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Pro: Calcium is routinely indicated during separation from cardiopulmonary bypass
PRO AND CON P a u l G. Barash, M D Section Editor
Pro: Calcium Is Routinely Indicated During Separation From Cardiopulmonary Bypass J a m e s A. D i N a r d o , M D , FAAP
NY DEBATE regarding the routine use of calcium during separation from cardiopulmonary bypass (CPB) must address three issues: 1. Does calcium administration facilitate separation from CPB by improving hemodynamics? 2. Is calcium administration during separation from CPB detrimental to myocardium that has experienced an ischemic insult? 3. Is calcium administration during separation from CPB associated with problems in any other organ system?
A
DOES CALCIUM ADMINISTRATION FACILITATE SEPARATION FROM CPB BY IMPROVING HEMODYNAMICS?
Depression of contractility and low systemic vascular resistance (SVR) are common problems encountered during separation from CPB. This is particularly true with the current emphasis on "fast-track" protocols for early extubation using inhalation anesthetic agents and propofol. In addition, the crystalloid and colloid solutions commonly used to prime the CPB circuit are known to induce hypocalcemia. Hypocalcemia reduces myocardial contractility and SVR. Despite normal parathyroid function serum ionized calcium levels at the time of rewarming on CPB are significantly lower than serum ionized calcium levels before CPB or at the time of chest closure. 1,2 Thus, although normal parathyroid function eventually returns serum ionized calcium levels to normal after CPB, serum ionized calcium levels are low at the critical juncture when CPB is terminated. Use of calcium chloride during separation from CPB has been criticized because it does not produce increases in cardiac index and peripheral oxygen delivery and is associated with increases in mean arterial blood pressure (MAP).3,4At the time of separation from CPB, the more important issue is whether calcium administration is associated with enhanced myocardial contractility and increased SVR. Enhancement of myocardial contractility and MAP during separation from CPB has potential to enhance ventricular performance in ways not detectable by simple determination of cardiac index. The ventricle in the postischemic/reperfusion interval is at risk for afterload mismatch. Afterload mismatch is the inability of the ventricle at a given level of contractility to maintain stroke volume in the face of an increased wall stress. Efforts to increase MAP with agents that increase SVR without increasing myocardial contractility (such as phenylephrine) are likely to exacerbate afterload
mismatch. This, in turn, produces ventricular dilatation that may produce functional mitral and tricuspid regurgitation and that definitely further elevates ventricular wall stress. Experimentally, calcium administration is associated with increases in myocardial contractility, and linear relationships between ionized calcium and myocardial contractility have been observed. 5,6 In addition, clinical studies demonstrate the ability of calcium chloride to increase myocardial contractility, MAR and SVR during separation from CPB. Calcium chloride, 5 mg/kg, has been shown to produce just such an effect in coronary artery bypass patients. 7 Calcium chloride, 10 mg/kg, has been shown to increase LV contractility immediately and to produce a slightly slower increase in SVR when used during separation from CPB. 8 Calcium chloride, 10 mg/kg, administered during separation from CPB, has been demonstrated to enhance right ventricular ejection fraction in patients with both normal and impaired right ventricular systolic function.9 This same study demonstrated that calcium administration has no effect on pulmonary vascular resistance (PVR) in patients with both normal and elevated PVR. Use of calcium chloride in cardiac surgical patients has been criticized because it attenuates dobutamine, and epinephrineinduced increases in cardiac index.lQH It should be pointed out that this attenuation was observed in the postoperative period and not during separation from CPB. In fact, calcium chloride, 5 mg/kg, was found to have no significant augmentation or inhibition of epinephrine's hemodynamic effects during separation from CPB.3 The transient nature of calcium chloride's hemodynamic effects (approximately 5 minutes) is ideal for providing the temporary support necessary to facilitate separation from CPB. In patients with good ventricular function and good myocardial preservation, this may be all that is needed. In patients with impaired systolic function, calcium chloride administration provides an initial improvement in contractility and SVR that
From the Department of Anesthesiology, University of Arizona Health Sciences Center, Tucson, AZ. Address reprint requests to James A. DiNardo, MD, FAAP, Associate Professor of Clinical Anesthesiology, PO Box 245114, Tucson, AZ 85724-5114. Copyright © 1997 by W.B. Saunders Company 1053-0770/97/1107-002153.00/0 Key words: calcium chloride, inotropes, vasoactive drugs, cardiopulmonary bypass, myocardial function
Journal of Cardiothoracic and Vascular Anesthesia, Vol 11, No 7 (December), 1997: pp 905-907
905
906
JAMES A. DINARDO
provides a grace period while inotropes and vasoactive agents are titrated and fine-tuned. IS CALCIUM ADMINISTRATION DURING SEPARATION FROM CPB DETRIMENTAL TO MYOCARDIUM THAT HAS EXPERIENCED AN ISCHEMIC INSULT?
Control of cardiac myocyte cytosolic calcium concentration [Ca++]i mediates systolic contraction, diastolic relaxation, and mitochondrial and enzymatic activity. 12,i3[Ca ÷+]i is maintained through the complex mechanisms outlined in Fig 1. In the resting state [Ca++]i is maintained at 100 nmol/L against a 10,000-fold concentration gradient across the sarcolemma primarily through an ATP-dependent Ca ++ pump. Depolarization of the myocyte triggers influx of Ca ++ through voltage-gated L-type Ca ++ channels. This, in turn, triggers release of Ca ++ from sarcoplasrnic reticulurn ryanodine receptor channels. This Ca++-induced release of Ca ++ increases [Ca++]i and allows cytosolic binding of Ca ÷+ to troponin C. This, in turn, induces a conformational change that allows interaction of actin and myosin and subsequent contraction. Generation of oxygen-derived free radicals with consequent oxidative damage and breakdown of Ca ÷÷ homeostasis resulting in increased [Ca++]i have been implicated in producing myocyte injury during reperfusion after transient periods of ischemia. 1446 These two processes are responsible for both stunning (reversible postischemic mechanical dysfunction) and
3-Receptor
Cardiac Myocyte8amolemma
pK°
TPhosphol~m~ban
Jj IGA 2a
3a++bindsto I~qluee~i tGnand
/I IP3 Receptor K
lic ReticularMembr~e) ~
Actin
infarction (myocyte death). Increased [Ca++]i after ischemia and reperfusion may produce excitation-contractionuncoupling and/or decreased myofibrillar sensitivity to Ca++. 15The source of the increased [Ca++] i after ischemia and reperfusion is uncertain, and more than one mechanism is probably involved. Although some authors have implicated impairment of the sarcolemmic Na+/Ca ++ exchanger, 17 others have implicated impairment of the sarcoplasmic reticulum. ~8,19Some or all of these impairments may be mediated through oxygen free radicals. In addition, stimulation of [3-adrenergic receptors may contribute to increased [Ca++]i during ischemia and reperfusion. 12 A two-stage model of Ca ++ homeostasis after ischemia has been proposed. This model is based on the evidence that calcium antagonists and calcium administered at varying stages of reperfusion have opposite effects. 2° It is clear that increases in [Ca++]i are responsible for ischernia-induced myocyte damage during ischemia and the early reperfusion period. Low [Ca +g] reperfusate solutions administered in the early reperfusion period and calcium channel blockers administered before ischemia or early in the reperfusion period improve myocardial function after sustained ischemia. 13,2°Later in the reperfusion period, there is good evidence that agents that increase cytosolic Ca ++, such as catecholamines or increased serum Ca ++, can induce increased or even normal contractile function.2° Providing a reperfusion interval after removal of the aortic cross-clamp during which the perfusate is low in calcium does not preclude use of calcium to enhance hemodynamics during termination of CPB. The timing of intravenous calcium administration to facilitate separation from CPB is important. Based on current understanding of rnyocyte Ca ++ homeostasis, intravenous administration of calcium should take place just before separation from CPB and after an interval of myocardial reperfusion (15-30 minutes) while on full or partial CPB.
IP3
C~++g
?,o,,o
Fig 1. Cardiac myocyte Ca ++ transport systems. (A) Transverse T-tubule and L-type Ca ++ channel, (B) Ca++-induced Ca ++ release through the sarcoplasmic reticulum (SR) ryanodine receptor Ca ++ channel. (C) Ca ++ binding to troponin C induces a conformational change in this inhibitory complex, allowing actin and myosin to interact. (D) Sarcoplasmic reticulum Ca++-ATPase sequesters Ca ++ after excitation-contraction coupling. (E) Calsequestrin and calreticulin bind intra-SR Ca ++, forming a stable matrix. (F) Na+/H + exchanger. (G) Na+/H ++ exchanger, (H) Beta-adrenergic-mediated upregulation of cyclic adenosine monophosphate (cAMP). (I) Select protein kinase C (PKC) isoforms activate phospholamban after activation by cAMR (J) Phospholamban mediates sarcoendoplasmic reticulum calcium ATPase (SERCA) 2a activity. (K) 1,4,5-inositol triphosphate (IP3) receptor-mediated SR Ca ++ channel. (DHP = dihydropyridine.) (Reprinted with permission from the Society of Thoracic Surgeons [The Annals of Thoracic Surgery, 1996, 61, 1273-1280],)
IS CALCIUM ADMINISTRATION DURING SEPARATION FROM CPB ASSOCIATED WITH PROBLEMS IN ANY OTHER ORGAN SYSTEM?
Using multivariate analysis, one study identified perioperative administration of calcium chloride as a significant risk factor in the development of pancreatic cellular injury (hyperamylasernia) after cardiac surgery using CPB. 21 More careful review of the study reveals that the doses of calcium chloride associated with pancreatic cellular injury were quite high (800 mg/rn2 or approximately 1,200 to 1,800 nag). Five to 10 mg/kg of calcium chloride in the average adult patient would be approximately one-quarter to one-half this amount.
CONCLUSION
Calcium chloride (5-10 mg/kg) should be routinely administered to facilitate separation from CPB for the following reasons: 1. Calcium chloride provides reliable, immediate increases in myocardial contractility and SVR that
PRO AND CON
907
provide an optimal hemodynamic state in patients who require augmentation of coronary perfusion pressure, but are at risk for afterload mismatch. 2. Despite normal parathyroid function, relative hypocalcemia exists in patients during the critical interval immediately surrounding separation from CPB. 3. Calcium chloride administration does not acutely influence use of other inotropic or vasoactive agents.
4. No firm evidence exists that calcium chloride administration adversely affects stunned myocardium after an appropriate (15-30 minutes) reperfusion interval. In fact, calcium chloride administration may be beneficial to stunned myocardium in the later phase of reperfusion. 5. Calcium chloride administered in appropriate doses does not increase the risk of pancreatic injury.
REFERENCES
1. Robertie PG, Butterworth JF IV, Royster RL, et al: Normal parathyroid hormone response to hypocalcemia during cardiopulmonary bypass. Anesthesiology 75:43-48, 1991 2. Robertie PG, Butterworth JF IV, Prielipp RC, et al: Parathyroid hormone responses to marked hypocalcemia in infants and young children undergoing repair of congenital heart disease. J Am Coll Cardio120:672-677, 1992 3. Royster RL, Butterworth JF IV, Prielipp RC, et al: A randomized, blinded, placebo-controlled evaluation of calcium chloride and epinephrine for inotropic support after emergence from cardiopulmonary bypass. Anesth Analg 74:3-13, 1992 4. Johnston WE, Robertie PG, Butterworth JF IV, et al: Is calcium or ephedrine superior to placebo for emergence from cardiopulmonary bypass? J Cardiothorac Vasc Anesth 6:528-534, 1992 5. Lang RM, Fellner SK, Neumann A, et al: Left ventricular contractility varies directly with blood ionized calcium. Ann Intern Med 108:524-529, 1988 6. Bristow MR, Schwartz HD, Binetti G, et al: Ionized calcium and the heart: Elucidation of in vivo concentration-response relationships in the open-chest dog. Circ Res 41:565-574, 1977 7. Lappas DG, Drop LJ, Bucktey MJ, et al: Hemodynamic response to calcium chloride during coronary artery surgery. Surg Forum 26:234-235, 1975 8. Shapira N, Schaff HV, White RD, Pluth JR: Hemodynamic effects of calcium chloride injection following cardiopulmonary bypass: Response to bolus injection and continuous infusion. Ann Thorac Surg 37:133-t40, 1984 9. Urban MK, Hines R: The effect of calcium on pulmonary vascular resistance and right ventricular function. J Thorac Cardiovasc Surg 104:327-332, 1992 10. Zaloga GP, Strickland RA, Butterworth JF IV, et al: Calcium
attentuates epinephrine's [3-adrenergic effects in postoperative heart surgery patients. Circulation 81:196-200, 1990 11. Butterworth JF IV, Zaloga GR Prielipp RC, et al: Calcium inhibits the cardiac stimulating properties of dobutamine but not of amrinone. Chest 101:174-180, 1992 12. Meldrum DR, Cleveland JC, Sheridan BC, et al: Cardiac surgical implications of calcium dyshomeostasis in the heart. Ann Thorac Surg 61:1273-1280, 1996 13. Chen RH: The scientific basis for hypocalcemic cardioplegia and reperfusion in cardiac surgery. Ann Thorac Surg 62:910-914, 1996 14. Shen AC, Jennings RB: Myocardial calcium and magnesium in acute ischemic injury. Am J Path 67:417-440, 1972 15. Bolli R: Myocardial "stunning" in man. Circulation 86:16711691, 1992 16. Steenbergen C, Fralix TA, Murphy E: Role of increased cytosolic free calcium concentration in myocardial ischemic injury. Basic Res Cardiol 88:456-470, 1993 17. Silverman HS, Stern MD: Ionic basis ofischemic cardiac injury: Insights from cellular studies. Cardiovasc Res 28:581-597, 1994 18. Chiamvimont N, O'Rourke B, Kamp TJ, et al: Functional consequences of sulfhydryl modification in the pore-forming subunits of cardiovascular Ca ++ and Na + channels. Circ Res 76:325-334, 1995 19. Zucchi R, Ronca-Testoni S, DiNapoli R et al: Sarcoplasmic reticulum calcium uptake in human myocardium subjected to ischemia and reperfusion during cardiac surgery. J Mol Cell Cardiol 28:16931701, 1996 20. Opie L: Myocardial stunning: A role for calcium antagonists during reperfusion? Cardiovasc Res 26:20-24, 1992 21. Fernandez-Del Castillo C, Harringer W, Warshaw AL, et al: Risk factors for pancreatic cellular injury after cardiopulmonary bypass. N Eng J Med 325:382-387, 1991
Pro: Calcium Is Routinely Indicated During Separation From Cardiopulmonary Bypass J a m e s A. D i N a r d o , M D , FAAP
NY DEBATE regarding the routine use of calcium during separation from cardiopulmonary bypass (CPB) must address three issues: 1. Does calcium administration facilitate separation from CPB by improving hemodynamics? 2. Is calcium administration during separation from CPB detrimental to myocardium that has experienced an ischemic insult? 3. Is calcium administration during separation from CPB associated with problems in any other organ system?
A
DOES CALCIUM ADMINISTRATION FACILITATE SEPARATION FROM CPB BY IMPROVING HEMODYNAMICS?
Depression of contractility and low systemic vascular resistance (SVR) are common problems encountered during separation from CPB. This is particularly true with the current emphasis on "fast-track" protocols for early extubation using inhalation anesthetic agents and propofol. In addition, the crystalloid and colloid solutions commonly used to prime the CPB circuit are known to induce hypocalcemia. Hypocalcemia reduces myocardial contractility and SVR. Despite normal parathyroid function serum ionized calcium levels at the time of rewarming on CPB are significantly lower than serum ionized calcium levels before CPB or at the time of chest closure. 1,2 Thus, although normal parathyroid function eventually returns serum ionized calcium levels to normal after CPB, serum ionized calcium levels are low at the critical juncture when CPB is terminated. Use of calcium chloride during separation from CPB has been criticized because it does not produce increases in cardiac index and peripheral oxygen delivery and is associated with increases in mean arterial blood pressure (MAP).3,4At the time of separation from CPB, the more important issue is whether calcium administration is associated with enhanced myocardial contractility and increased SVR. Enhancement of myocardial contractility and MAP during separation from CPB has potential to enhance ventricular performance in ways not detectable by simple determination of cardiac index. The ventricle in the postischemic/reperfusion interval is at risk for afterload mismatch. Afterload mismatch is the inability of the ventricle at a given level of contractility to maintain stroke volume in the face of an increased wall stress. Efforts to increase MAP with agents that increase SVR without increasing myocardial contractility (such as phenylephrine) are likely to exacerbate afterload
mismatch. This, in turn, produces ventricular dilatation that may produce functional mitral and tricuspid regurgitation and that definitely further elevates ventricular wall stress. Experimentally, calcium administration is associated with increases in myocardial contractility, and linear relationships between ionized calcium and myocardial contractility have been observed. 5,6 In addition, clinical studies demonstrate the ability of calcium chloride to increase myocardial contractility, MAR and SVR during separation from CPB. Calcium chloride, 5 mg/kg, has been shown to produce just such an effect in coronary artery bypass patients. 7 Calcium chloride, 10 mg/kg, has been shown to increase LV contractility immediately and to produce a slightly slower increase in SVR when used during separation from CPB. 8 Calcium chloride, 10 mg/kg, administered during separation from CPB, has been demonstrated to enhance right ventricular ejection fraction in patients with both normal and impaired right ventricular systolic function.9 This same study demonstrated that calcium administration has no effect on pulmonary vascular resistance (PVR) in patients with both normal and elevated PVR. Use of calcium chloride in cardiac surgical patients has been criticized because it attenuates dobutamine, and epinephrineinduced increases in cardiac index.lQH It should be pointed out that this attenuation was observed in the postoperative period and not during separation from CPB. In fact, calcium chloride, 5 mg/kg, was found to have no significant augmentation or inhibition of epinephrine's hemodynamic effects during separation from CPB.3 The transient nature of calcium chloride's hemodynamic effects (approximately 5 minutes) is ideal for providing the temporary support necessary to facilitate separation from CPB. In patients with good ventricular function and good myocardial preservation, this may be all that is needed. In patients with impaired systolic function, calcium chloride administration provides an initial improvement in contractility and SVR that
From the Department of Anesthesiology, University of Arizona Health Sciences Center, Tucson, AZ. Address reprint requests to James A. DiNardo, MD, FAAP, Associate Professor of Clinical Anesthesiology, PO Box 245114, Tucson, AZ 85724-5114. Copyright © 1997 by W.B. Saunders Company 1053-0770/97/1107-002153.00/0 Key words: calcium chloride, inotropes, vasoactive drugs, cardiopulmonary bypass, myocardial function
Journal of Cardiothoracic and Vascular Anesthesia, Vol 11, No 7 (December), 1997: pp 905-907
905
906
JAMES A. DINARDO
provides a grace period while inotropes and vasoactive agents are titrated and fine-tuned. IS CALCIUM ADMINISTRATION DURING SEPARATION FROM CPB DETRIMENTAL TO MYOCARDIUM THAT HAS EXPERIENCED AN ISCHEMIC INSULT?
Control of cardiac myocyte cytosolic calcium concentration [Ca++]i mediates systolic contraction, diastolic relaxation, and mitochondrial and enzymatic activity. 12,i3[Ca ÷+]i is maintained through the complex mechanisms outlined in Fig 1. In the resting state [Ca++]i is maintained at 100 nmol/L against a 10,000-fold concentration gradient across the sarcolemma primarily through an ATP-dependent Ca ++ pump. Depolarization of the myocyte triggers influx of Ca ++ through voltage-gated L-type Ca ++ channels. This, in turn, triggers release of Ca ++ from sarcoplasrnic reticulurn ryanodine receptor channels. This Ca++-induced release of Ca ++ increases [Ca++]i and allows cytosolic binding of Ca ÷+ to troponin C. This, in turn, induces a conformational change that allows interaction of actin and myosin and subsequent contraction. Generation of oxygen-derived free radicals with consequent oxidative damage and breakdown of Ca ÷÷ homeostasis resulting in increased [Ca++]i have been implicated in producing myocyte injury during reperfusion after transient periods of ischemia. 1446 These two processes are responsible for both stunning (reversible postischemic mechanical dysfunction) and
3-Receptor
Cardiac Myocyte8amolemma
pK°
TPhosphol~m~ban
Jj IGA 2a
3a++bindsto I~qluee~i tGnand
/I IP3 Receptor K
lic ReticularMembr~e) ~
Actin
infarction (myocyte death). Increased [Ca++]i after ischemia and reperfusion may produce excitation-contractionuncoupling and/or decreased myofibrillar sensitivity to Ca++. 15The source of the increased [Ca++] i after ischemia and reperfusion is uncertain, and more than one mechanism is probably involved. Although some authors have implicated impairment of the sarcolemmic Na+/Ca ++ exchanger, 17 others have implicated impairment of the sarcoplasmic reticulum. ~8,19Some or all of these impairments may be mediated through oxygen free radicals. In addition, stimulation of [3-adrenergic receptors may contribute to increased [Ca++]i during ischemia and reperfusion. 12 A two-stage model of Ca ++ homeostasis after ischemia has been proposed. This model is based on the evidence that calcium antagonists and calcium administered at varying stages of reperfusion have opposite effects. 2° It is clear that increases in [Ca++]i are responsible for ischernia-induced myocyte damage during ischemia and the early reperfusion period. Low [Ca +g] reperfusate solutions administered in the early reperfusion period and calcium channel blockers administered before ischemia or early in the reperfusion period improve myocardial function after sustained ischemia. 13,2°Later in the reperfusion period, there is good evidence that agents that increase cytosolic Ca ++, such as catecholamines or increased serum Ca ++, can induce increased or even normal contractile function.2° Providing a reperfusion interval after removal of the aortic cross-clamp during which the perfusate is low in calcium does not preclude use of calcium to enhance hemodynamics during termination of CPB. The timing of intravenous calcium administration to facilitate separation from CPB is important. Based on current understanding of rnyocyte Ca ++ homeostasis, intravenous administration of calcium should take place just before separation from CPB and after an interval of myocardial reperfusion (15-30 minutes) while on full or partial CPB.
IP3
C~++g
?,o,,o
Fig 1. Cardiac myocyte Ca ++ transport systems. (A) Transverse T-tubule and L-type Ca ++ channel, (B) Ca++-induced Ca ++ release through the sarcoplasmic reticulum (SR) ryanodine receptor Ca ++ channel. (C) Ca ++ binding to troponin C induces a conformational change in this inhibitory complex, allowing actin and myosin to interact. (D) Sarcoplasmic reticulum Ca++-ATPase sequesters Ca ++ after excitation-contraction coupling. (E) Calsequestrin and calreticulin bind intra-SR Ca ++, forming a stable matrix. (F) Na+/H + exchanger. (G) Na+/H ++ exchanger, (H) Beta-adrenergic-mediated upregulation of cyclic adenosine monophosphate (cAMP). (I) Select protein kinase C (PKC) isoforms activate phospholamban after activation by cAMR (J) Phospholamban mediates sarcoendoplasmic reticulum calcium ATPase (SERCA) 2a activity. (K) 1,4,5-inositol triphosphate (IP3) receptor-mediated SR Ca ++ channel. (DHP = dihydropyridine.) (Reprinted with permission from the Society of Thoracic Surgeons [The Annals of Thoracic Surgery, 1996, 61, 1273-1280],)
IS CALCIUM ADMINISTRATION DURING SEPARATION FROM CPB ASSOCIATED WITH PROBLEMS IN ANY OTHER ORGAN SYSTEM?
Using multivariate analysis, one study identified perioperative administration of calcium chloride as a significant risk factor in the development of pancreatic cellular injury (hyperamylasernia) after cardiac surgery using CPB. 21 More careful review of the study reveals that the doses of calcium chloride associated with pancreatic cellular injury were quite high (800 mg/rn2 or approximately 1,200 to 1,800 nag). Five to 10 mg/kg of calcium chloride in the average adult patient would be approximately one-quarter to one-half this amount.
CONCLUSION
Calcium chloride (5-10 mg/kg) should be routinely administered to facilitate separation from CPB for the following reasons: 1. Calcium chloride provides reliable, immediate increases in myocardial contractility and SVR that
PRO AND CON
907
provide an optimal hemodynamic state in patients who require augmentation of coronary perfusion pressure, but are at risk for afterload mismatch. 2. Despite normal parathyroid function, relative hypocalcemia exists in patients during the critical interval immediately surrounding separation from CPB. 3. Calcium chloride administration does not acutely influence use of other inotropic or vasoactive agents.
4. No firm evidence exists that calcium chloride administration adversely affects stunned myocardium after an appropriate (15-30 minutes) reperfusion interval. In fact, calcium chloride administration may be beneficial to stunned myocardium in the later phase of reperfusion. 5. Calcium chloride administered in appropriate doses does not increase the risk of pancreatic injury.
REFERENCES
1. Robertie PG, Butterworth JF IV, Royster RL, et al: Normal parathyroid hormone response to hypocalcemia during cardiopulmonary bypass. Anesthesiology 75:43-48, 1991 2. Robertie PG, Butterworth JF IV, Prielipp RC, et al: Parathyroid hormone responses to marked hypocalcemia in infants and young children undergoing repair of congenital heart disease. J Am Coll Cardio120:672-677, 1992 3. Royster RL, Butterworth JF IV, Prielipp RC, et al: A randomized, blinded, placebo-controlled evaluation of calcium chloride and epinephrine for inotropic support after emergence from cardiopulmonary bypass. Anesth Analg 74:3-13, 1992 4. Johnston WE, Robertie PG, Butterworth JF IV, et al: Is calcium or ephedrine superior to placebo for emergence from cardiopulmonary bypass? J Cardiothorac Vasc Anesth 6:528-534, 1992 5. Lang RM, Fellner SK, Neumann A, et al: Left ventricular contractility varies directly with blood ionized calcium. Ann Intern Med 108:524-529, 1988 6. Bristow MR, Schwartz HD, Binetti G, et al: Ionized calcium and the heart: Elucidation of in vivo concentration-response relationships in the open-chest dog. Circ Res 41:565-574, 1977 7. Lappas DG, Drop LJ, Bucktey MJ, et al: Hemodynamic response to calcium chloride during coronary artery surgery. Surg Forum 26:234-235, 1975 8. Shapira N, Schaff HV, White RD, Pluth JR: Hemodynamic effects of calcium chloride injection following cardiopulmonary bypass: Response to bolus injection and continuous infusion. Ann Thorac Surg 37:133-t40, 1984 9. Urban MK, Hines R: The effect of calcium on pulmonary vascular resistance and right ventricular function. J Thorac Cardiovasc Surg 104:327-332, 1992 10. Zaloga GP, Strickland RA, Butterworth JF IV, et al: Calcium
attentuates epinephrine's [3-adrenergic effects in postoperative heart surgery patients. Circulation 81:196-200, 1990 11. Butterworth JF IV, Zaloga GR Prielipp RC, et al: Calcium inhibits the cardiac stimulating properties of dobutamine but not of amrinone. Chest 101:174-180, 1992 12. Meldrum DR, Cleveland JC, Sheridan BC, et al: Cardiac surgical implications of calcium dyshomeostasis in the heart. Ann Thorac Surg 61:1273-1280, 1996 13. Chen RH: The scientific basis for hypocalcemic cardioplegia and reperfusion in cardiac surgery. Ann Thorac Surg 62:910-914, 1996 14. Shen AC, Jennings RB: Myocardial calcium and magnesium in acute ischemic injury. Am J Path 67:417-440, 1972 15. Bolli R: Myocardial "stunning" in man. Circulation 86:16711691, 1992 16. Steenbergen C, Fralix TA, Murphy E: Role of increased cytosolic free calcium concentration in myocardial ischemic injury. Basic Res Cardiol 88:456-470, 1993 17. Silverman HS, Stern MD: Ionic basis ofischemic cardiac injury: Insights from cellular studies. Cardiovasc Res 28:581-597, 1994 18. Chiamvimont N, O'Rourke B, Kamp TJ, et al: Functional consequences of sulfhydryl modification in the pore-forming subunits of cardiovascular Ca ++ and Na + channels. Circ Res 76:325-334, 1995 19. Zucchi R, Ronca-Testoni S, DiNapoli R et al: Sarcoplasmic reticulum calcium uptake in human myocardium subjected to ischemia and reperfusion during cardiac surgery. J Mol Cell Cardiol 28:16931701, 1996 20. Opie L: Myocardial stunning: A role for calcium antagonists during reperfusion? Cardiovasc Res 26:20-24, 1992 21. Fernandez-Del Castillo C, Harringer W, Warshaw AL, et al: Risk factors for pancreatic cellular injury after cardiopulmonary bypass. N Eng J Med 325:382-387, 1991