1 about 15 minutes before commencing CPB and at the beginning of rewarming after the period of circulatory arrest. A continuous infusion of nitroprusside during cooling and again during rewarming is preferred to either of these agents by some groups. Nitroprusside reduces arterial blood pressure (by ≈ 25 mmHg), yet maintains cerebral blood flow during moderately hypothermic CPB.
Opinions differ about the advisability of routinely administering (or adding to the perfusate) corticosteroids and the appropriate agent to use. Available evidence suggests that corticosteroids improve tissue perfusion and lessen the increase in extracellular water that usually accompanies CPB. Although some studies have reported improved clinical status when steroids are given in the manner described, this matter remains controversial. Methylprednisolone in a single dose of 30 mg · kg −1 or dexamethasone in a single dose of 1 mg · kg −1 given at the onset of CPB and not repeated may be advantageous. These agents do not appear to reduce complement activation, but there is evidence to support the hypothesis that they attenuate complement-mediated leukocyte activation, particularly that associated with reperfusion of the heart and lungs in the latter part of CPB. In piglets, corticosteroids provide brain protection during operations that involve hypothermic CPB and circulatory arrest.
The powerful antifibrinolytic agent aprotinin is a biological product that acts as a serine proteinase inhibitor. It may have a favorable effect on some platelet membrane-specific receptors, specifically GPIb. Aprotinin has been shown in several randomized studies to reduce bleeding after CPB by about 50%, but as mentioned previously, the drug is no longer available for use during cardiac surgical procedures. ε-Aminocaproic acid (EACA) and tranexamic acid are two other antifibrinolytic agents that can be administered before, during, and after CPB to reduce bleeding and the need for allogeneic blood transfusions. EACA is administered using an empirical dose of 10 g before the skin incision, 10 g during the procedure, and 10 g early postoperatively. Alternatively, it can be given at a dose of 150 mg · kg −1 at the time of the skin incision, with an additional 30 mg · kg −1 for 4 hours upon initiation of CPB. Tranexamic acid is given at a dose of 1 g before the skin incision, 500 mg in the pump prime, and 400 mg · h −1 during the procedure.
Changes during Cardiopulmonary Bypass
During CPB for cardiac surgery, blood loss in the operative field and gradual increase in interstitial fluid and urinary output combine to steadily deplete the patient-machine blood volume. Usual practice is for the perfusionist to add increments of a balanced electrolyte solution to maintain the volume at a safe level; in adults, up to 2000 mL may be added. Unless special precautions are taken, such as avoiding return of irrigating fluids to the pump-oxygenator by cardiotomy pump suckers and using ultrafiltration during the final stages of CPB, severe hemodilution results and persists into the postbypass period.
In neonates and infants, ultrafiltration immediately after CPB (before removal of cannulae) is often advisable using the modified ultrafiltration (MUF) technique introduced by Elliot. Its efficacy has been confirmed by others. In children and adults, ultrafiltration may be performed during the latter part of CPB if the hematocrit is below about 0.25 and there is excess volume in the pump-oxygenator. If not, it may be performed after discontinuing CPB, slowly circulating blood through the patient before any cannulae are removed. A third option, and one that is frequently used, is ultrafiltration of the volume remaining in the pump-oxygenator after CPB is discontinued and the venous cannulae have been removed. Hemoconcentrated pump-oxygenator volume is then infused slowly into the patient before the arterial cannula is removed (see Pump-Oxygenator in Section III ).
Total Systemic Blood Flow
Although total CPB has generally been considered to require two separate caval cannulae and occlusive tapes around each cannula, a single large, properly designed, and properly positioned venous cannula can direct all venous return to the pump-oxygenator and provide total CPB.
During total CPB, systemic blood flow (perfusion flow rate) is controlled by the perfusionist. It can be set at an arbitrary level or may be kept equal to the venous return from the patient. A rational approach is to set it at an arbitrary level.
In clinical practice, when body temperature is at 28°C or greater, a flow of 2.5 L · min −1 · m −2 is usually chosen for infants and children younger than about age 4 years, and a flow of 2.2 L · min −1 · m −2 for older patients. For adults with a body surface area of 2.0 m 2 or more, a flow of 1.8 to 2.0 L · min −1 · m −2 may be chosen to avoid the disadvantage of high flow through the oxygenator. When moderate hypothermia is chosen, the CPB flow can safely be reduced to about 1.7 L · min −1 · m −2 for prolonged periods ( Fig. 2-11 ). When cardiac operations are performed with body temperature reduced to 18°C to 20°C in neonates, infants, or adults, CPB flows of 1 L · min −1 · m −2 are adequate for prolonged periods, at least as judged by persistence of the somatosensory evoked response (SSER) under these circumstances. Flows as low as 0.5 L · min −1 · m −2 (20-30 mL · min −1 · kg −1 ) have been shown to be adequate at these temperatures to maintain cerebral oxygen consumption and ATP levels for at least 30 to 60 minutes.
When flow rates are lower than optimal for more than a short time, 
is considerably subnormal (<85% of the asymptote of the temperature-specific curve in Fig. 2-11 is considered subnormal), primarily as a result of perfusion of less than the total capillary bed. Also, the areas of the capillary bed that are open are underperfused, resulting in lactic acidemia and metabolic acidosis.
and saturation ( 
) have been widely used as indices of adequate perfusion flow rate (see Box 2-3 ; for references, see Harris and colleagues ), the assumption being that these values reflect average cellular P o 2 . If 
is high and the entire microcirculation perfused, this is true. However, it has been shown that during CPB, with 
within the conventional range, 
is inversely related to 
. This might have been predicted from the Fick equation:
Box 2-3
Mixed Venous Oxygen Levels
), mixed venous oxygen pressure ( 
), and mixed venous oxygen content ( 
) may all be used to express mixed venous oxygen levels. The equation is: 
is in mL · dL −1 , [Hb] is hemoglobin concentration in g · dL −1 , 
is a decimal fraction, and 
is in mmHg. where Ca o 2 is arterial oxygen content, 
is mixed venous oxygen content, and 
is flow rate.
If 
and Ca o 2 are fixed, 
increases with 
. If instead 
and Ca o 2 are fixed, 
increases as 
decreases, and 
may decrease, despite a perfectly adequate 
, if the capillary bed is not evenly perfused. In this case, the distance between perfused capillaries and many tissue cells increases, and these cells do not obtain their oxygen requirement. In effect, this amounts to a shunt of arterial blood into the venous system. This effective shunt may at times amount to half the total flow. Rudy and colleagues, using microspheres in normothermic rhesus monkeys during CPB, found that shunting was only 1.4% of total 
.
A high 
or 
does not, therefore, mean that cellular oxygenation is satisfactory whatever the 
. A 
at or near the whole-body requirement does. The 
is not difficult to calculate during CPB; the problem is, rather, to decide what the oxygen requirement is in a given case. Moreover, if 
is less than the usual levels at conventional 
, increasing 
probably will not increase 
(see Fig. 2-11 ). The fault is not in 
but in the capillary bed or at the cellular level.
As might be expected, high 
is achieved at the expense of some loss of safety and convenience in other variables. Blood trauma in the oxygenator is probably greater when high blood flows pass through it. With a bubble oxygenator, risks of gaseous emboli are also greater. Pressure gradients across the arterial cannula are greater at high 
. This increases cavitation, blood trauma, and the risk of bubbles forming as blood emerges from the cannula.
Arterial Pressure Waveform
CPB is usually conducted in such a manner that the arterial pressure pulse is very narrow and essentially nonpulsatile, but if desired, a pulsatile arterial input can be achieved in several ways. One is by using left ventricular ejection. With no tapes around the caval cannulae, arterial flow to the patient may be temporarily increased over venous return, or venous return may be temporarily reduced by partially occluding the venous tubing. Atrial pressures and thus ventricular filling pressures are increased, left ventricular ejection augments systemic blood flow, and a somewhat pulsatile arterial blood flow results. In other words, pulsation is achieved by partial CPB. This mechanism is used during cooling and rewarming whenever cardiac action is sufficiently vigorous to prevent overdistention of the heart during the process. The procedure of partial CPB produces not only some arterial pressure pulsations but some pulmonary blood flow as well, with its favorable effect.
A pulsatile waveform can also be produced by using intraaortic balloon pumping during bypass. A third method is to use a pulsatile arterial pump.
Effects on the organism of using a system that results in a pulsatile rather than nonpulsatile arterial waveform during CPB have been questioned since the beginning of clinical CPB. An already complex problem is still further complicated by an almost universal failure to describe the energy of the pulsatile flow in a proper manner, such as by energy-equivalent pressure .
Intuitively, pulsatile flow seems advantageous over nonpulsatile flow. Several physiologic studies lend strong support to this idea, demonstrating that with nonpulsatile flow, vascular resistance increases, red blood cells aggregate, renal function is impaired, renin is released, and cellular hypoxia leads to metabolic acidosis. It is not clearly established that pulsatile flow during CPB results in fewer functional derangements than nonpulsatile flow. A number of studies have concluded that pulsatile perfusion is beneficial, but not all of them present convincing evidence, and several have found little or no benefit. Extensive reviews of this subject have been presented.
A randomized clinical study by Singh and colleagues investigated pulsatile versus nonpulsatile flow during moderately hypothermic (25°C-30°C) CPB. No statistically significant differences between the two techniques were found in whole-body 
, blood lactate concentration, systemic vascular resistance, urine flow, or thermal gradients. Thus, no evidence was found that pulsatile flow improved perfusion of the microcirculation during clinical CPB. It is possible that pulsatile flow would result in fewer functional derangements at lower flows than were used in this study. Bixler and colleagues found that nonpulsatile perfusion of a hypertrophied fibrillating dog's heart at a mean pressure of 50 mmHg resulted in subendocardial ischemia, whereas pulsatile flow did not. When the mean perfusion pressure was 80 mmHg, neither pulsatile nor nonpulsatile flow resulted in subendocardial ischemia.
It is also possible, but not proven, that pulsatile flow has an advantage over nonpulsatile flow in infants. Williams and colleagues drew this conclusion from a clinical study in which they found more rapid cooling and rewarming and greater urine flow with pulsatile flow. Results of this study are difficult to interpret, however. Finally, pulsatile flow could prove beneficial in high-risk patients who come to operation desperately ill with end-stage disease (low cardiac output, acidosis, or renal failure).
Currently, there is insufficient evidence to conclude that pulsatile flow from the pump-oxygenator importantly reduces the ill effects of the relatively short periods of CPB required for cardiac surgery in the great majority of patients.
Systemic Venous Pressure
During CPB, systemic venous pressure is determined by the techniques used, because:
where 
is mean systemic venous pressure, 
is systemic blood flow rate, and f means “a function of.” The cross-sectional area and length of the single or multiple venous cannulae, and to a lesser extent (because it usually has a large diameter) those of the venous tubing, are fixed factors determining venous pressure during total CPB. For this reason, the largest venous cannulae compatible with the clinical situation are commonly used, mindful of the need for the cannulae to lie loosely, not snugly, in the caval veins. When smaller cannulae are used, the other variables in Equation 2-2 can be manipulated. For example, systemic blood flow can be reduced or suction applied to the venous return to ensure an acceptable venous pressure (see “ Vacuum-Assisted Venous Return ,” earlier).
There is no apparent physiologic advantage in having a central venous pressure greater than zero during total CPB. Increasing the venous pressure requires more intravascular volume and often additional priming volume. Venous pressure should therefore be kept close to zero, and certainly not more than 10 mmHg, to minimize increases in extracellular fluid.
Pulmonary Venous Pressure
Ideally, pulmonary venous pressure should be at zero during total CPB, and certainly not more than 10 mmHg. Undue elevations are dangerous because they produce increased extravascular lung water and eventually gross pulmonary edema, according to the Starling law of transcapillary fluid exchange (neglecting lymph flow):
where P c is effective blood pressure within the capillary, P t is tissue turgor pressure (interstitial fluid pressure), π c is osmotic pressure of the plasma (colloid) inside the capillary, and π t is osmotic pressure of the extracellular fluid (tissue colloid osmotic pressure).
Increase in extracellular lung water is related to duration of elevation of pulmonary venous or pulmonary capillary pressure, other things being equal. Not only can pulmonary edema result, but a combination of the damaging effects of CPB and increased pulmonary venous pressure can lead to pulmonary hemorrhage. Maintaining a very low pulmonary venous pressure will not always eliminate these complications.
Maintenance of a low pulmonary venous pressure can be ensured by monitoring left atrial pressure in patients undergoing CPB (see Section III ). In most clinical settings, there is little tendency for pulmonary venous pressure to increase. If it does, the pulmonary venous system can be decompressed by suction on either a catheter (or an opening) in the pulmonary trunk, because no valves are present in pulmonary veins, or a catheter inside the left atrium or left ventricle.
Temperature
Since the introduction by Brown and colleagues of an efficient heat exchanger for extracorporeal circulation, temperature of the perfusate, and secondarily of the patient, has been controlled by the perfusionist. In decisions regarding temperature of the patient during CPB, several facts must be considered. Flexibility of CPB is achieved when it is combined with hypothermia. Hypothermia of even moderate degree appears to blunt some of the damaging effects of CPB. It allows use of lower pump 
with less blood trauma and achieves better myocardial protection and protection of other organs than normothermic CPB. Systemic hypothermia also provides a margin of safety for organ protection if equipment failure occurs. The patient's body temperature is the most important determinant of the length of safe circulatory arrest time (see Section I ).
Moderate hypothermia is used in many patients, and we consider at least mild hypothermia (31°C-34°C) to be advisable in essentially all cases. A nasopharyngeal temperature of 14°C to 20°C is chosen when circulatory arrest is required.
During core cooling, blood entering the patient's aorta should be kept no greater than 10°C to 14°C below the nasopharyngeal temperature to minimize the tendency for gas to come out of solution when the cold blood is warmed by the patient. This is a conservative recommendation, in that some groups use the coldest perfusate temperature obtainable (4°C-5°C) once CPB is initiated.
Because blood is damaged by temperatures greater than 42°C, and the boundary layer of blood next to the wall surface of the heat exchanger probably reaches the temperature of that surface and thus of the water on the other side of the wall, water temperature should not exceed 42°C during rewarming. Blood temperature should not exceed 39.5°C during rewarming. Solubility of gas in blood is decreased when blood is warmed, but this is not a problem when the heat exchanger is upstream (proximal) to the oxygenator. When it is downstream (distal) to the oxygenator, it is a potential problem during rewarming, and a bubble trap may be interposed in the arterial tubing downstream to both. In general, maintenance of a temperature gradient from the heat exchanger to the blood of not more than 10°C to 12°C will prevent bubble formation.
Response Variables
Alberts and colleagues state in their textbook: “There is a paradox in the growth of scientific knowledge. As information accumulates in ever more intimidating quantities, disconnected facts and impenetrable mysteries give way to rational explanations, and simplicity emerges from chaos. The essential principles of a subject gradually come into focus.” The patient response to CPB using current techniques and equipment is still largely described by “disconnected facts and impenetrable mysteries,” but considerable effort has been made to develop simplicity and reduce chaos. Continued interest in this response has stimulated the search for more cohesive knowledge and ways of minimizing unfavorable outcomes of cardiac surgery using CPB and whole-body perfusion from a pump-oxygenator.
Unfavorable aspects of the response of the patient to CPB and use of a pump-oxygenator were evident during the early days of open cardiac surgery, but tended to be overlooked in the excitement generated by this new technology. Subsequently, surgeons observed that (1) diffuse bleeding was more common with CPB than after other types of surgery; (2) some patients, particularly small ones, became edematous during the procedure; (3) occasionally severe and truly malignant hyperthermia occurred with no demonstrable infection; (4) pulmonary dysfunction was sometimes unexpectedly prominent; and (5) the heart often did not perform as well as anticipated after its repair. Yet they also noted that many patients appeared to be free of these developments, and most survived. Since then, more information has been gathered, but not as much as is desirable.
Whole-Body (Nonspecific) Inflammatory Response to Use of a Pump-Oxygenator
Diversion of blood through nonendothelialized channels to, through, and from pumps and the oxygenator appears to stimulate the organism to recognize the extracorporeal system as nonself. Thus, potential is present for the specific immune and nonspecific inflammatory response systems to be activated. Specific immune responses of an immunologically naive (unprepared) patient are slow to develop and not in evidence during the first few days after CPB. In any event, they are generally not strong. Nonspecific inflammatory responses appear rapidly, and in a few patients they dominate the early minutes, hours, and days after use of a pump-oxygenator. We initially named this response the whole-body inflammatory response, which we hypothesized unified the many diffuse responses to exposure of blood to abnormal events. It is now often called the systemic inflammatory response syndrome (SIRS) because processes other than CPB can stimulate it.
Humoral Response
Initial response is probably humoral, initiated by the contact of plasma with the foreign surfaces of the tubing and pump-oxygenator and with air. Gas exchange requires a large surface area; it is therefore in the oxygenator that the greatest stimulus to this response occurs. Humoral response appears to begin with activation of specialized plasma proteins, developed and conditioned through centuries of life to recognize and repel transcutaneous invaders. Whereas previously this invasion has generally been a relatively small, localized, and often extravascular process, in the patient exposed to a pump-oxygenator it is a massive intravascular process. Even though the patient is heparinized, parts of the coagulation cascade respond virtually immediately to the activating capability of the foreign surface, as do the complement, kallikrein, fibrinolytic, and other cascades. Activation of Hageman factor (factor XII) may be the initial event in activation of these cascades, although platelets appear to be independently activated at about the same time. Nearly all the split products resulting from these multiple activations can be found in the patient's blood during and, for a time, after bypass. Mechanisms for their disappearance have not been elucidated, but presumably they are to some extent metabolized, taken up by specific cell-surface receptors, dissipated into extravascular fluids, including peritoneal and pleural fluids, and excreted in the urine.
Products of activation of these cascades have powerful physiologic effects, both directly and by activation of other systems and cells. The complement cascade, once activated, results in the production of powerful anaphylatoxins (C3a and C5a) that increase vascular permeability, cause smooth muscle contraction, mediate leukocyte chemotaxis, and facilitate neutrophil aggregation and enzyme release. Complement activation occurs through either the classic or the alternative pathway.
Contact activation of Hageman factor also immediately initiates the kallikrein-bradykinin cascade, resulting in the production of bradykinin. Plasma kallikrein circulates in the blood as a precursor, prekallikrein, 75% of which is bound to high-molecular-weight kininogen (HMWK) in the plasma. Bradykinin, formed largely from HMWK, increases vascular permeability, dilates arterioles, initiates smooth muscle contraction, and elicits pain. Kallikrein also activates Hageman factor and plasminogen to form plasmin, again demonstrating the complex interactions and feedback loops between the various reactions of blood to nonself.
Once activated, the contact activation system overcomes its normal regulating system, and all the responses are amplified. Because plasma kallikrein leads to conversion of plasminogen to plasmin, whose basic function in the circulation is to digest fibrin clots and thrombi, the fibrinolytic cascade is activated by this and other humoral and cellular mechanisms.
Cellular Response
Blood cells and endothelial cells participate in the nonspecific inflammatory response to use of a pump-oxygenator. Lymphocytes (both antibody-forming B cells and T cells) are part of the specific immune system and, as indicated earlier, participate little in the response to CPB in the usual immunologically naive patient. Eosinophilic granulocytes also seem to have limited participation. Basophilic granulocytes (mast cells) may well participate, but the extent to which they do so is not clear, and the same is true of the natural killer (NK) cells within the leukocyte family. Monocytes, once activated, participate in the cellular response.
Neutrophilic granulocytes (polymorphonuclear leukocytes) play a major role in the response to CPB. Neutrophils are activated by complement and other soluble inflammatory mediators. When activated, they migrate directionally toward areas of higher complement concentration (usually in the tissues, but during CPB, probably in blood), change their shape, become more adhesive, and secrete cytotoxic substances, including oxygen-derived free radicals. Of importance—and possibly a clue as to why most patients recover uneventfully from cardiac operations in which CPB is used, despite the strong humoral and cellular response—is the fact that complement can also desensitize neutrophils, thereby reducing their ability to participate in the inflammatory response. Neutrophils are also activated by other humoral agents participating in the cascades in the blood, including kallikrein, as well as by other inflammatory mediators (cytokines) generated by cells, including tumor necrosis factor (TNF) and platelet activating factor (PAF). These molecules also have been shown to increase in amounts both during and early after CPB.
Platelets are strongly affected by CPB using a pump-oxygenator, but in a complex manner that has been well summarized by Edmunds and colleagues. As in the case of neutrophils, platelets must be activated from their normally passive state; this occurs within 1 minute of the start of CPB. The precise initial trigger is uncertain, but possibilities include direct surface contact, abnormal shear stresses, mechanical lysis, exposure to adenosine diphosphate, and unidentified chemical agonists. The mechanism for activation of platelets is exposure on the surface of the platelet of numerous specific membrane receptors. Exposure of the fibrinogen glycoprotein receptors (GPIIb-IIIa complex), and subsequent binding of fibrinogen to them, are essential for adherence of platelets to the foreign surfaces of the pump-oxygenator and for their aggregation. Many other specific receptor sites are expressed and exposed by activated platelets. Control, feedback, and amplification mechanisms regulate platelets as well as the humoral systems, all of which are involved in the response to CPB.
Endothelial cells do not pass through the pump-oxygenator, but their complex activities are affected while the patient is connected to it. Triggering mechanisms are not clearly defined, but they probably include abnormal pressures and shear stresses, localized ischemia, and increased concentrations of normal and abnormal substances and cells in the blood. As a result, endothelial surface receptors are exposed, substances are elaborated and extruded, and spaces between the endothelial cells and their membranes are enlarged.
Endothelial and other cells, particularly those in the locally ischemic areas that surely exist during CPB, express phospholipid molecules derived from arachidonic acid (eicosanoids). These are important mediators of inflammation and include the prostaglandins, thromboxanes, leukotrienes, and lipoxins. Other cells in areas of acute inflammation that may be present during CPB can produce soluble factors (cytokines) that normally act on other cells to regulate their function; after CPB, they can induce elevation of body temperature, among other things.
Metabolic Response
Magnitude of the acute elevation of catecholamine levels in the blood that develops during CPB (see “ Catecholamine Response ” later in this section) is a measure of severity of the stress reaction induced by most cardiac surgery using CPB. Thus, in addition to the responses induced by CPB, cardiac operations and CPB induce the important perturbations associated with other major operations and trauma. Characteristics of this “metabolic response to stress” have been intensively studied by a number of investigators and clinicians. Among the first was Cuthbertson in 1930, and among the most prominent, Francis D. Moore. The essence of this process has been well summarized by Wilmore :
The human body responds to these stresses with dramatic resilience. For example, following injury, clotting mechanisms are immediately activated to reduce blood loss; body fluids shift from the extravascular compartment to restore blood volume; blood flow is redistributed to ensure perfusion of vital organs; and respiratory and renal functions compensate to maintain acid-base neutrality and body fluid tonicity. Following these acute adaptations, other changes occur; these responses are more gradual and prolonged but are apparently necessary for recovery of the injured organism. A variety of immunologic alterations are initiated; leukocytes are mobilized, macrophages and specialized T cells are produced, and “acute phase” plasma proteins are synthesized by the liver. Inflammatory cells invade the injured area, set up a perimeter defense, and engulf the dead and dying cells and other wound contaminants. These initial steps are followed rapidly by ingrowth of blood vessels, appearance of fibroblasts that build collagen scaffolding, and a host of other local changes that aid wound repair.
Local changes that occur at the injury site are accompanied by systemic alterations in body physiology and metabolism. Cardiac output is elevated, minute ventilation is increased, and the patient becomes febrile. Lipolysis and skeletal muscle proteolysis are accelerated, providing an ongoing fuel supply and an immediate source of amino acids that are utilized for wound healing and synthesis of “acute phase” proteins and new glucose. The glucose provides essential energy for the brain and other vital organs and for healing of the wound.
Phenomena associated with CPB not only produce their own damage but also interfere with the metabolic response to stress, a process necessary for recovery. Uneventful recovery of most patients after cardiac surgery means that a vast array of control and counteractive phenomena of both humoral and cellular types is in place, many of which await discovery and exploitation.
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