Cardiopulmonary Bypass: Principles and Practice

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CHAPTER 17: ENDOCRINE, METABOLIC, AND ELECTROLYTE RESPONSES

JOHN F. BUTTERWORTH

RICHARD C. PRIELIPP

Quick Links to Sections in this Chapter

–PITUITARY HORMONES

–ADRENAL HORMONES

–ATRIAL NATRIURETIC FACTOR

–RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

–THYROID

–EICOSANOIDS

–OTHER HUMORAL EFFECTS

–CALCIUM

–MAGNESIUM

–POTASSIUM

–METAL IONS: ZINC, COPPER, AND IRON

–CONCLUSIONS

–KEY POINTS

–References

J. F. Butterworth Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009.

R. C. Prielipp: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009.

Surgical procedures using cardiopulmonary bypass (CPB) produce physiologic alterations not found in other major surgical procedures. During total CPB, the heart and lungs are not perfused and can neither secrete hormones nor make their normal contributions to drug metabolism. Exposure to the pump-oxygenator and its tubing traumatizes cellular blood elements, causes plasma proteins to be adsorbed and removed from the circulation, and stimulates an immune response, as is well described in other chapters in this volume. Hemodilution (from blood-free priming solutions) and heparin anticoagulation alter blood concentrations of electrolytes, hormones, and serum proteins during CPB. Finally, moderate to profound hypothermia is generally used, reducing the rates of biochemical reactions and further perturbing hormonal responses.

Additional characteristics of extracorporeal perfusion contribute to the endocrine, metabolic, and electrolyte alterations produced. Nonpulsatile perfusion may change the distribution of flow both among and within organs. As a consequence, some hormonal alterations during CPB can be lessened or prevented by pulsatile perfusion. CPB increases "stress" hormones disproportionate to the apparent levels of physiologic disturbance, and it remains unclear which factor—hypothermia, hemodilution, decreased perfusion of endocrine glands, or denaturation of hormones by foreign surfaces—most contributes to these changes. Additionally, some hormone concentrations increase above normal levels after termination of bypass with the return of pulsatile warm perfusion to endocrine glands (1). Consistent with expectations, one study shows that deeper planes of anesthesia attenuate or eliminate the exaggerated endocrine responses to CPB and reduce mortality (2). Finally, interest in the use of spinal and epidural anesthesia for cardiac surgery has recently developed, and these techniques have long been known to inhibit the neuroendocrine response to abdominal and lower extremity surgery.

The literature regarding endocrine, metabolic, and electrolyte responses to CPB is difficult to summarize because of marked variations in patient populations, perfusion and cardioplegia techniques, perfusate temperatures, priming solutions, and anesthetic and adjuvant drugs. Early hormone assays often were not specific for intact active hormones. When possible, this chapter emphasizes the most recent studies in which current anesthesia, cardioplegia, perfusion, and hormone measurement techniques were used.

PITUITARY HORMONES

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The anterior portion of the pituitary gland secretes hormones that regulate the adrenal cortex, thyroid, ovaries, and testes. Several aspects of pituitary response are considered in subsequent sections. Gonadotropin responses during CPB have not been reported.

Pituitary apoplexy, a rare but potentially devastating complication, has been reported after CPB (3–7), typically in patients with pituitary adenomas. These patients demonstrated varying combinations of ptosis, ophthalmoplegia, nonreactive and dilated pupils, decreased visual acuity, and visual field defects in addition to the characteristic hormonal deficits. Ischemia, hemorrhage, and edema of the gland appear to be the mechanisms for pituitary failure after bypass. The diagnosis can be confirmed with cranial computed tomography or magnetic resonance imaging (Fig. 17.1). Hormonal replacement and prompt hypophysectomy are indicated, and experience suggests that the latter may be safely performed early after cardiac surgery (3).

FIG 17.1. Cranial tomographic scan of a 56-year-old man 3 days after mitral valve repair. The patient presented with unilateral pupillary mydriasis, complete ophthalmoplegia, and loss of sensation in divisions I and II or cranial nerve V upon extubation several hours after his surgery. Note the mass in the sella turcica and bony erosion of the sphenoid "wing," as indicated by the arrows. (From Meek EN, Butterworth J, Kon ND, et al. New onset of cranial nerve palsies immediately following mitral valve repair. Anesthesiology 1998;89:1580–1582, with permission.)


Vasopressin

Vasopressin, or antidiuretic hormone (ADH), secreted by the posterior pituitary gland, is a potent regulator of renal water excretion (8). At high concentrations, ADH may increase peripheral vascular resistance, decrease cardiac contractility, and decrease coronary blood flow (8,9). ADH increases renal vascular resistance, reducing renal blood flow (9), and stimulates the release of the von Willebrand factor, perhaps improving hemostasis during and after cardiac surgery (see Chapter 28). Stimuli provoking ADH release include increased plasma osmolality, decreased blood volume or blood pressure, hypoglycemia, angiotensin, stress, and pain (8). General anesthesia and surgery are associated with moderate increases in ADH (10,11). Cardiac surgery with CPB is associated with striking increases in ADH concentration, far above those seen during other major surgical procedures (11–15), and these effects may persist for hours postoperatively (12–15) (Fig. 17.2).

FIG 17.2. Plasma concentration of arginine vasopressin (AVP) during nonpulsatile bypass for mitral valve replacement (MVR, n = 8), aortic valve replacement (AVR, n = 5), or coronary artery bypass grafting (CABG, n = 5). Data are presented as means ± SEM. As indicated, measurements were obtained at 1) anesthesia induction, 2) sternotomy, 3) 10 minutes after initiation of cardiopulmonary bypass, 4) 10 minutes before termination of cardiopulmonary bypass, 5) upon arrival in the critical care unit, 6) 6 hours after bypass, 7) 18 hours after bypass, 8) 30 hours after bypass, and 9) 48 hours after bypass. All three groups of patients demonstrated significant increases in AVP concentrations during bypass. Only at sample 5 did the mitral valve patients demonstrate significantly greater AVP concentration than the CABG patients. p values on the figure indicate comparisons between sample 1 and subsequent samples in the same surgical group. (From Kaul TK, Swaminathan R, Chatrath RR, et al. Vasoactive pressure hormones during and after cardiopulmonary bypass. Int J Artif Organs 1990;13:293–299, with permission.)


The exaggerated ADH response to CPB could be initiated by any number of stimuli, including the decrease in circulating blood volume upon initiating bypass. Left atrial pressure decreases markedly, especially with left ventricular venting, thereby simulating volume depletion, which is a potent stimulus for ADH release. The transient hypotension normally occurring at the onset of bypass may lead to increased ADH secretion. Pulsatile perfusion during CPB attenuates the exaggerated ADH response, particularly after bypass, but does not eliminate it (13,15,16) (Fig. 17.3). Pulsatile perfusion does not seem to significantly increase urinary output, despite reduced ADH concentrations (15).

FIG 17.3. Effect of pulsatile (n = 5) or nonpulsatile (n = 8) perfusion on arginine vasopressin (AVP) responses to mitral valve replacement. See legend to Figure 17.1 for measurement times. Significant differences between the two groups were observed after cardiopulmonary bypass (sample 5 and later). In this study, pulsatile bypass did not attenuate AVP responses during coronary bypass or aortic valve replacement. (From Kaul TK, Swaminathan R, Chatrath RR, et al. Vasoactive pressure hormones during and after cardiopulmonary bypass. Int J Artif Organs 1990;13:293–299, with permission.)


Certain anesthetic techniques, for example, maintenance of anesthesia with large doses of synthetic opioids (fentanyl or sufentanil) or with regional anesthesia, attenuate the hormonal responses associated with noncardiac surgical procedures. Indeed, Kuitunen et al. (17) found that patients anesthetized with 50 g/kg fentanyl demonstrated significantly reduced arginine vasopressin concentration after bypass than patients who received a lighter plane of general anesthesia using inhaled enflurane. However, even opioid anesthesia will not completely ablate the release of ADH at the onset of CPB (14,18). Unfortunately, multiple studies provide conflicting data as to whether higher peak ADH concentrations occur in patients undergoing coronary surgery or valve surgery during and after CPB (12,13,15) (Fig. 17.2). In summary, ADH concentrations increase markedly during CPB irrespective of the anesthesia or perfusion technique.

ADRENAL HORMONES

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Catecholamines

The catecholamines epinephrine and norepinephrine are products of the adrenal medulla and (in the latter case) of peripheral sympathetic and central nerve terminals. Marked elevations of plasma epinephrine and norepinephrine concentrations occurring during CPB may underlie many hemodynamic sequelae of bypass, including peripheral vasoconstriction and shifts in intraorgan blood flow (16,19–22). With hypothermia, the plasma epinephrine concentrations may increase as much as 10-fold over the pre-bypass concentrations; norepinephrine concentrations typically increase to a lesser extent (4-fold) (2,16,20,22), and deepening hypothermia attenuates these (Table 17.1). In early studies, peak increases in both norepinephrine and epinephrine occurred when the heart and lungs were excluded from the circulation (21,22). However, norepinephrine and epinephrine were found to peak at different times. In a recent study, patients undergoing cardiac surgery were randomly assigned to have CPB with mild (34°C) or moderate (28°C) hypothermia. With both bypass temperatures, peak norepinephrine concentrations were observed after release of the aortic cross-clamp and rewarming, whereas peak epinephrine concentrations were observed at the target hypothermic temperature (23). Neonates, infants, and young children, much like adults, demonstrate marked increases in catecholamine concentrations during CPB (2,24,25).

"Deeper" planes of general anesthesia (whether accomplished with larger doses of synthetic opioids, addition of a propofol infusion, higher concentrations of volatile anesthetic vapors, or addition of epidural anesthesia) significantly reduce the catecholamine concentrations of patients undergoing coronary artery bypass surgery compared with patients less deeply anesthetized (26–29). Furthermore, in critically ill neonates undergoing correction of congenital heart disease, deeper planes of general anesthesia from large intravenous doses of sufentanil not only produced lower catecholamine concentrations in response to CPB (Fig. 17.4) but also reduced mortality compared with lighter planes of general anesthesia with halothane/morphine (2). Consistent with these observations regarding anesthetic depth, infusion of propofol during bypass (4 mg/kg/hr) resulted in markedly reduced concentrations of epinephrine and norepinephrine compared with a single bolus injection of diazepam 0.1 mg/kg (27). Addition of thoracic epidural anesthesia to a "high-dose opioid" general anesthetic, including either fentanyl or sufentanil, significantly reduces catecholamine concentrations during and after bypass relative to concentrations measured without thoracic epidural anesthesia (28,29) (Fig. 17.5).

FIG 17.4. Perioperative changes in plasma epinephrine and norepinephrine in neonates undergoing cardiac surgery with either high-dose sufentanil (; n = 30) or halothane-morphine (; n = 15) anesthesia. Pre CPB, before bypass; DHCA, after deep hypothermic circulatory arrest; End OP, end of operation; 6 hr, 12 hr, 24 hr, 6, 12, or 24 hours after operation. p values determined with Mann-Whitney U test. (From Anand KJS, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1–9, with permission.)


FIG 17.5. Effects of thoracic epidural anesthesia with bupivacaine 0.5% (, n = 8) versus control (, n = 9) on catecholamine concentrations measured during coronary artery surgery. All 17 patients studied received general anesthesia with sufentanil 20 g/kg. Samples were obtained 1) before anesthesia, 2) after anesthesia induction, 3) after 30 min of surgery, 4) after 30 min of cardiopulmonary bypass (CPB), 5) after 60 min of CPB, 6) 1 hr after CPB, 7) 2 hr after CPB, 8) 4 hr after CPB, 9) 6 hr after CPB, and 10) 24 hr after CPB. *p < 0.05, **p < 0.01 for between group differences. Adrenaline, epinephrine; NA, noradrenaline or norepinephrine. (From Moore CM, Cross MH, Desborough JP, et al. Hormonal effects of thoracic extradural analgesia for cardiac surgery. Br J Anaesth 1995;75:387–393, with permission.)


The effect of pulsatile perfusion on catecholamine concentrations during CPB remains controversial (16,30). Although early studies demonstrated that catecholamine concentrations were increased during bypass whether or not pulsatile perfusion was used (16), a more recent study of elective coronary surgery patients showed significant reductions in epinephrine and norepinephrine concentrations with pulsatile perfusion (30) (Fig. 17.6).

FIG 17.6. Effects of pulsatile (PP) and nonpulsatile (NP) perfusion on catecholamine responses in 30 patients undergoing coronary artery bypass grafting. Pulsatile perfusion significantly reduced both epinephrine and norepinephrine concentrations during bypass. Values are means ± SE. (From Minami K, Körner MM, Vyska K, et al. Effects of pulsatile perfusion on plasma catecholamine levels and hemodynamics during and after cardiac operations with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:82–91, with permission.)


Some increase in catecholamine concentrations during and after bypass may be unavoidable with current anesthetic and surgical techniques; nevertheless, higher doses of opioids, inhaled general anesthetics, and epidural local anesthesia can limit the increases.

Adrenal cortical hormones

Secretion of cortisol is one of the central features of the metabolic stress response (18). In the classic studies by Hume et al. (31) of patients undergoing major surgery (without bypass perfusion), cortisol concentrations rose quickly to a maximum and then slowly returned to baseline 24 hours postoperatively. CPB modifies cortisol responses to surgery. Total plasma cortisol concentrations typically decrease immediately upon initiation of bypass, likely as a consequence of hemodilution (32–35) (Fig. 17.7). During bypass, cortisol concentrations return to values significantly above baseline values (2,32–36). After CPB, patients exhibit markedly elevated concentrations of cortisol (both free and total) for more than 48 hours (35–37). Free cortisol remains elevated for 24 hours. Tinnikov et al. (38) studied 14 children undergoing repair of ventricular septal defects with deep hypothermia and circulatory arrest without the use of extracorporeal circulation. Maximal perioperative concentrations of cortisol and minimal perioperative concentrations of cortisol binding globulin were recorded at the first assessment after circulatory arrest. Thus, hypothermia and circulatory arrest initiate a cortisol-stress response even in the absence of bypass perfusion.

FIG 17.7. The effects of either enflurane or fentanyl anesthesia with or without dexamethasone treatment on cortisol and adrenocorticotropic hormone responses to cardiac surgery. All groups demonstrated significant increases in both cortisol and adrenocorticotropic hormone in response to surgery. The combination of fentanyl and dexamethasone significantly attenuated the adrenocorticotropic hormone response to surgery relative to the other three groups ( = p<0.05 compared with the no dexamethasone, no fentanyl group; = p<0.05 compared with the dexamethasone-treated, no fentanyl group). (From Raff H, Norton AJ, Flemma RJ, et al. Inhibition of the adrenocorticotropin response to surgery in humans: interaction between dexamethasone and fentanyl. J Clin Endocrinol Metab 1987;65:295–298, with permission.)


Cortisol responses during bypass appear to be perfusion temperature-dependent. Taggart et al. (39) showed that the rise in cortisol concentration during CPB can be blunted by perfusion with blood at 20°C rather than at the more usual 28°C. Cortisol concentrations during bypass were decreased by deeper planes of anesthesia in both adults and children (2,35,36) (Fig. 17.8). Stenseth et al. (28) found that compared with high-dose fentanyl anesthesia alone, high-dose fentanyl anesthesia plus thoracic epidural anesthesia resulted in a delayed increase in cortisol concentrations during coronary artery surgery and lower concentrations during bypass. Similarly, Moore et al. (29) found that thoracic epidural anesthesia combined with sufentanil 20 g/kg was associated with markedly lower cortisol concentrations compared with sufentanil anesthesia alone.

FIG 17.8. Cortisol responses during and after correction of congenital heart lesions with either halothane-morphine (n = 15, ) or sufentanil (n = 30, ) anesthesia. The narcotic-based techniques significantly attenuated the "stress" response to cardiac surgery. (From Anand KJS, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1–9, with permission.)


CPB modifies adrenocorticotropic hormone responses in surgical patients. In the previously mentioned study by Hume et al. (31), surgical patients not undergoing bypass showed no increase in cortisol concentrations after an injection of adrenocorticotropic hormone, indicating that adrenal secretion of cortisol was already maximal. Amado and Diago (40) observed a blunted response to corticotropin-releasing hormone during bypass, similar to responses seen in patients with hypothalamic corticotropin-releasing hormone deficiency. In contrast, when patients undergoing extracorporeal perfusion received adrenocorticotropic hormone, cortisol concentrations increased (32). Taylor et al. (41) measured a progressive fall in adrenocorticotropic hormone concentrations during bypass, with a subsequent increase 1 hour after pulsatile perfusion was restored. More recently, Raff et al. (34) showed that although neither high-dose fentanyl anesthesia nor dexamethasone 40 mg alone blunted the increase in adrenocorticotropic hormone concentration in response to CPB, concurrent administration of both agents significantly reduced the adrenocorticotropic hormone concentration (Fig. 17.7).

Unlike some other hormones, cortisol and adrenocorticotropic hormone responses to CPB have generally not been influenced by pulsatile perfusion. To be sure, one study found that total plasma cortisol rose during pulsatile bypass but fell dramatically in patients undergoing nonpulsatile perfusion (33). In another study, patients with and without pulsatile perfusion showed initial increases in cortisol, adrenocorticotropic hormone, and aldosterone, followed by a gradual decline in concentrations of all three hormones during bypass and then a subsequent increase in all three hormones after bypass perfusion (42). After correction for the effect of hemodilution, there was no decrease in calculated free cortisol concentrations and a slight increase in adrenocorticotropic hormone concentrations, irrespective of whether pulsatile perfusion was used. In children undergoing bypass with either pulsatile or nonpulsatile perfusion, Pollock et al. (43) found large increases in cortisol and adrenocorticotropic hormone during CPB, followed by a slow decline toward baseline concentrations of both hormones over 24 hours with both pulsatile and nonpulsatile CPB techniques.

Although there is no evidence for true adrenocortical hypofunction during or after CPB, the inflammatory response initiated by the triad of blood contact with the foreign surfaces of the extracorporeal membrane, reperfusion injury, and endotoxemia may be attenuated by large doses of exogenous glucocorticoids (44). This inflammatory response triggers tissue injury in the heart, kidneys, hemostatic system, and especially the lung, which is the only organ exposed to the entire cardiac output. Previous investigations have studied small numbers of cardiac surgery patients randomized to variable doses of different corticosteroids (most commonly 1 mg/kg dexamethasone or 30 mg/kg methylprednisolone) initiated at varying intervals between induction of anesthesia and the start of CPB (44). Unfortunately, few if any of these studies have addressed outcome issues such as morbidity and mortality, intensive care unit or hospital length of stay, and other aspects of hospital resource utilization. Rather, process variables of the inflammatory pathways were used as surrogate endpoints. Thus, results generally demonstrate an amelioration of the inflammatory response, with decreases in cytokine formation (tumor necrosis factor and the interleukin-1, -6, and -8) but inconsistent effects on C3a and elastase concentrations. Leukotrienes such as LTB4 are decreased in a dose-dependent fashion (44). In addition, large doses of methylprednisolone can block upregulation of neutrophil integrin adhesion receptors, whereas dexamethasone decreases endothelial production of certain adhesion molecules (45). Clinically, glucocorticoid therapy may result in an increased cardiac index and decreased systemic vascular resistance (46). Dietzman et al. (47) showed improvement in tissue perfusion and a decrease in peripheral vascular resistance when a large dose of glucocorticoid was given just before bypass (48). Routine glucocorticoid supplementation has also been advocated as part of an accelerated recovery program (49), albeit without much supporting evidence.

In summary, current data nearly uniformly demonstrate large increases in cortisol and adrenocorticotropic hormone concentrations with initiation of bypass. These rises may be attenuated by deeper planes of general anesthesia or addition of thoracic epidural anesthesia to general anesthesia. Pulsatile perfusion does not appear to reduce these exaggerated responses. Moreover, it is not clear whether elevated corticosteroid concentrations during bypass are deleterious or beneficial.

Glucose homeostasis

Carbohydrate metabolism is regulated by insulin, glucagon, cortisol, growth hormone, and epinephrine, the concentrations of which are generally perturbed during and after CPB. After onset of CPB, blood glucose concentrations rise steadily (50–52). Despite marked hyperglycemia, insulin concentrations decline from their control values during hypothermic bypass (50–52). Normoglycemia can be maintained only with great difficulty during hypothermic nonpulsatile CPB in nondiabetic adults, even with large doses of insulin. Thus, hyperglycemia, hypoinsulinemia, and insulin resistance are produced by hypothermic nonpulsatile CPB in adults (50–52).

Counter-regulatory hormones also decline from pre-bypass concentrations during hypothermic bypass (53). With rewarming, insulin concentrations rise spontaneously to appropriate high levels; nonetheless, blood glucose remains elevated (51). Normoglycemia is better preserved in children undergoing hypothermic CPB when washed red blood cells rather than conventional packed cells (suspended in adenine-glucose-mannitol-saline) are used in the pump priming solution (53,54). Blood glucose concentrations in packed red cells range from 400 to 700 mg/dL (54).

Concentrations of glucose, insulin, and glucagon are higher during normothermic than hypothermic CPB (52,55). Nagaoka et al. (50) compared pulsatile with nonpulsatile perfusion in patients undergoing cardiac surgery with moderate hypothermia (body temperature approximately 26°C). In both groups, blood glucose concentrations increased with CPB and rose further with hypothermia, reaching values greater than 200 mg/dL (Table 17.2). Blood glucose concentrations remained elevated for at least 5 hours postoperatively, but the patients receiving pulsatile perfusion showed a more rapid return to baseline glucose concentration than did patients receiving nonpulsatile perfusion. Insulin concentration, C peptide concentration, and the insulin-to-glucagon molar ratio increased significantly compared with baseline during pulsatile but not during nonpulsatile CPB. Type I ("juvenile onset") diabetics require no greater doses of insulin to control blood glucose during CPB than do nondiabetic control subjects, whereas type II ("adult onset") diabetics exhibit marked insulin resistance compared with type I diabetics and nondiabetic control patients during CPB (52). Children receiving deeper anesthesia demonstrated lower blood glucose concentrations upon termination of bypass than did children receiving lighter anesthetic techniques (2,56) (Fig. 17.9).

FIG 17.9. Total fentanyl dose is inversely correlated with blood glucose concentrations in 24 children undergoing correction of congenital heart disease with hypothermic circulatory arrest (but without profound hypothermia or circulatory arrest). Blood samples were withdrawn within 30 minutes after cessation of bypass. p = 0.0007 for the slope of the regression line. (From Ellis DJ, Steward DJ. Fentanyl dosage is associated with reduced blood glucose in pediatric patients after hypothermic cardiopulmonary bypass. Anesthesiology 1990;72:812–815, with permission.)


In patients undergoing coronary artery surgery, growth hormone was found to increase significantly during and after CPB (57,58). The increase in growth hormone could be prevented using opioid general anesthetic techniques (58). The physiologic significance of this growth hormone response is unclear, because it can be inhibited by prior administration of somatostatin without an effect on glucose or glutamine metabolism.

ATRIAL NATRIURETIC FACTOR

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Atrial natriuretic factor denotes a family of biologically active peptides first isolated from cardiac atria (59). These peptides, released in response to atrial distention, increase glomerular filtration; inhibit renin release; reduce aldosterone concentrations in blood; antagonize renal vasoconstrictors such as vasopressin, norepinephrine, and angiotensin; and reduce arterial blood pressure. Atrial natriuretic factor regulates vascular volume by increasing sodium excretion and decreasing vasomotor tone (59).

Plasma atrial natriuretic factor has been measured before, during, and after CPB, with conflicting conclusions. Patients with cardiac valve lesions, especially those with arrhythmias and congestive failure, may demonstrate elevated preoperative atrial natriuretic factor concentrations, whereas coronary artery surgery patients may have normal preoperative atrial natriuretic factor concentrations (60–64). In one study, no significant changes were noted during induction of anesthesia or during CPB; however, after separation from CPB, both arterial and venous concentrations of atrial natriuretic factor increased in these patients having coronary artery surgery (64). In contrast, most other studies found significant alterations of atrial natriuretic factor concentrations during bypass, particularly during aortic cross-clamping. Curello et al. (62) measured atrial natriuretic factor in patients undergoing either coronary artery bypass or mitral valve replacement for mitral stenosis (Fig. 17.10). Although there was no change in atrial natriuretic factor concentrations during bypass in the coronary surgery group, patients undergoing mitral valve replacement demonstrated significantly reduced concentrations during CPB. After release of the aortic clamp, atrial natriuretic factor concentrations in both groups of patients rose to values equal to those found preoperatively in the mitral valve patients (62).

FIG 17.10. Measurements of plasma atrial natriuretic factor (ANF) in six patients undergoing aortocoronary bypass () and eight patients undergoing mitral valve replacement (•). Data are presented as means ± SEM. Despite large differences between the groups before aortic clamping, differences were minimal during and early after the ischemic period. (From Curello S, Ceconi C, De Giuli F, et al. Time course of human atrial natriuretic factor release during cardiopulmonary bypass in mitral valve and coronary artery diseased patients. Eur J Cardiothorac Surg 1991;5:205–210, with permission.)


Nearly identical responses were observed by Northridge et al. (65) in their study of 12 patients undergoing aortocoronary bypass grafting with hypothermic nonpulsatile perfusion. In another study, arterial concentrations of atrial natriuretic factor decreased significantly after aortic cross-clamping (66). Interestingly, this study also found evidence for atrial natriuretic factor release from the brain during bypass. Ashcroft et al. (61) found a significant reduction in atrial natriuretic factor concentrations during bypass, with return to baseline values postoperatively. Haug et al. (67) studied 33 patients undergoing coronary artery surgery and found significantly increased concentrations of atrial natriuretic factor after CPB, with a further increase measured at the end of surgery that was maintained in measurements 24 hours after the operation. Pasaoglu et al. (68) found that atrial natriuretic factor concentrations were elevated (relative to normal values) before induction of anesthesia for coronary artery surgery. Atrial natriuretic factor concentrations increased significantly (relative to baseline values) after surgical incision and remained elevated during and after surgery, with the highest mean values recorded on the fifth postoperative day; however, no measurements were made during CPB. In 16 patients undergoing aortocoronary bypass grafting or mitral valve replacement, atrial natriuretic factor concentrations decreased significantly during hypothermic extracorporeal perfusion and aortic cross-clamping (63).

Two recent studies comparing atrial natriuretic factor concentrations in systemic and pulmonary venous and arterial blood identified secretion of atrial natriuretic factor into the left atrium and its clearance by the lungs in adults and children (66,69). Atrial natriuretic factor concentrations declined significantly during aortic cross-clamping, but rebounded rapidly after release of the aortic clamp (62,65,66).

Multiple studies of both children and adults demonstrated no correlation between atrial pressure and atrial natriuretic factor concentration during and after cardiac surgery. This is particularly apparent when patients demonstrated paradoxical increased atrial natriuretic factor concentrations during rewarming, despite reduced atrial pressure at the time (60,62,63,65,66,69,70). After CPB, urine flow and sodium excretion increased concurrently with increased atrial natriuretic factor and normal vasopressin concentrations; thus, this diuresis could be the result of elevated atrial natriuretic factor concentrations (70). The relationship between atrial natriuretic factor concentration and atrial pressure remained abnormal in the first few hours after bypass but returned to normal after 24 hours (60,63). Despite no correlation between atrial pressure and atrial natriuretic factor concentrations during bypass, a 30-minute infusion of atrial natriuretic factor (1.67 g/min) significantly increased urinary output and sodium excretion compared with placebo, indicating preserved end-organ responses to the hormone during bypass (71) (Fig. 17.11).

FIG 17.11. Diuresis and natriuresis in response to atrial natriuretic factor (n = 6, ) or placebo (n = 6, ) infused during cardiopulmonary bypass. Responses were recorded during and after drug administration. V, urine volume; UNaV, urine sodium concentration times urine volume. (From Hynynen M, Palojoki R, Heinonen J, et al. Renal and vascular effects of atrial natriuretic factor during cardiopulmonary bypass. Chest 1991;100:1203–1209, with permission.)


Amano et al. (72) infused 1 mL/kg of 10% saline to patients before and after heart or lung operations. Patients having lung surgery showed normal atrial natriuretic factor responses to saline before and after surgery; conversely, patients showed a normal increase in atrial natriuretic factor with saline infusion before undergoing cardiac surgery but had no significant response to the same stimulus delivered after surgery (72).

In summary, the preponderance of recent evidence suggests that atrial natriuretic factor concentrations are reduced during CPB, especially during hypothermia and aortic cross-clamping. Decreases in hormone concentration are most evident in patients with preoperative elevations in atrial natriuretic factor, which is especially common with valvular heart disease. Most patients will demonstrate distinctly elevated atrial natriuretic factor concentrations (relative to those measured during aortic cross-clamping) during rewarming and after discontinuation of bypass. Finally, patients will fail to demonstrate the normal relationship between atrial natriuretic factor concentrations and atrial pressure during bypass and the early postoperative period or the normal response of atrial natriuretic factor to saline infusion after bypass.

RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

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The renin-angiotensin-aldosterone axis regulates arterial blood pressure, intravascular volume, and electrolyte balance (73). The renal juxtaglomerular apparatus secretes renin in response to sodium depletion, falls in blood volume, or reduced renal perfusion. Conversely, factors that increase blood volume, renal perfusion, and sodium load inhibit the release of renin. The sympathetic nervous system stimulates renin release in response to pain, emotion, and stress. Renin catalyzes the conversion of angiotensinogen to the decapeptide angiotensin I in the blood. Angiotensin-converting enzyme, present in blood vessel walls (particularly of the pulmonary vasculature), catalyzes the conversion of angiotensin I to angiotensin II (an octapeptide). Conversion of angiotensin I to angiotensin II is nearly complete during a single pass through the lungs. Angiotensin II raises blood pressure through two mechanisms: direct vasoconstriction and stimulation of aldosterone secretion by the adrenal glands. Aldosterone stimulates the renal distal tubules to reabsorb sodium and secrete potassium and hydrogen ions into tubular fluid.

Serial measurements taken before, during, and after CPB have shown that renin activity increases during and shortly after CPB (64). Similarly, angiotensin II and aldosterone concentrations rise significantly during and shortly after bypass in patients undergoing nonpulsatile perfusion (74–77). Pulsatile perfusion during CPB eliminates the intraoperative and postoperative increases in plasma renin activity and postoperative increases in both angiotensin II and aldosterone (77,78) (Fig. 17.12). Goto et al. (79) found no significant differences between pulsatile and nonpulsatile perfusion on concentrations of renin, angiotensin II, or aldosterone, with concentrations of all three hormones declining upon initiation of CPB and only aldosterone increasing during and after CPB.

FIG 17.12. Pulsatile perfusion () reduces concentrations of angiotensin II and aldosterone (versus nonpulsatile perfusion, •) during cardiopulmonary bypass. (From Nagaoka H, Innami R, Arai H. Effects of pulsatile cardiopulmonary bypass on the renin-angiotensin-aldosterone system following open heart surgery. Jpn J Surg 1988;18:390–396, with permission.)


Angiotensin-converting enzyme concentrations change markedly during and after cardiac surgery; however, if corrected for hemodilution, minimal response to CPB or hypothermia is observed (22). Absolute and corrected concentrations of angiotensin-converting enzyme are depressed during rewarming, after separation from bypass, and during the first 24 hours of recovery (22,80,81). By 24 hours after bypass, angiotensin-converting enzyme concentrations recover to baseline values (80,81). Secretion of angiotensin-converting enzyme into the vascular compartment by the lungs remains diminished in the period immediately after CPB (22,80,81). These studies suggest that depression of angiotensin-converting enzyme activity during CPB begins after the induction of hypothermia but before rewarming (22). Angiotensin-converting enzyme concentration may also serve as a biologic marker of thyroid hormone [free triiodothyronine (T3)] action during and after cardiac surgery (81).

The role of the renin-angiotensin-aldosterone axis in the maintenance of blood pressure and peripheral vascular resistance during and after CPB remains unclear (82). Preoperative administration of an angiotensin-converting enzyme inhibitor did not impair blood pressure regulation during anesthesia and CPB (83). Two studies have documented that concentrations of renin, angiotensin II, and aldosterone during bypass did not correlate with intraoperative or postoperative hypertension (75,76). In another study, postoperative hypertension and the need for vasodilators were associated with high vasopressin concentrations but not with angiotensin II concentrations (82). A fourth study found that postoperative hypertension could not be related to elevated renin levels; moreover, hypertension was not treated effectively by saralasin blockade of angiotensin II (84). Similarly, preoperative administration of angiotensin-converting enzyme inhibitors failed to prevent hypertension after coronary artery bypass grafting (83). Thus, the preponderance of evidence would suggest that both intraoperative and postoperative hypertension is at best only loosely related to the abnormal concentrations of renin, angiotensin II, or aldosterone seen during and after bypass.

THYROID

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A variety of acute illnesses leads to alterations of peripheral thyroid hormone metabolism. Characteristically, serum concentrations of T3 (the active thyroid hormone species) are reduced, thyroxine (T4) is normal or reduced, free thyroxine is reduced, and thyrotropin (thyroid-stimulating hormone) concentrations are normal, producing the so-called sick euthyroid syndrome (85). Multiple studies have documented the presence of this syndrome during and after CPB in adults and children. Recent evidence confirms the sick euthyroid syndrome also is seen in patients undergoing normothermic (35 ± 1°C) CPB (86). In theory, the concentration of T3 would be especially important for patients having cardiac surgery because T3 regulates the number of -adrenergic receptors and their sensitivity to agonists (87). Jones et al. (88) demonstrated a frequent (greater than 10%) incidence of preoperative abnormalities in thyroid function in patients undergoing CPB. Nevertheless, there appeared to be no association between abnormal laboratory results and adverse outcome (88).

Before CPB, administration of heparin leads to small increases in free T3 and free T4, because heparin displaces hormones from binding proteins (89–92). Total T3 concentrations drop precipitously with bypass and remain depressed 24 hours after surgery (22,87,93,94) (Fig. 17.13). T3 values corrected for hemodilution (using albumin concentration) are not altered by the initiation of CPB or by the initiation of hypothermic perfusion (22). Similarly, the free and the dialyzable fractions of T3 increase after the onset of bypass and hypothermia (22,89). These alterations in T3 and T4 during bypass are independent of thyrotropin-stimulating hormone secretion because adjustments in T3 and T4 concentrations normally are delayed by 2 to 4 hours after a change in thyrotropin-stimulating hormone concentration (95). Absolute thyrotropin-stimulating hormone and total T3 concentrations return to normal after surgery, at a time that varies from study to study (94,96).

FIG 17.13. Response of free T3 concentration to cardiovascular surgery in 14 patients. T3 declined during cardiopulmonary bypass (CPB) and then declined further during the first 24 hours after operation. Concentrations of free T3 during cardiac surgery in 14 patients. Concentrations were measured preoperatively (Pre), after administration of heparin (Hep), after initiation of CPB (CPB), at the nadir of hypothermia (Hypo), after rewarming (Warm), and at 2 (2 Hr), 8 (8 Hr), and 24 hours (24 Hr) after CPB. Statistical comparisons were made between the preoperative and subsequent measurements. (From Holland FW II, Brown PS Jr, Weintraub BD, et al. Cardiopulmonary bypass and thyroid function: a "euthyroid sick syndrome." Ann Thorac Surg 1991;52:46–50, with permission.)


The central regulating mechanism for thyroid hormone is the thyrotropin-releasing hormone-thyrotropin axis in the hypothalamus and pituitary gland. In adults, thyrotropin concentrations are unchanged during normothermic bypass; however, thyrotropin declines upon initiation of hypothermic bypass and then steadily rises during perfusion (89,93) (Fig. 17.14). During the first postoperative day, thyrotropin concentrations decline below baseline values (81,93,97). During and shortly after CPB, the normal increase in thyrotropin concentration in responses to exogenous administration of thyrotropin-releasing hormone is blunted (97–99) (Fig. 17.15). Because of the reduced total T3 concentrations during bypass, an increased sensitivity to thyrotropin-releasing hormone might have been anticipated. The cause of this pituitary hypofunction remains unknown; however, rises in endogenous dopamine (100) or somatostatin (101) concentrations or nonpulsatile blood flow to the anterior pituitary gland are possible etiologies (99).

FIG 17.14. Effect of cardiovascular surgery on thyroid-stimulating hormone (TSH) concentration in 44 patients. TSH reached its nadir 6 hours after bypass and remained low through the fourth postoperative day. Statistical comparisons (as indicated on the figure) all compare subsequent TSH concentrations versus those measured before anesthesia. (From Chu S-H, Huang T-S, Hsu R-B, et al. Thyroid hormone changes after cardiovascular surgery and clinical implications. Ann Thorac Surg 1991;52:791–796, with permission.)


FIG 17.15. Serum thyrotropin hormone response to thyrotropin-releasing hormone (TRH) in euthyroid subjects before, 1 day after, and 1 week after coronary bypass surgery with hypothermic nonpulsatile perfusion. TSH, thyroid stimulating hormone. (From Zaloga GP, Chernow B, Smallridge RC, et al. A longitudinal evaluation of thyroid function in critically ill surgical patients. Ann Surg 1985;201:456–464, with permission.)


Children undergoing correction of congenital heart disease demonstrate thyroid hormonal responses similar to those of adults, demonstrating the sick euthyroid syndrome at 24 hours after surgery (102) (Fig. 17.16). Curiously, patients having deep hypothermia and circulatory arrest demonstrate better preservation of the relationship between thyrotropin and T3 during and early after CPB than do patients undergoing cardiac repair without circulatory arrest. Deep hypothermia with circulatory arrest may better preserve the hypothalamo-pituitary axis than conventional hypothermic bypass without circulatory arrest (102). Nevertheless, any benefit is only transitory: At 24 hours patients demonstrate decreased thyrotropin and T3 concentrations whether or not circulatory arrest was used (102). Murzi et al. (103) measured concentrations of thyroid hormones for up to 8 days after correction of congenital heart defects and observed return of thyrotropin concentrations to baseline preoperative values by the third postoperative day; nevertheless, T3 concentrations continued to be depressed below baseline values at the seventh postoperative day. Mainwaring et al. (104) studied 10 neonates undergoing either repair of D-transposition of the great arteries or total anomalous pulmonary venous drainage. Free T3 was unchanged immediately after institution of bypass but was significantly reduced 1 hour and 1 day after surgery. Five days after surgery, free T3 was increasing but remained significantly less than baseline values. Thyrotropin was significantly reduced relative to baseline during CPB, 1 hour and 1 day after the operation. Five days postoperatively, the thyrotropin concentration was significantly increased relative to baseline, consistent with a normal relationship between thyrotropin and T3. Saatvedt and Lindberg (105) associated depressed concentrations of T3 after CPB in children with elevated concentrations of interleukin-6, an inflammatory cytokine that has been shown to decrease secretion of thyrotropin, T3, and T4 in rats (106).

FIG 17.16. Concentrations of free triiodothyronine (T3) and thyrotropin (TSH) in infants and young children undergoing correction of congenital heart disease with cardiopulmonary bypass (CPB) (n = 12) or CPB and deep hypothermic circulatory arrest (DHCA) (n = 11). Blood samples were obtained PreCPB, after anesthesia induction before heparin; CPB1, immediately after onset of bypass; CPB2, during cooling, halfway to the target temperature; CPB3, at the lowest core temperature (CPB group); CPB4, during rewarming; CPB5, just before separation from CPB; PostCPB, after placement of sternal wires; POD1, on the morning after surgery; POD2, on the second morning after surgery. Note that both groups have inappropriately low TSH concentrations given the free T3 concentrations on the first and second postoperative days. (From Ririe DG, Butterworth JF, Hines M, et al. Effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep hypothermia? Anesth Analg 1998;87:543–548, with permission.)


In an early study, pulsatile flow during bypass maintained a normal thyrotropin response to exogenously administered thyrotropin-releasing hormone, contrasting with the abnormal responses observed during nonpulsatile perfusion (107). In a more recent study of pulsatile flow in 30 patients undergoing coronary artery surgery, Buket et al. (108) found sharp decreases in free and total T3 and thyrotropin upon initiation of bypass whether or not pulsatile perfusion was used. Later measurements demonstrated a lesser decrease in free and total T3 in patients undergoing pulsatile bypass compared with nonpulsatile bypass (108). Patients making an uncomplicated recovery from surgery demonstrated a sharp increase in thyrotropin, total T3, and total T4 on day 4 after surgery, whereas patients with complications after surgery did not demonstrate such pronounced increases in these hormone concentrations (94).

These studies of thyroid function during and after CPB may have important clinical implications. T3 serves to regulate cardiac rate, contractility, and oxygen consumption. Cyclic AMP production in response to -adrenergic receptor agonists is markedly reduced in hypothyroid cardiac, adipose, and hepatic tissue. Cyclic AMP regulates intracellular calcium transients and myocardial contractility (109,110). Experimental studies have shown improved myocardial contractility in animals receiving T3 after CPB (111,112). Patients with preoperative left ventricular ejection fraction greater than 40% receiving T3 demonstrated significantly greater cardiac outputs after CPB than control patients. Patients with preoperative left ventricular ejection fraction less than 40% receiving T3 required much less dobutamine and furosemide than did control patients (113). On the other hand, two recent controlled clinical trials failed to show that patients receiving T3 prophylactically were less likely to require inotropic drug support than those receiving placebo (114,115).

Caution must be exercised in considering thyroid replacement in patients with concurrent hypothyroidism and chronic ischemic heart disease, however. Levothyroxine or T3 hormone replacement therapy may precipitate myocardial ischemia and infarction, or even adrenal insufficiency. Indeed, patients with mild to moderate hypothyroidism appear to tolerate cardiac surgery without excess morbidity or mortality, though practitioners must be cognizant of the potential for delayed emergence from anesthesia, hypotension, bleeding, and the need for exogenous corticosteroids (116).

EICOSANOIDS

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The lungs are actively involved in the metabolism of vasoactive substances, including eicosanoids; thus, the separation of the lungs from the circulation during extracorporeal perfusion may significantly alter the plasma concentrations and kinetics of prostaglandins and thromboxanes (117). The endoperoxide prostaglandin H2can isomerize (catalyzed by isomerases) into PGE2, PGF2, or PGD2, or be chemically converted (catalyzed by either prostacyclin or thromboxane synthetase, respectively), into either prostacyclin (PGI2) or thromboxane (TXA2). The predominant prostaglandins formed in the bronchial tree and in the pulmonary vasculature are prostaglandin E2and prostacyclin (PGI2) (117,118). PGEs are dilators in most vascular beds. PGD2and PGF2 are pulmonary vasoconstrictors. In addition to synthesis and release of prostaglandins, the lungs are a major site for metabolism of prostaglandins of the E and F types (117). These substances are nearly completely cleared during a single passage through the pulmonary circulation. PGI2can disaggregate platelets and act as a potent vasodilator (117). Conversely, thromboxane A2potently stimulates platelet aggregation and vasoconstricts.

Concentrations of 6-keto-prostaglandin F1 (the stable metabolite of prostacyclin) rose significantly after aortic and atrial cannulation and remained elevated during CPB in children and adults (118–124). 6-Keto-prostaglandin F1 concentrations rose at the beginning of bypass, continued rising upon aortic clamping, but decreased progressively after termination of bypass and reperfusion of the lungs. There were no significant differences between patients undergoing cardiac surgery with or without bypass (122).

Thromboxane B2(the stable metabolite of thromboxane A2) concentrations increased and reached peak arterial levels just before termination of bypass, a markedly different pattern from that seen in patients undergoing cardiac surgery without bypass (122) (Fig. 17.17). After completion of the cardiac repair and discontinuation of CPB, concentrations of prostacyclin and thromboxane metabolites decreased progressively (118–121,123,124). Compared with adults, children have greater and more sustained increases in thromboxane metabolites (121,123). Infants undergoing extracorporeal membrane oxygenation, a form of long-term CPB, demonstrate increased prostacyclin metabolite concentrations after initiation of therapy (125). With continued use of extracorporeal membrane oxygenation, prostacyclin metabolite concentrations slowly fell. Prostacyclin metabolite concentrations rose again as the patients were weaned from extracorporeal membrane oxygenation; concentrations remained elevated for about a day thereafter (125).

FIG 17.17. Thromboxane metabolite (TxB2) concentrations in children undergoing correction of congenital heart defects either with (n = 21) or without (n = 9) cardiopulmonary bypass (CPB). See the legend to Figure 17.12 for details of sampling. The CPB group demonstrated significantly elevated concentration compared with the non-bypass (control) group. (From Greeley WJ, Bushman GA, Kong DL, et al. Effects of cardiopulmonary bypass on eicosanoid metabolism during pediatric cardiovascular surgery. J Thorac Cardiovasc Surg 1988;95:842–849, with permission.)


Although increased concentrations of prostacyclin and thromboxane during bypass may have important effects on systemic and pulmonary vascular resistance and vasoreactivity, studies have not shown a consistent effect (118,121). Administration of the protease inhibitor aprotinin reduces the surge in thromboxane B2associated with bypass but has no effect on 6-keto-prostaglandin F1 concentrations (122). These aprotinin-induced changes in prostaglandin metabolism were associated with better preserved platelet function, potentially significant in preventing postoperative hemorrhage.

A rapid increase in prostaglandin E2concentrations at the onset of CPB has been confirmed in several studies (118,120) (Fig. 17.18). Minimal differences between arterial and venous concentrations confirm limited prostaglandin E2metabolism in the lungs during CPB (120). Prostaglandin E2concentrations fall promptly after termination of bypass and reinstitution of pulmonary perfusion. Aspiration of shed pulmonary venous blood from open pleural cavities reduces mean arterial pressure during CPB and increases systemic concentrations of prostaglandin E2and 6-keto-prostaglandin F1, probably as a consequence of the high concentrations of prostaglandin E2and 6-keto-prostaglandin F1 measured in shed pulmonary venous blood (126).

FIG 17.18. Prostaglandin E2 concentration in arterial and venous plasma samples before, during, and after cardiopulmonary bypass (CPB) in seven patients having coronary bypass. Stars indicate a significant change from the preceding measurement. Circled stars indicate a significant difference between arterial and venous values. (From Faymonville ME, Deby-Dupont G, Larbuisson R, et al. Prostaglandin E2, prostacyclin, and thromboxane changes during nonpulsatile cardiopulmonary bypass in humans. J Thorac Cardiovasc Surg 1986;91:858–866, with permission.)


In summary, the role of prostanoids and thromboxanes in producing desired or adverse effects during bypass remains controversial. Perhaps most significant in maintaining this controversy is the usual practice of measuring agent concentrations in systemic blood, which ignores the importance of prostanoids and thromboxanes in local regulation of blood flow within organs.

OTHER HUMORAL EFFECTS

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Histamine

Elevated blood concentrations of histamine may produce vasodilation and hypotension. Numerous drugs administered to patients undergoing cardiac surgery will induce histamine release, including opioids (especially morphine and meperidine), muscle relaxants (especially tubocurarine), antibiotics, heparin, and protamine (127). Current anesthetic practice favors the use of agents that have negligible likelihood of inducing histamine release. In adults, plasma histamine concentrations rise at the time of systemic heparinization and remain elevated throughout the period of CPB (128). Comparable measurements of histamine concentration in children are problematic because, unlike adults, children often have blood products added to priming solutions used for CPB to prevent excessive hemodilution (54,129). Marath et al. (129) measured markedly elevated histamine concentrations in over 70% of blood product-containing priming solutions before their use during pediatric CPB, prompting speculation by these authors that the delivery of this massive histamine load to patients could have adverse effects. In children, particularly striking increases in histamine concentrations occur at the time the aortic cross-clamp is released, probably from reperfusion of the lungs (130). Infusion of prostacyclin during CPB diminishes the concentrations of histamine (128). van Overveld et al. (131) prevented elevated concentrations of histamine in serum during and after CPB for coronary artery surgery by administering methylprednisolone 30 mg/kg during induction of anesthesia. Histamine concentrations in patients with the cold urticaria syndrome, a relatively rare disorder, are increased nearly 10-fold during hypothermic CPB (132). In current practice, elevated histamine concentrations may be of greatest concern when blood-containing priming solutions are used or when histamine-releasing agents must be administered.

CALCIUM

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The availability of calcium ions in the sarcoplasmic reticulum determines the magnitude of the increased intracellular calcium concentrations during depolarizations, which regulates the inotropic state of the heart (133). Calcium ions are also necessary for normal electrical conduction and rhythm of the heart. Calcium in blood exists in three fractions: ionized (approximately 50%), protein bound (approximately 40%), and chelated (approximately 10%). The free ionized fraction is the physiologically active component. In critical illnesses, the distribution of calcium among these forms can be altered; thus, measurements of total calcium may be misleading (134). The blood calcium concentration is maintained within the normal range by parathormone and 1,25-dihydroxycholecalciferol (calcitriol or vitamin D) actions on bone and kidney. Parathormone secretion is stimulated by decreasing ionized calcium concentration, overt hypocalcemia, and by mild hypomagnesemia. Parathormone secretion is suppressed by rising or normal (unchanging) ionized calcium concentrations and by severe hypomagnesemia.

Changes in the total and ionized calcium fractions during and after CPB are influenced by the inclusion of exogenous calcium salts or blood products in the pump priming solution and by the frequent administration of calcium salts at discontinuation of extracorporeal perfusion. Clinical studies uniformly demonstrate a fall in ionized calcium concentration upon initiation of CPB (135–148). When blood-free priming solutions are used during bypass, both total and ionized calcium decrease as a consequence of hemodilution; ionized calcium concentrations may further decrease if albumin (which binds calcium) is added to priming solutions (147). Total calcium, total magnesium, ultrafiltrable magnesium (analogous to ionized magnesium), and total protein likewise decline upon initiation of CPB (147). During cardiac surgery, parathormone concentrations rise appropriately in response to declines in ionized calcium concentration and in response to rising ionized calcium concentrations.

As has been demonstrated in other circumstances, there is hysteresis in the relationship between parathormone and ionized calcium concentrations measured intraoperatively (147–149). Change in ionized calcium concentration and the absolute concentration regulates parathormone secretion. When ionized calcium concentration is rising in response to increased concentrations of parathormone, secretion of parathormone will decrease at ionized calcium concentrations below "normal" that would elicit increased parathormone secretion if approached from a higher rather than a lower initial ionized calcium concentration.

Studies of parathormone concentrations using assays sensitive only to the intact hormone have found reductions at the beginning of bypass, increases to maximal concentrations during hypothermia, and a slow return toward normal values as ionized calcium concentrations approach normal values during rewarming (147). It should be noted that some early studies, using assays sensitive to both parathormone and its biologically inactive fragments, have reported falls in parathormone concentration upon initiation of bypass without appropriate increases in response to hypocalcemia thereafter (138).

Studies in adults have demonstrated that reduced magnesium concentrations do not influence the response of the calcium-parathyroid-vitamin D axis during CPB (147). Calcium and parathormone concentrations and responses were identical in patients receiving magnesium salt supplementation during bypass and in control patients in which magnesium concentrations were permitted to fall without correction. Calcitriol (vitamin D) is a fat-soluble vitamin; thus, it is not surprising that calcitriol concentrations are minimally altered by hemodilution and CPB and that this vitamin plays a minimal role in the alterations in calcium concentration seen during cardiac surgery (147).

CPB is managed differently in infants and young children than in adults. Even with the use of smaller sized extracorporeal circuits, priming solution volumes represent a much greater fraction of the pediatric patient's blood volume, and blood products are often included in the priming solutions to avoid excessive degrees of hemodilution (53,54). However, the responses of the calcium-parathyroid-calcitriol axis in 12 infants and 6 young children were similar to those of adults (148). Despite demonstrating much greater declines in ionized calcium concentration upon initiation of CPB, infants' parathyroid hormone concentrations peaked at values similar to those achieved by children and adults (147,148) (Fig. 17.19). Moreover, parathyroid gland "sensing" of increasing and decreasing ionized calcium concentrations was also similar, with infants and young children demonstrating hysteresis in a similar manner to adults (147–149). Infants and young children differed from adults in that ionized calcium concentrations did not recover as completely before termination of CPB. This was likely a consequence of the considerably shorter duration of bypass in the children compared with the adults that were studied, although impaired bone reabsorption in response to parathyroid hormone could not be ruled out. There are important clinical implications from these studies. Unlike the case for many other hormones, parathormone secretion is minimally altered by hypothermic CPB (147,148). Ionized hypocalcemia, even to severe degrees, produced no obvious adverse effects during these studies (143,147,148). Moreover, hypercalcemia may lead to accelerated adenosine triphosphate breakdown (a calcium-dependent process) and unnecessarily increase contractility and myocardial oxygen consumption (150). Systemic hypocalcemia coupled with anoxic cardiac arrest and calcium-free cardioplegia may lead to a beneficial reduction in adenosine triphosphate breakdown (151). Rewarming and reperfusion after aortic clamp removal, essential for resynthesis of high energy phosphates, should be accompanied by minimal myocardial oxygen consumption. Exogenous calcium during this time might unnecessarily increase the myocardial inotropic state, leading to depletion of adenosine triphosphate.

FIG 17.19. Response of the calcium-magnesium-parathormone-calcitriol axis to coronary artery bypass grafting. Cai , ionized calcium; PTH, parathormone; Vit D, calcitriol; MgT , total magnesium; Tot. prot, total protein. Measurements were performed 1) before anesthesia, 2) after induction of anesthesia, 3) after heparin administration, 4) 2 minutes after initiation of bypass, 5) 5 minutes after aortic cross-clamping, 6) early during rewarming, 7) shortly before separation from bypass, and 8) during sternal closure after bypass. Data are presented as means ± SEM. Asterisks denote significant deviation from control values. (From Robertie PG, Butterworth JF IV, Royster RL, et al. Normal parathyroid hormone responses to hypocalcemia during cardiopulmonary bypass. Anesthesiology 1991;75:43–48, with permission.)


The empirical use of calcium salts at the end of CPB (supposedly for inotropic support) is almost a tradition in cardiac surgery, despite limited evidence of clinical efficacy in controlled trials and the usual absence of serious hypocalcemia in adult patients. In addition, excessive use of calcium salts is a possible cause of perioperative pancreatitis (147,152–159) and may also reduce the efficacy of -adrenergic receptor agonists (152–155,160). Ideally, calcium salts should be administered only when all of the following three conditions are met: bypass is about to be terminated, ionized calcium concentration is reduced, and increased inotropy and blood pressure are needed for resumption of full myocardial activity.

MAGNESIUM

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Magnesium is the second most abundant intracellular cation (after potassium) and is a key cofactor in enzyme systems maintaining transmembrane electrolyte gradients and energy metabolism, enzymes involved in synthesis of second messengers (e.g., adenylyl cyclase), ion channels, and hormone secretion and action (e.g., insulin and parathormone) (161). Much like calcium, magnesium in the blood exists in three fractions: ionized (approximately 55%), chelated (approximately 15%), and protein bound (approximately 30%). The ultrafiltrable fraction includes only the ionized and chelated fractions and, due to the small contribution from the chelated ions, approximates the ionized fraction (162). Because there is a dynamic equilibrium between intracellular and extracellular magnesium, the magnesium concentration in blood may be normal in the presence of magnesium depletion.

Cardiac surgery patients frequently develop hypomagnesemia, which may be due to insufficient dietary intake, increased excretion (secondary to diuretics), diabetes, aminoglycoside antibiotics, cardiac glycosides, ethanol abuse, pancreatic disease, or administration of citrated blood products or albumin (161,163–165). Blood magnesium concentrations decrease during and after CPB in adults and children (147,148,163–167). During CPB, total magnesium concentrations decline in concert with the ultrafiltrable fraction as a consequence of chelation by albumin and other blood products and hemodilution (147). Urinary excretion of magnesium during bypass is not increased (164). Magnesium concentrations, unlike calcium concentrations, once reduced during CPB, return to normal only slowly in the absence of active treatment because of the lack of a specific hormonal regulatory system (147,148) (Fig. 17.19).

Hypomagnesemia in the post-bypass period commonly contributes to cardiac dysrhythmias (165,167). Infusion of magnesium salts prevents hypomagnesemia and its complications during and after CPB (147,167). During CPB, cardiac muscle is preferentially depleted of magnesium (compared with skeletal muscle). Magnesium may suppress arrhythmias by multiple mechanisms that include a direct myocardial membrane effect, a direct or indirect effect on cellular potassium and sodium concentrations, antagonism of calcium entry into cells, prevention of coronary artery vasospasm, antagonism of catecholamine action (168), or improvement of the myocardial oxygen supply/demand ratio (169). In addition, magnesium may also inhibit the calcium current during the plateau phase of the myocardial action potential. Finally, magnesium may also inhibit dysrhythmias by antagonizing accumulation of excess intracellular calcium induced by ischemia-related mediators such as lysophosphatidylcholine (170).

Supplemental magnesium decreases the incidence of dysrhythmias after cardiac surgery as noted above and during myocardial ischemia or infarction (171–173). The Leicester Intravenous Magnesium Intervention II Trial used 8 mmol of magnesium sulfate acutely, followed by 65 mmol as a continuous infusion over 24 hours in patients having an acute myocardial infarction (174). This intervention significantly reduced both mortality (p = 0.04) and left ventricular failure (p = 0.009) without producing excess hypotension. A meta-analysis of 930 patients with myocardial infarction concluded that intravenous magnesium reduced ventricular tachycardia and fibrillation by 49% and decreased overall mortality by 54% (175).

Magnesium is a critical cofactor for numerous cellular enzymes and partially regulates transmembrane calcium movement (176). Magnesium salts dilate coronary arteries (177), regulate myocardial metabolism (176), lower systemic vascular resistance, protect against catecholamine-induced myocardial necrosis (178), and modify platelet aggregation and thrombus formation. Clinically, magnesium salts are used for the treatment of both atrial and ventricular dysrhythmias (167,171–173,179), coronary artery vasospasm, myocardial ischemia (167,179), myocardial infarction (171–173), pregnancy-induced hypertension, and even therapy of bronchospasm (180).

Moderate magnesium supplementation (1 to 2 g magnesium sulfate intravenously per hour of CPB maintains serum magnesium concentrations greater than 1 mM) has minimal effects on blood pressure in normotensive patients. Renal insufficiency may predispose to magnesium toxicity exhibited as deep tendon hyporeflexia, somnolence, and even respiratory insufficiency. However, only very high concentrations of extracellular magnesium directly depress myocardial contractility. Of special note, though, magnesium potentiates neuromuscular blocking drugs, which may produce clinical weakness and respiratory insufficiency in patients with residual paralysis from previous administration of neuromuscular blocking drugs. Overall, magnesium salts are safe, effective, low-cost therapy that may be used on a routine basis for prevention or treatment of many atrial and ventricular arrhythmias. The routine occurrence of hypomagnesemia during CPB and rapid renal excretion of magnesium allows the clinician to administer moderate doses of magnesium salts empirically without the need for frequent measurement of magnesium blood concentrations.

POTASSIUM

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Maintaining normal blood potassium concentrations is important in cardiac surgical patients. Patients receiving diuretics may come to operation hypokalemic; those with renal failure may be hyperkalemic. During and after CPB, potassium flux is also influenced by myocardial protectant solutions (cardioplegia), anesthetic drugs, priming solutions, renal function, carbon dioxide tension, arterial pH, hypothermia, insulin treatment of hyperglycemia, catecholamine infusion, and mineralocorticoids.

Potassium depletion may occur in as many as 40% of patients having valve surgery (181,182). Hypokalemia, the most frequent abnormality of potassium concentration observed after CPB, is common (183–186). Before the era of potassium cardioplegia, hyperkalemia was uncommon except in patients with diabetes or renal failure. Currently, brief episodes of hyperkalemia may be more common, especially immediately after the release of the aortic cross-clamp. Hyperkalemia may also be more common during normothermic than hypothermic bypass, likely due to the increased volumes of cardioplegic solutions that are required during normothermic bypass (187). Potassium loss during CPB is related to urine flow, implying that urine potassium concentration must remain nearly constant (188). Bumetanide produces less kaliuresis during CPB than furosemide for a similar diuretic response (189). Increased urinary potassium loss is characteristic of the post-bypass period (190).

Moffitt et al. (191) reported that whole blood priming may cause greater decreases in serum potassium than blood-free priming solutions. Maintenance of normocalcemia during CPB may better maintain potassium concentration than the more usual techniques that tolerate hypocalcemia (192,193). The ionic constituents of blood-free priming solutions (other than calcium and potassium ions) have little effect on potassium concentration. Careful studies of potassium intake and output and red blood cell potassium, rates of hemolysis, and serum hemoglobin have shown that much of the fall in serum potassium concentration is not accounted for by dilution or excretion. Likewise, repeated studies have failed to identify the organ into which potassium is lost from blood (194).

In the absence of potassium cardioplegia, the fall in potassium concentration during clinical CPB appears to be proportional to the decrease in body temperature (195). Conversely, potassium concentration increases with warming (196). Blood glucose rises and insulin falls during hypothermic CPB (see previous glucose metabolism discussion). Insulin favors intracellular transport of glucose and potassium.

Increased concentrations of cortisol, aldosterone, and catecholamines during CPB may contribute to hypokalemia. Cortisol and aldosterone increase the urinary excretion of potassium. Catecholamines increase potassium uptake by skeletal muscle and decrease serum potassium (197). -Adrenergic blockade with propranolol inhibits the uptake of potassium by skeletal muscle but does not inhibit the hepatic release of potassium by -adrenergic stimulation and may contribute to hyperkalemia (198). Hypokalemia during CPB may be lessened if albumin is added to the priming solution, because the negatively charged albumin molecules help maintain adequate blood concentrations of positively charged potassium (199).

Potassium concentrations are usually monitored frequently during CPB, although strict normokalemia need be present only when normal cardiac electrical activity is desired (200). Increases in systemic vascular resistance have been observed with bolus intravenous potassium injections of 8 mEq or greater during CPB. With smaller bolus doses, an initial fall followed by a slight rise in systemic vascular resistance is common (201).

In summary, potassium concentrations rarely remain constant during or after CPB. Hypokalemia, formerly a frequent problem during bypass, now is uncommon due to the widespread use of multiple doses of potassium-containing cardioplegic solutions. Postoperative potassium loss and hypokalemia continues to be common after CPB.

METAL IONS: ZINC, COPPER, AND IRON

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Reductions in blood iron and zinc concentrations and increases in copper concentrations occur as part of the nonspecific "acute phase reaction" to trauma, prolonged infections, burns, and major surgery (202). In adults, zinc concentrations decline at the onset of CPB and remain low for 1 to 3 days postoperatively (203–205). Zinc concentrations usually return to normal by the seventh postoperative day. Urinary excretion of zinc is unaffected by cardiac surgery. Taggart et al. (206) monitored iron and zinc concentrations before, during, and after coronary surgery in 20 patients perfused at either 20 or 28°C. Significant alteration of the metal-to-protein molar binding ratios preceded falls in the concentrations of both ions as a consequence of the acute phase reaction to surgical trauma. Patients perfused at 20°C had less alterations of iron and zinc metabolism during surgery than those perfused at 28°C. No differences were seen after surgery, when both groups demonstrated reduced serum iron and zinc concentrations. However, a reduced concentration of iron in blood may be advantageous. Administration of deferoxamine (an iron chelator) was associated with reduced production of free radicals during CPB (207).

Copper concentrations fell rapidly at the onset of bypass but usually returned to normal by the third postoperative day (203,205,206). The alterations in copper concentration appear to be caused by hemodilution (203). Zhao (204) found a more transient (relative to other authors) nadir in blood copper concentration 30 minutes after perfusion, with a return to normal concentrations 1 to 2 days postoperatively and a rise to supranormal concentrations between postoperative days 3 and 9.

Alterations in zinc and copper concentrations in blood were studied in 13 children undergoing correction of congenital heart disease (208). Concentrations of both zinc and copper were markedly reduced (compared with preoperative measurements) 6 hours after CPB. Recovery toward baseline values was not seen in the first postoperative 24 hours but was nearly complete 48 hours after bypass (208).

CONCLUSIONS

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CPB produces widespread alterations in endocrine, humoral, and metabolic functions, some of which may be lessened by the use of pulsatile CPB, larger doses or higher concentrations of general anesthetic drugs, or addition of thoracic epidural anesthesia. The magnitude and direction of these changes may be influenced by the duration of bypass and the techniques used (such as the degree of hypothermia, cardiac venting, and contents of the priming solution). For the most part, the mechanisms for these neuroendocrine alterations during bypass are poorly understood. In only rare patients will endocrine alterations influence the likelihood of successful recovery from surgery. However, the importance of these changes may increase with longer durations of CPB or extracorporeal circulatory support.

KEY POINTS

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  • A variety of pituitary-related hormonal activities is influenced by CPB: ADH and adrenocorticotropin levels increase markedly and thyroid-stimulating hormone levels are typically normal, but T3 and T4 responses to TSH are reduced, consistent with "sick euthyroid syndrome."

  • Adrenal responses affected by CPB include marked increases in catecholamine, aldosterone, and cortisol levels that can be attenuated to varying degrees by deeper anesthesia, thoracic epidural anesthesia, and pulsatile perfusion; and the rise in aldosterone levels is stimulated by activation of the renin-angiotensin system.

  • Hyperglycemia, hypoinsulinemia, and insulin resistance occur with hypothermic nonpulsatile CPB.

  • Atrial natriuretic factor concentrations decrease early in CPB but typically increase during rewarming. The secretion of atrial natriuretic factor in response to the usual physiologic stimuli is blunted during and after CPB.

  • Ionized calcium concentrations decrease at the onset of CPB and then rise slowly toward normal, with physiologic parathormone responses to these changes. Routine calcium supplementation upon emergence from CPB is not recommended.

  • Hypomagnesemia commonly occurs during CPB, and prophylactic treatment of this deficiency with intravenous magnesium supplementation reduces the incidence of post-CPB atrial and ventricular dysrhythmias and may reduce the incidences of coronary vasospasm and myocardial ischemia.

  • Plasma potassium concentrations fluctuate during CPB under the influence of a variety of factors, especially cardioplegia composition and dosing.

References

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