Hammon
J
Wi
. Extracorporeal Circulation: Organ Damage.
Cohn Lh, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2008:389-414.
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CHAPTER 12C |
Cardiopulmonary bypass can preempt normal reflex and chemoreceptor control of the circulation, initiate coagulation, activate blood cells, release circulating cell-signaling proteins, generate vasoactive and cytotoxic substances, and produce a variety of microemboli. Venous pressure can be elevated, plasma colloid osmotic pressure is reduced, flow is nonpulsatile, and temperature is manipulated. Tissues and organs may suffer from regional malperfusion that is independent of physiologic controls, and is caused by microemboli, increased interstitial water, and perfusion with a variable amount of cytotoxic substances. Reversible and irreversible cell injury may occur, but damage is diffusely distributed throughout the entire body as individual cells or small groups of cells are affected. Ischemia-reperfusion injury augments damage to the heart and on occasion to other organs. Amazingly, the body is able to withstand and for the most part repair the cellular damage, although some abnormalities may appear later. This section summarizes the reversible and permanent organ damage produced by cardiopulmonary bypass (CPB) and complements the preceding two sections of this chapter.
Cardiac output during CPB is carefully monitored and synchronized with temperature and hemoglobin concentration to ensure that the entire body is adequately supplied with oxygen (see earlier section on extracorporeal perfusion systems). Excessive hemodilution reduces oxygen delivery,685 and hemoglobin concentrations significantly below 8 g/L cause organ dysfunction at temperatures above 30°C.686 However, regional hypoperfusion is not monitored,687 is independent of reflex and chemoreceptor controls, and is influenced by the inflammatory response, which produces circulating vasoactive substances.688–689 Regional perfusion is also influenced by acid-base relationships during cooling and may affect postoperative organ function.690–691 Alpha-stat management (pH increases during cooling) decreases cerebral perfusion during hypothermia; pH stat (pH 7.40 is maintained by adding CO2) improves organ perfusion but may increase embolic injury.692 Temperature differences within the body and within organs produce regional temperature-perfusion mismatch,693 which can precipitate regional hypoperfusion and acidosis due to inadequate oxygen delivery.
The inflammatory response produces the cytotoxic compounds and activated neutrophils and monocytes that can and do destroy organ and tissue cells (see section 12B). These agents directly access the specialized cells of every organ by passing between endothelial cell junctions to reach the interstitial compartment. Reduced plasma colloid osmotic pressure, elevated venous pressure, and widened endothelial cell junctions694 increase the volume of the interstitial space during CPB in proportion to the duration of bypass, magnitude of the dissection, transfusions, and other factors. In prolonged complicated perfusions the interstitial compartment may increase 18 to 33%,695 but intracellular water does not increase during CPB.
Microemboli are defined as particles less than 500 microns in diameter. They enter the circulation during CPB from a variety of sources.696 Table 12-5 summarizes sources of gas, foreign, and blood-generated microemboli, which are more fully discussed in section 12A. Air entry into the perfusion circuit produces the most dangerous gas emboli because nitrogen is poorly soluble in blood and is not a metabolite. Carbon dioxide is rapidly soluble in blood and is sometimes used to flood the surgical field to displace air.697 Foreign emboli, largely generated in the surgical wound, reach the circulation from the surgical field via the cardiotomy reservoir. The cardiotomy reservoir is the primary source of foreign emboli and the major source of blood-generated emboli, particularly fat emboli.698 Extensive activation and physical damage to blood elements produce a wide variety of emboli, which tend to increase with the duration of perfusion.692,699
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Although discussed in earlier sections, the principal methods for reducing circulating microemboli deserve emphasis and include the following: adequate anticoagulation; membrane oxygenator; washing blood aspirated from the surgical wound;700 filtering the cardiotomy reservoir; secure purse-string sutures around cannulas; strict control of all air entry sites within the perfusion circuit; removal of residual air from the heart and great vessels; avoidance of atherosclerotic emboli; and selective filtration of cerebral vessels.701–702
Many intraoperative strategies are available to reduce cerebral atherosclerotic embolization. These include routine epicardial echocardiography of the ascending aorta to detect both anterior and posterior atherosclerotic plaques and to find sites free of atherosclerosis for placing the aortic cannula.703 Recently, special catheters with or without baffles or screens have been developed to reduce the number of atherosclerotic emboli that reach the cerebral circulation.701,704 In patients with moderate or severe ascending aortic atherosclerosis a single application of the aortic clamp, as opposed to partial or multiple applications, is strongly recommended and has been shown to reduce postoperative neuronal and neurocognitive deficits in a large clinical series.705 Retrograde cardioplegia is preferred over antegrade cardioplegia in these patients to avoid a sandblasting effect of the cardioplegic solution.706 No aortic clamp may be safe or even possible in some patients with severe atherosclerosis or porcelain aorta. If intracardiac surgery is required in these patients, deep hypothermia may be used with or without graft replacement of the ascending aorta. If only revascularization is needed, pedicled single or sequential arterial grafts,707 T or Y grafts from a pedicled mammary artery,708 or vein grafts anastomosed to arch vessels can be used.
In-depth or screen filters (see section 12A) are essential for cardiotomy reservoirs and are usually used in arterial lines. The efficacy of arterial line filters is controversial since screen filters with a pore size less than 20 microns cannot be used because of flow resistance across the filter. However, air and fat emboli can pass through filters, although 20-micron screen filters more effectively trap microemboli than larger sizes.709
It is difficult to separate postoperative cardiac dysfunction from injury due to CPB, ischemia/reperfusion, direct surgical trauma, the disease being treated, and maladjustment of preload and afterload to myocardial contractile function. The heart, like all organs and tissues, is subject to microemboli, protease and chemical cytotoxins, activated neutrophils and monocytes, and regional hypoperfusion during CPB before and after cardioplegia or fibrillatory arrest. However, the heart is protected from CPB for at least one-half of the case when the aorta is cross-clamped. Some degree of myocardial "stunning" during the period coronary blood flow is interrupted is inevitable,710 as is some degree of reperfusion injury after ischemia. Both myocardial edema and distention of the flaccid cardioplegic heart during aortic cross-clamping711 reduce myocardial contractility. Lastly, if myocardial contractility is weak, excessive preload or high afterload during weaning from CPB increases ventricular end-diastolic volume, myocardial wall stress, and oxygen consumption. Thus postoperative performance of the heart depends on many variables and not just the injuries produced by CPB.
Because the brain controls all body activity, even small injuries may produce symptomatic, functional losses that are not detectable or important in other organs. Regional hypoperfusion, edema, microemboli, and circulating cytotoxins may cause subtle losses in cognitive function, behavioral patterns, and physiologic and physical function that can pass unnoticed, be accepted and dismissed, or profoundly compromise the patient’s quality of life. Thus the brain is the most sensitive organ exposed to damage by CPB and also the organ that with the heart is most important to protect.
Routine assessment of neurologic injury due to CPB is not done for most patients because of the priority of the cardiac lesion and because of costs in time and money. General neurologic examinations by untrained individuals or by members of the surgical team are not adequate to rule out subtle neurologic injuries, and this is the principal reason that the incidence of post-CPB nonstroke neurologic injury varies widely in the surgical literature.712–714
For studies designed to assess or reduce neurologic injury caused by CPB, nonroutine preoperative and postoperative tests are required. These special tests include a complete neurologic examination by a trained neurologist. To improve accuracy, a single neurologist should conduct all serial examinations. A standardized protocol of examination should be followed, with uniform reporting of results. The basic, structured examination includes a mental state examination; cranial nerve, motor, sensory, and cerebellar examinations; and examination of gait, station, deep tendon, and primitive reflexes.
The most obvious neuropsychologic abnormalities are coma, delirium, and confusion, but transitory episodes of delirium and confusion are often dismissed as due to anesthesia or medications. More subtle losses are determined by comparison of preoperative and postoperative performances using a standard battery of neuropsychologic tests prepared by a group of neuropsychologists.715 A 20% decline in two or more of these tests suggests a neuropsychologic deficit that should be followed until resolved or not resolved.716
Computed axial tomograms or magnetic resonance imaging (MRI) scans are essential for the definitive diagnosis of stroke, delirium, or coma. Preoperative imaging is usually not necessary when new techniques such as diffusion-weighted MRI imaging, MRI spectroscopy, or MRI angiography are used to assess possible new lesions after operation.717–719
Biochemical markers of neurologic injury after cardiac surgery are relatively nonspecific and inconclusive. Neuron-specific enolase (NSE) is an intracellular enzyme found in neurons, normal neuroendocrine cells, platelets, and erythrocytes.720 S-100 is an acidic calcium-binding protein found in the brain.721–722 The beta dimer resides in glial and Schwann cells. Both S-100 and NSE increase in spinal fluid with neuronal death721–722 and may correlate with neurologic injury after CPB.723 However, plasma levels are contaminated by aspiration of wound blood into the pump and hemolysis, and are often elevated following prolonged CPB in patients without otherwise detectable neurologic injury.724
Advancing age increases the risk of stroke or cognitive impairment in the general population, and surgery, regardless of type, increases the risk still higher.725 A European study compared 321 elderly patients without surgery to 1218 patients who had noncardiac surgery and found a 26% incidence of cognitive dysfunction 1 week after operation and a 10% incidence at 3 months.726 Between 1974 and 1990 the number of patients undergoing cardiac surgery over age 60 and over age 70 increased twofold and sevenfold, respectively.727 Figure 12-21 illustrates the relationship between age and cognitive dysfunction after coronary artery bypass graft and demonstrates a steep increase after the age of 60. Genetic factors also influence the incidence of cognitive dysfunction following cardiac surgery.728 The incidence of cognitive dysfunction at 1 week following cardiac surgery is approximately double that of noncardiac surgery.
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The two major causes of organ dysfunction and injury during CPB are microemboli and hypoperfusion, which are to some extent mutually exclusive. Microemboli are distributed in proportion to blood flow;735 thus reduced cerebral blood flow reduces microembolic injury but increases the risk of hypoperfusion.736 During CPB both alpha-stat acid-base management and phenylephrine reduce cerebral injury in adults, probably by causing cerebral vessel vasoconstriction and reducing the number of microemboli.736–737 Air,738 atherosclerotic debris,739 and fat are the major types of microemboli causing brain injury in clinical practice, and all cause neuronal necrosis by blocking small cerebral vessels.692 Massive air embolism causes a large ischemic injury, but gaseous cerebral microemboli may directly damage endothelium in addition to blocking blood flow.740 The recent identification of unique small capillary arteriolar dilatations in the brain associated with fat emboli (Fig. 12-22)741 raises the possibility that these emboli not only block small vessels, but also release cytotoxic free radicals, which may significantly increase the damage to lipid-rich neurons.
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Additional Neuroprotective Strategies
Primary strategies for avoiding air, atherosclerotic particulates, and blood-generated microembolism are presented above and in section 12A. Recommended conditions for protecting the brain during CPB include mild hypothermia (32 to 34°C) and hematocrit above 25%.744 Temporary increases in cerebral venous pressure caused by superior vena cava obstruction and excessive rewarming above blood temperatures of 37°C should be avoided.745–746 A randomized study in which patients were mildly rewarmed to 35°C core temperature demonstrated improved neurocognitive outcomes over patients rewarmed to 37°C.746 Either jugular venous bulb oxygen saturation or near-infrared cerebral oximetry are recommended for monitoring cerebral perfusion in patients who may be at high risk for cerebral injury.747
Barbiturates reduce cerebral metabolism by decreasing spontaneous synaptic activity748 and provide a definite neuroprotective effect during clinical cardiac surgery using CPB.749 Unfortunately, these agents delay emergence from anesthesia and prolong intensive care unit stays. A recent study of high-risk patients randomized to aprotinin or placebo found a powerful protective effect against stroke for full-dose aprotinin in coronary artery bypass graft patients.750 A larger randomized multi-institutional study is planned. N-methyl-D-aspartate antagonists, which are effective in animals, provide mild protection compared to control patients, but have a high incidence of neurologic side effects.751 A small study demonstrated a neuroprotective effect of lidocaine.752 Currently no pharmacologic agent is recommended for protection of the central nervous system during CPB.
Off-pump myocardial revascularization theoretically avoids many of the causes of cerebral injury due to CPB, but as noted above, many causes of neuronal injury are independent of CPB and related to atherosclerosis and air entry sites into the circulation. Nonrandomized measurements of carotid emboli by Doppler ultrasound indicate fewer emboli and slightly improved neurocognitive outcomes in high-risk patients who have off-pump surgery.753 A randomized trial of off-pump versus on-pump patients failed to show a significant difference in neurologic outcome between methods.754
Neuropsychologic deficits that are present after 3 months are almost always permanent.755 Assessments after that time are confounded by development of new deficits, particularly in aged patients.756
Patient factors and the separate effects of operation and CPB combine to compromise lung function early after operation. Chronic smoking and emphysema are the most common patient factors, but muscular weakness, chronic bronchitis, occult pneumonia, preoperative pulmonary edema, and unrelated respiratory disease are other contributors to postoperative pulmonary dysfunction. Incisional pain, lack of movement, shallow respiratory sighs, increased work of breathing, reduced pulmonary compliance, weak cough, increased pulmonary arterial-venous shunting, and interstitial edema, to some degree are consequences of anesthesia and any operation. CPB significantly adds to this injury.
During CPB the lungs are supplied by the bronchial arteries and pulmonary arterial blood flow may be absent or minimal. Whether or not alveolar cells suffer ischemic/reperfusion injury is unclear, but the lungs are subject to many insults that combine to increase pulmonary capillary permeability and interstitial lung water. Hemodilution, reduced plasma oncotic pressure, and temporary elevation of left atrial or pulmonary venous pressure during CPB or during weaning from CPB increase extravascular lung water.757,758 Microemboli759 and circulating cellular, vasoactive, and cytotoxic mediators of the inflammatory response760–764 reach the lung via bronchial arteries during CPB and with resumption of the pulmonary circulation during weaning. These agents increase pulmonary capillary permeability, perivascular edema, and bronchial secretions, and perhaps cause observed changes in alveolar surfactant.765 The combination of increased interstitial lung water and bronchial secretions, altered surfactant, patient factors, and the consequences of operation reduces pulmonary compliance and functional residual capacity and increases the work of breathing.766 All of these changes combine to enhance regional atelectasis, increase susceptibility to infection, and increase the physiologic arterial-venous shunt, which reduces systemic arterial PaO2.
Postoperative respiratory care is based upon restoring normal pulmonary capillary permeability and interstitial lung volume; preventing atelectasis; reinflating atelectatic segments; maintaining normal arterial blood gases; and preventing infection and facilitating removal of bronchial mucus. Improved postoperative respiratory care, an understanding of the mechanisms of lung injury during CPB, and efforts to prevent or control the causes of injury767,768 have markedly reduced the incidence of pulmonary complications in recent years769 (see Chapter 16 for a more detailed discussion of postoperative care).
Acute respiratory distress syndrome is a rare complication of lung injury during cardiopulmonary bypass and is usually caused by intrabronchial bleeding from traumatic injury by the endotracheal tube or pulmonary artery catheter,766 or to extravasation of blood into alveoli from acute increases in pulmonary venous pressure or severe pulmonary capillary toxic injury.
As with other organs, the preoperative health of the kidneys is a major factor in the ability of that organ to withstand the microembolic, cellular,770 and regional malperfusion injuries caused by CPB. Risk factors for postoperative renal dysfunction include age over 70 years, diabetes mellitus, previous cardiac surgery, congestive heart failure, and a complex, prolonged operation.771 The incidence of acute renal failure requiring dialysis after CPB is remarkably low, averaging 1%; however, the incidence increases to 5% with complex operations.772
Some degree of renal injury is inevitable during CPB773 and postperfusion proteinuria occurs in all patients.774 Increased expression of neutrophil CD11b receptors and elevated neutrophil count are significantly related to postoperative acute renal failure, defined as a 150% increase in plasma creatinine over baseline.775 Renal blood and plasma flow, creatinine clearance, free water clearance, and urine volume decrease without hemodilution.776 Hemodilution attenuates most of these functional changes and also reduces the risk of hemoglobin precipitation in renal tubules if plasma-binding proteins become saturated with free hemoglobin during extracorporeal perfusion. Hemoglobin is toxic to renal tubules and precipitation can block both blood and urine flow to the tubules.777 Hemodilution dilutes plasma hemoglobin; improves flow to the outer renal cortex; improves total renal blood flow; increases creatinine, electrolyte, and water clearance; and increases glomerular filtration and urine volume.775
Perioperative periods of low cardiac output and/or hypotension added to the microembolic, cellular, and cytotoxic injuries of CPB, and to any preoperative renal disease are the major causes of postoperative renal failure.770,777 Low cardiac output reduces renal perfusion pressure and causes angiotensin II production and renin release, which further decrease renal blood flow. Kidneys, already compromised by preoperative disease and the CPB injury, are particularly sensitive to ischemic injury secondary to low cardiac output and hypotension. Thus perioperative management includes efforts to maximize cardiac output using dopamine or dobutamine if necessary,778 avoiding renal arterial vasoconstrictive drugs, providing adequate crystalloid infusions to maintain urine volume, and alkalinizing urine to minimize precipitation of tubular hemoglobin if excessive hemolysis has occurred. Preliminary studies with a natriuretic peptide found in human urine, urodilantin, indicate the possibility of attenuating postoperative oliguria.779
If perioperative low cardiac output and hypotension do not occur,780 the normal kidney has sufficient functional reserve to provide adequate renal function during and after operation. The appearance of oliguric renal failure is ominous and usually requires dialysis, which is generally permanent if required for more than 2 weeks.780 Oliguric renal failure markedly increases morbidity and mortality by approximately eightfold.781
INJURY TO THE LIVER AND GASTROINTESTINAL ORGANS
Although subjected to microemboli, cytotoxins, and regional malperfusion during CPB, the enormous functional reserve and reparative processes of the normal liver nearly always overcome the injury without consequences. Often liver enzymes are mildly elevated,782 and 10 to 20% of patients are mildly jaundiced.783 Extensive red cell hemolysis increases the likelihood of mild jaundice. Persistent and rising bilirubin two or more days after CPB may precede development of liver failure and is associated with increased morbidity and mortality.784 Catastrophic liver failure, however, occurs in patients with overwhelming sepsis, oliguric renal failure, anesthetic or drug toxicity, or after a prolonged period of low cardiac output or an episode of hemorrhagic shock and multiple blood transfusions and is uniformly fatal.785 The liver usually is involved in patients who develop multiorgan failure and is often presaged by sudden hypoglycemia.
Less than 1% of patients develop clinical pancreatitis after CPB, but approximately 30% develop a transitory, asymptomatic increase in plasma amylase and/or lipase.786–788 Autopsy studies of the pancreas soon after CPB indicate occasional evidence of histologic pancreatitis.789 A history of recurrent pancreatitis, perioperative circulatory shock or hypotension, excessively prolonged CPB, and continuous high doses of inotropic agents are risk factors for developing postoperative pancreatitis.790 Experimentally and clinically, high doses of calcium increase intracellular trypsinogen activation and histologic evidence of pancreatitis.791–793 Fulminant pancreatitis is very rare, but is often fatal.794
CPB at adequate flow rates does not decrease splanchnic blood flow.795 Risk factors for gastrointestinal complications include advanced age, emergency surgery, prolonged CPB, postoperative low cardiac output or shock, prolonged vasopressor therapy, and elevated preoperative systemic venous pressure.796
CPB decreases gastric pH, which declines further after operation.797 Prior to the advent of histamine blockers and regular use of antacids, duodenal and/or gastric erosion, ulcer, and bleeding were frequent complications following clinical cardiac surgery798 and were associated with mortality that approached 33 to 50%.799 These complications are now uncommon.
Several days to 1 week after operation very elderly patients rarely may develop mesenteric vasculitis or severe mesenteric vasoconstriction that proceeds to small bowel ischemia and/or infarction in response to vasopressors. New-onset abdominal pain with a silent, rigid abdomen and abrupt rise in white blood cell count may be the only signs of this catastrophic complication, which is frequently fatal. If suspected before infarction, infusion of papaverine or alternative vasodilators directly into the mesenteric arteries may prevent or limit subsequent infarction.800 The role of CPB in the etiology of this complication is not known.
The author would like to acknowledge the contributions of the authors of this chapter in the preceding edition: L. Henry Edmunds, Jr., Eugene A. Hessel, II, Robert W. Colman, and Philippe Menasche.
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