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Con: Glucose priming solutions should not be used for cardiopulmonary bypass
Con: Glucose Priming Solutions Should Not be Used for Cardiopulmonary Bypass Brad H m d m a n , M D
TH ANY THERAPY, potential advantages must outweigh potential risks. In this author's oplmon, the advantages of glucose-containing priming solutions are of minimal clinical importance. The associated risks, on the other hand, are so potentmlly serious that, at least for now, it is prudent to avoid exogenous glucose during cardiopulmonary bypass (CPB).
W
POTENTIAL ADVANTAGES
The advantages of a glucose-containing CPB priming solution were reported by Metz and Keats. I In their study, 107 nondiabetlc patients undergoing elective coronary artery bypass grafting were randomized to receive either lactated Ringer's (LR) or DsLR as priming and maintenance fluid during surgery. During CPB,,the DsLR group had glucose concentrations ranging from 600 to 800 mg/dL, whereas the LR group had glucose concentrations from 200 to 250 mg/dL. During CPB, DsLR patients had greater urine output than LR patients (937 +- 481 v 537 -+ 370 mL, [mean -+ SD], respectively) and required less fired to maintain reservoir volume (144 _+ 270 v 1,147 +-1,149 mL, respectively). As a result, net intraoperative fluid gain was less in the DsLR group than in the LR group (+2,821 _ 805 i, +4,336 _+ 1,278 mL, respectively). On the fifth postoperative day, DsLR patients had lost 1 _+ 3 kg relative to their preoperative weight, whereas LR patients had a weight gain o f l _+ 3kg. Although DsLR patients needed and retained less fluid, there was no other benefit associated with use of DsLR. There was no difference between groups in fluid balance after CPB, nor differences In duration of intubatlon, intensive care unit (ICU) stay, or hospitalization. Thus, although patients will have a little less peripheral edema if the pump is primed with DsLR, in this author's opinion, that is a modest benefit. POTENTIAL RISKS
The risks associated with glucose-containing CPB priming solutions relate mainly to the issue of whether hyperglycemia during CPB might exacerbate neurologic injury occurring during surgery. Current prospective studies indicate that 2% to 6% of adult cardiac surgery patients sustain unequivocal focal neurologic injury (stroke) in the perioperatlve period. 24 Tuman et al found that patients with new central nervous system deficits after coronary artery bypass grafting had three times longer ICU stay (9 +- 11 days v 3 +- 3 days) and nine times greater perioperatwe mortality (36% v 4%) than those free of perioperative neurologic injury. 2 Furthermore, even when the routine neurologic examination is normal, patients are not necessarily free of neurologic injury Impairment of cogmtion, memory, and psychomotor coordination occurs in 30% to 50% of patients whose condition might, on first appearance, appear normal after cardiac surgery. 6,7 Impairment of neuropsychologic performance after cardiac surgery is almost certainly caused by subclinical brain injury. Thus, neurologic complications
are fairly common and pose a very serious threat both to the life and to the quality of life of cardiac surgery patients. The literature uniformly and unequivocally demonstrates that hyperglycemia exacerbates neurologic injuries whenever neurologic insults, either focal s-l° or global, 11-13have an associated reperfusion phase. Hyperglycemia, by providing more substrate for anaerobic glycolysls, results in a greater degree of intracellular lactic acidosis in lschemlc tissue. 14-I8 Ischemic intracellular acidosis is associated with loss of neuronal ion and volume control, lactate clearance, and mitochondnal adenosine triphosphate (ATP) generation. 19 In addition, intracellular acidosis damages endothelial and glial cells such that postischemic blood brain barrier disruption is made worse by hyperglycemia.2° Thus, in cardiac surgical procedures where temporary cerebral ischemia is planned, such as circulatory arrest, avoidance of hyperglycemia is prudent and well justified. Metz and Keats concede this In their original article. I However, most neurologic injuries associated with adult cardiac surgery are probably the result of permanent focal cerebral emboli, either larger atheroemboh from the ascending aorta zl-23 or microemboh from the CPB pump. 24 Although permanent focal lesions have no reperfusion phase, they often have associated zones of marginal viability ("ischemlc penumbra") that depend on residual collateral blood flow and other compensatory mechanisms (increased oxygen extraction, anaerobic ATP generation) to maintain viability.25 The literature is inconsistent as to whether hyperglycemia has beneficial26,27 or detrimental 28,29 effects on penumbral neurons in the setting of permanent focal lschemia. The effect of hyperglycemia on penumbral neurons probably depends both on the level of residual blood flow1° and time. If penumbral blood flow reductions are not too extreme, hyperglycemia can aid penumbral neurons by providing additional substrate for anaerobic ATP generation. 15,16Viability is maintained as long as critical intracellular acidosis does not occur. 14-16Hyperglycemia also appears to inhibit recurrent membrane depolarizations in the penumbra. 3° These depolarizations increase neuronal metabohc demand, 3° further worsening energy depletion, 31 and result in a more extensive infarction. 32,33 Thus, when assessed in the first few hours after the onset of permanent focal lschemia, animal studies find that hyperglycemia appears to reduce infarction volume. 26,z7 Unfortunately, that protection is probably not sustained. Neuronal tolerance to lntracellular acidosis diminishes over time (2 to 6 hours). 34 Thus, although intracellular acidosis may be
From the Department of Anesthesla, Collegeof Med~cme, Untverstty of Iowa, Iowa Cay, IA Address repnnt requests to Brad Hmdman, MD, Department of Anesthesia, College of Medlcme, Umverszty of Iowa, Iowa Czty, 1/1 52245 Copyright © 1995 by W B Saunders Company 1053-0770/95/0905-002553 00/0 Key words cardtopulmonary bypass, brain, glucose, comphcattons
Journal of Cardlothoractc and VascularAnesthesla, Vol 9, No 5 (October), 1995' pp 605-607
605
606
BRAD HINDMAN
tolerated for a while, especially if ATP is generated, acidotic penumbral tissue will eventually progress to infarction. Furthermore, neuronal death secondary to lntracellular acidosis has a latency period as long as 48 hours. 34 Hence, only with long-term evaluation ( > 48 hours) can the final effect of hyperglycemia on infarction volume and neurologic outcome be accurately assessed. In studies where ammals have been allowed to recover for longer periods after permanent focal ischemia (2 to 14 days), the effect of hyperglycemia to mcrease infarction volumes has been marked and unequtvocal. 28.29 Somewhat surprisingly, despite the strong experimental evidence that hyperglycemia should worsen neurologic injuries occurring during cardiac surgery, clinical studies give no indication of this. Metz and Keats reported no neurologic deficits m the DsLR group versus one stroke and one patient with hallucinations in the LR group. I These findings should be accepted with caution. Metz and Keats did not describe either the methods or timing of neurologic examinations. Prospective studies show that only 40% to 60% of new gross neurologic deficits and a far smaller percentage of new subtle findings are detected in routine postoperative evaluations. 35 Thus, for reliable results, a fully trained and experienced neurologic examiner is essential. Given a 2% to 6% stroke rate in large prospectwe studies (discussed previously), the stroke rate reported by Metz and Keats (1 out of 107) appears low and, in this author's opinion, is probably caused by insensitive detection methods. The lack of any new neurologic signs ]n DsLR patients must be viewed with skepticism. Thus, formal neuropsychologic testing might have been a better (more sensitive) way to assess whether hyperglycemia during CPB adversely affected neurologic outcome. To date, studies of the effect of glucose on neuropsychologic outcome after cardiac surgery have been published only in abstract form. 36,37Frasco et al performed neurologic examinations and psychometric tests before and after cardiac surgery in 60 adults. 36 During CPB, blood glucose concentration varied between 103 and 379 mg/dL, and glucose concentrations greater than 250 mg/dL were treated with insulin. Postoperative test scores indicated significant new cognitive dysfunction was present in the study population. Nevertheless, m 11 of 12 tests, there was no correlation between mean glucose during CPB and postoperative neuropsychologic performance. Shevde et al randomized 59 adults to either "tight" glucose control during surgery and CPB (n = 27, mean glucose = 189 mg/dL) or minimal control (n = 28, mean glucose = 269 mg/dL). 37 Although
there was evidence of acute cognitive/neuropsychologic dysfunction on postoperative day 3, there was no difference between groups. Thus, even when sensitive tests of neurologic function have been used, hyperglycemia during CPB has not appeared to adversely affect neurologic outcome. How is it possible to reconcile the apparent discordance between the animal literature and the human literature? In the human studies cited earlier, CPB was conducted with moderate hypothermia. Lundgren et al showed that even mild hypothermia (32 ° to 33°C) markedly attenuates the detrimental effects (both neurologic and histologlc) of hyperglycemia in rats undergoing 10 to 15 minutes of cerebral ischemia. 38 More recently, Dietrich et al have shown that hypothermia (30°C) limits hyperglycemic exacerbation of blood brain barrier disruption after an ischemic result, 2° and Nedergaard et al showed that delayed neuronal necrosis secondary to acidosis could be prevented by a period of hypothermia (32°C).94 Thus, the lack of a detrimental effect of hyperglycemia on neurologic outcome in human CPB studies might possibly be ascribed to the use of hypothermia. The findings of a recent large clinical trial are consistent with that possibility.39 Martin et al observed a greater incidence of neurologic complications (4.5%) in a group of 493 patients randomized to warm ( > 35°C) surgery and CPB as compared with a group of 508 patients randomized to a hypothermic ( < 28°C) technique (1.4%). 39 However, the authors noted that normothermic patients had greater blood glucose concentrations during CPB than did hypothermic patients. It is impossible to know whether worse neurologic outcome in the normothermic group was caused by warmer brain temperatures, greater blood glucose, or the combination of the two. Nevertheless, the implication is clear. During CPB, the normothermic brain is far more likely to be sensitive to the adverse effects of hyperglycemia than the hypothermic brain. SUMMARY
In conclusion, the advantages of glucose-containing CPB priming solutions are quite modest. In contrast, the weight of current evidence strongly supports the notion that hyperglycemia is far more likely to be detrimental than beneficial to a brain challenged by ischemia, especially when there is reperfusion (hypotension or circulatory arrest) or when the brain is normothermic. Because neurologic comphcations pose such a serious threat to cardiac surgery patients, avoidance of hyperglycemia during surgery and CPB seems prudent at this time. Hence, CPB priming solutions should not contain glucose.
REFERENCES
1 Metz S, Keats AS Benefits of a glucose-containing priming solut]on for cardlopulmonary bypass. Anesth Analg 72:428-434, 1991 2 Tuman KJ, McCarthy RJ, Najafi H, et al: Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 104 1510-1517, 1992 3. Zaidan JR, Klochany AI, Martin WM, et al Effect of thiopental on neurologic outcome following coronary artery bypass grafting Anesthesiology 74:406-411, 1991 4. Slogoff S, Reul GJ, Keats AS, et al: Role of perfuslon
pressure and flow m major organ dysfunction after cardlopulmonary bypass. Ann Thorac Surg 50'911-918, 1990 5 Shaw PJ, Bates D, Cartlidge NEF, et al Neurological complications of coronary artery bypass graft surgery: Six month follow-up study. Br Med J 293:165-167, 1986 6. Arts A, Solanes H, Camara ML, et al Arterial line filtration during cardlopulmonary bypass. J Thorac Cardiovasc Surg 91 526533, 1986 7 Shaw PJ, Bates D, Carthdge NEF, et al. Early intellectual dysfuncUon following coronary bypass surgery. Q J Med 58'59-68, 1986
CON: GLUCOSE-PRIMING SOLUTIONS
8. de Courten-Myers GM, Kleinholz M, Wagner KR, et al Fatal strokes in hyperglycemic cats. Stroke 20'1707-1715, 1989 9 Nedergaard M Transient focal lschemia in hyperglycemic rats IS associated with increased cerebral infarction Brain Research 408:79-85, 1987 10. Prado R, Ginsberg MD, Dietrich WD, et al' Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. J Cerebral Blood Flow Metab 8:186-192, 1988 11 Lanier WL, Stangland KJ, Scheithauer BW, et al' The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates Examination of a model. Anesthesiology 66:39-48, 1987 12 Nakaklmura K, Fleisher JE, Drummond JC, et al' Glucose administration before cardiac arrest worsens neurologIc outcome in cats Anesthesiology 72:1005-1011, 1990 13 Warner DS, Glonet TX, Todd MM, et al Insulin-induced normoglycemia improves IschemIc outcome In hyperglycemic rats. Stroke 23:1775-1781, 1992 14. Combs D J, Dempsey RJ, Maley M, et al Relationship between plasma glucose, brain lactate, and mtracellular pH during cerebral ischemia in gerbils. Stroke 21.936-942, 1990 15 Folbergrov~i J, Memezawa H, Smith M-L, et al' Focal and perlfocal changes in tissue energy state during middle cerebral artery occlusion in normo- and hyperglycemic rats. J Cerebral Blood Flow Metab 12'25-33, 1992 16 Wagner KR, Klelnholz M, de Courten-Myers GM, et al Hyperglycemic versus normoglycemlc stroke Topography of brain metabohtes, lntracellular pH, and infarct size J Cerebral Blood Flow Metab 12'213-222, 1992 17. Anderson RV, Slegman MG, Balaban RS, et al Hyperglycemia increases cerebral lntracellular acidosis during circulatory arrest Ann Thorac Surg 54:1126-1130, 1992 18 Wagner SR, Lanier WL Metabolism of glucose, glycogen, and high-energy phosphates during complete cerebral lschemia A comparison of normoglycemlc, chronically hyperglycemic diabetic, and acutely hyperglycemic nondiabetac rats Anesthesiology 81 15161526, 1994 19. Siesjo BK Pathophyslology and treatment of focal cerebral ischemla Part II' Mechanisms of damage and treatment J Neurosurg 77.337-354, 1992 20 Dietrich WD, Alonso O, Busto R' Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrain lschemia in rats Stroke 24.111-116, 1993 21 Blauth CI, Cosgrove DM, Webb BW, et al' Atheroembolism from the ascending aorta An emerging problem in cardiac surgery. J Thorac Cardiovasc Surg 103' 1104-1112, 1992 22 Katz ES, Tunick PA, Ruslnek H, et al Protruding aortic atheromas predict stroke In elderly patients undergoing cardiopulmonary bypass: Experience with intraoperatlve transesophageal echocardiography J Ain Coll Cardiol 20.70-77, 1992 23. D~ivila-Rom~in VG, Barzilal B, Waremg TH, et al' Atherosclerosis of the ascending aorta Prevalence and role as an independent predictor of cerebrovascular events In cardiac patients Stroke 25 2010-2016, 1994
607
24 Blauth CI, Smith PL, Arnold JV, et al: Influence of oxygenator type on the prevalence and extent of microembohc retinal lschemia during cardlopulmonary bypass Assessment by digital image analysis J Thorac Cardlovasc Surg 99 61-69, 1990 25. Sieslo BK. Pathophyslology and treatment of focal cerebral lschemla. Part I Pathophyslology J Neurosurg 77 169-184, 1992 26. Zasslow MA, Pearl RG, Shuer LM, et al. Hyperglycemia decreases acute neuronal lschemic changes after middle cerebral artery occlusion in cats. Stroke 20 519-523, 1989 27. Kraft SA, Larson C, Shuer LM, et al' Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemla. Stroke 21 447-450, 1990 28. de Courten-Myers G, Myers RE, Schoolfield L' Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats Stroke 19'623-630, 1988 29 de Courten-Myers GM, Klelnholz M, Wagner KR, et al Normoglycemla (not hypoglycemia) optimizes outcome from middle cerebral artery occlusion J Cerebral Blood Flow Metab 14.227236, 1994 30 Nedergaard M, Astrup J' Infarct n m Effect of hyperglycemia on direct current potential and [Iac]2-deoxyglucose phosphorylatlon J Cerebral Blood Flow Metab 6'607-615, 1986 31. Back T, Kohno K, Hossmann KA Cortical negatwe DC deflections following middle cerebral artery occlusion and KC1induced spreading depression' Effect on blood flow, tissue oxygenatlon, and electroencephalogram. J Cerebral Blood Flow Metab 14'12-19, 1994 32. Gill R, Andlne P, Hillered L, Persson L, et al' The effect of MK-801 on cortical spreading depression in the penumbral zone following focal lschaemla in the rat. J Cerebral Blood Flow Metab 12.371-379, 1992 33. Chen Q, Chopp M, Bodzln G, et al. Temperature modulation of cerebral depolarization during focal cerebral lschemla in rats. Correlation with Ischemlc Injury J Cerebral Blood Flow Metab 13.389-394, 1993 34 Nedergaard M, Goldman SA, Desal S, et al. Acid-induced death in neurons and gha J Neuroscl 11:2489-2497, 1991 35 Sotanlemi KA Cerebral outcome after extracorporeal circulation Comparison between prospective and retrospectwe evaluations. Arch Neuro140 75-77, 1983 36 Frisco P, Croughwell N, Blumenthal J, et al' Association between blood glucose level during cardiopulmonary bypass and neuropsychIatrlc outcome Anesthesiology 75.A55, 1991 37. Shevde K. Kharode S, Harigopal P Neuropsychologlcal dysfunction following cardiac surgery. The role of intraoperatlve plasma glucose Anesthesiology 81.A222, 1994 38 Lundgren J, Smith ML, Slesjo BK' Influence of moderate hypothermia on lschemic brain damage incurred under hyperglycemic conditions Exp Brain Res 84'91-101, 1991 39. Martin TD, Craver JM, Gott JP, et al' Prospective, randomlzed trial of retrograde warm blood cardioplegia Myocardial benefit and neurologlc threat. Ann Thorac Surg 57'298-304, 1994
TH ANY THERAPY, potential advantages must outweigh potential risks. In this author's oplmon, the advantages of glucose-containing priming solutions are of minimal clinical importance. The associated risks, on the other hand, are so potentmlly serious that, at least for now, it is prudent to avoid exogenous glucose during cardiopulmonary bypass (CPB).
W
POTENTIAL ADVANTAGES
The advantages of a glucose-containing CPB priming solution were reported by Metz and Keats. I In their study, 107 nondiabetlc patients undergoing elective coronary artery bypass grafting were randomized to receive either lactated Ringer's (LR) or DsLR as priming and maintenance fluid during surgery. During CPB,,the DsLR group had glucose concentrations ranging from 600 to 800 mg/dL, whereas the LR group had glucose concentrations from 200 to 250 mg/dL. During CPB, DsLR patients had greater urine output than LR patients (937 +- 481 v 537 -+ 370 mL, [mean -+ SD], respectively) and required less fired to maintain reservoir volume (144 _+ 270 v 1,147 +-1,149 mL, respectively). As a result, net intraoperative fluid gain was less in the DsLR group than in the LR group (+2,821 _ 805 i, +4,336 _+ 1,278 mL, respectively). On the fifth postoperative day, DsLR patients had lost 1 _+ 3 kg relative to their preoperative weight, whereas LR patients had a weight gain o f l _+ 3kg. Although DsLR patients needed and retained less fluid, there was no other benefit associated with use of DsLR. There was no difference between groups in fluid balance after CPB, nor differences In duration of intubatlon, intensive care unit (ICU) stay, or hospitalization. Thus, although patients will have a little less peripheral edema if the pump is primed with DsLR, in this author's opinion, that is a modest benefit. POTENTIAL RISKS
The risks associated with glucose-containing CPB priming solutions relate mainly to the issue of whether hyperglycemia during CPB might exacerbate neurologic injury occurring during surgery. Current prospective studies indicate that 2% to 6% of adult cardiac surgery patients sustain unequivocal focal neurologic injury (stroke) in the perioperatlve period. 24 Tuman et al found that patients with new central nervous system deficits after coronary artery bypass grafting had three times longer ICU stay (9 +- 11 days v 3 +- 3 days) and nine times greater perioperatwe mortality (36% v 4%) than those free of perioperative neurologic injury. 2 Furthermore, even when the routine neurologic examination is normal, patients are not necessarily free of neurologic injury Impairment of cogmtion, memory, and psychomotor coordination occurs in 30% to 50% of patients whose condition might, on first appearance, appear normal after cardiac surgery. 6,7 Impairment of neuropsychologic performance after cardiac surgery is almost certainly caused by subclinical brain injury. Thus, neurologic complications
are fairly common and pose a very serious threat both to the life and to the quality of life of cardiac surgery patients. The literature uniformly and unequivocally demonstrates that hyperglycemia exacerbates neurologic injuries whenever neurologic insults, either focal s-l° or global, 11-13have an associated reperfusion phase. Hyperglycemia, by providing more substrate for anaerobic glycolysls, results in a greater degree of intracellular lactic acidosis in lschemlc tissue. 14-I8 Ischemic intracellular acidosis is associated with loss of neuronal ion and volume control, lactate clearance, and mitochondnal adenosine triphosphate (ATP) generation. 19 In addition, intracellular acidosis damages endothelial and glial cells such that postischemic blood brain barrier disruption is made worse by hyperglycemia.2° Thus, in cardiac surgical procedures where temporary cerebral ischemia is planned, such as circulatory arrest, avoidance of hyperglycemia is prudent and well justified. Metz and Keats concede this In their original article. I However, most neurologic injuries associated with adult cardiac surgery are probably the result of permanent focal cerebral emboli, either larger atheroemboh from the ascending aorta zl-23 or microemboh from the CPB pump. 24 Although permanent focal lesions have no reperfusion phase, they often have associated zones of marginal viability ("ischemlc penumbra") that depend on residual collateral blood flow and other compensatory mechanisms (increased oxygen extraction, anaerobic ATP generation) to maintain viability.25 The literature is inconsistent as to whether hyperglycemia has beneficial26,27 or detrimental 28,29 effects on penumbral neurons in the setting of permanent focal lschemia. The effect of hyperglycemia on penumbral neurons probably depends both on the level of residual blood flow1° and time. If penumbral blood flow reductions are not too extreme, hyperglycemia can aid penumbral neurons by providing additional substrate for anaerobic ATP generation. 15,16Viability is maintained as long as critical intracellular acidosis does not occur. 14-16Hyperglycemia also appears to inhibit recurrent membrane depolarizations in the penumbra. 3° These depolarizations increase neuronal metabohc demand, 3° further worsening energy depletion, 31 and result in a more extensive infarction. 32,33 Thus, when assessed in the first few hours after the onset of permanent focal lschemia, animal studies find that hyperglycemia appears to reduce infarction volume. 26,z7 Unfortunately, that protection is probably not sustained. Neuronal tolerance to lntracellular acidosis diminishes over time (2 to 6 hours). 34 Thus, although intracellular acidosis may be
From the Department of Anesthesla, Collegeof Med~cme, Untverstty of Iowa, Iowa Cay, IA Address repnnt requests to Brad Hmdman, MD, Department of Anesthesia, College of Medlcme, Umverszty of Iowa, Iowa Czty, 1/1 52245 Copyright © 1995 by W B Saunders Company 1053-0770/95/0905-002553 00/0 Key words cardtopulmonary bypass, brain, glucose, comphcattons
Journal of Cardlothoractc and VascularAnesthesla, Vol 9, No 5 (October), 1995' pp 605-607
605
606
BRAD HINDMAN
tolerated for a while, especially if ATP is generated, acidotic penumbral tissue will eventually progress to infarction. Furthermore, neuronal death secondary to lntracellular acidosis has a latency period as long as 48 hours. 34 Hence, only with long-term evaluation ( > 48 hours) can the final effect of hyperglycemia on infarction volume and neurologic outcome be accurately assessed. In studies where ammals have been allowed to recover for longer periods after permanent focal ischemia (2 to 14 days), the effect of hyperglycemia to mcrease infarction volumes has been marked and unequtvocal. 28.29 Somewhat surprisingly, despite the strong experimental evidence that hyperglycemia should worsen neurologic injuries occurring during cardiac surgery, clinical studies give no indication of this. Metz and Keats reported no neurologic deficits m the DsLR group versus one stroke and one patient with hallucinations in the LR group. I These findings should be accepted with caution. Metz and Keats did not describe either the methods or timing of neurologic examinations. Prospective studies show that only 40% to 60% of new gross neurologic deficits and a far smaller percentage of new subtle findings are detected in routine postoperative evaluations. 35 Thus, for reliable results, a fully trained and experienced neurologic examiner is essential. Given a 2% to 6% stroke rate in large prospectwe studies (discussed previously), the stroke rate reported by Metz and Keats (1 out of 107) appears low and, in this author's opinion, is probably caused by insensitive detection methods. The lack of any new neurologic signs ]n DsLR patients must be viewed with skepticism. Thus, formal neuropsychologic testing might have been a better (more sensitive) way to assess whether hyperglycemia during CPB adversely affected neurologic outcome. To date, studies of the effect of glucose on neuropsychologic outcome after cardiac surgery have been published only in abstract form. 36,37Frasco et al performed neurologic examinations and psychometric tests before and after cardiac surgery in 60 adults. 36 During CPB, blood glucose concentration varied between 103 and 379 mg/dL, and glucose concentrations greater than 250 mg/dL were treated with insulin. Postoperative test scores indicated significant new cognitive dysfunction was present in the study population. Nevertheless, m 11 of 12 tests, there was no correlation between mean glucose during CPB and postoperative neuropsychologic performance. Shevde et al randomized 59 adults to either "tight" glucose control during surgery and CPB (n = 27, mean glucose = 189 mg/dL) or minimal control (n = 28, mean glucose = 269 mg/dL). 37 Although
there was evidence of acute cognitive/neuropsychologic dysfunction on postoperative day 3, there was no difference between groups. Thus, even when sensitive tests of neurologic function have been used, hyperglycemia during CPB has not appeared to adversely affect neurologic outcome. How is it possible to reconcile the apparent discordance between the animal literature and the human literature? In the human studies cited earlier, CPB was conducted with moderate hypothermia. Lundgren et al showed that even mild hypothermia (32 ° to 33°C) markedly attenuates the detrimental effects (both neurologic and histologlc) of hyperglycemia in rats undergoing 10 to 15 minutes of cerebral ischemia. 38 More recently, Dietrich et al have shown that hypothermia (30°C) limits hyperglycemic exacerbation of blood brain barrier disruption after an ischemic result, 2° and Nedergaard et al showed that delayed neuronal necrosis secondary to acidosis could be prevented by a period of hypothermia (32°C).94 Thus, the lack of a detrimental effect of hyperglycemia on neurologic outcome in human CPB studies might possibly be ascribed to the use of hypothermia. The findings of a recent large clinical trial are consistent with that possibility.39 Martin et al observed a greater incidence of neurologic complications (4.5%) in a group of 493 patients randomized to warm ( > 35°C) surgery and CPB as compared with a group of 508 patients randomized to a hypothermic ( < 28°C) technique (1.4%). 39 However, the authors noted that normothermic patients had greater blood glucose concentrations during CPB than did hypothermic patients. It is impossible to know whether worse neurologic outcome in the normothermic group was caused by warmer brain temperatures, greater blood glucose, or the combination of the two. Nevertheless, the implication is clear. During CPB, the normothermic brain is far more likely to be sensitive to the adverse effects of hyperglycemia than the hypothermic brain. SUMMARY
In conclusion, the advantages of glucose-containing CPB priming solutions are quite modest. In contrast, the weight of current evidence strongly supports the notion that hyperglycemia is far more likely to be detrimental than beneficial to a brain challenged by ischemia, especially when there is reperfusion (hypotension or circulatory arrest) or when the brain is normothermic. Because neurologic comphcations pose such a serious threat to cardiac surgery patients, avoidance of hyperglycemia during surgery and CPB seems prudent at this time. Hence, CPB priming solutions should not contain glucose.
REFERENCES
1 Metz S, Keats AS Benefits of a glucose-containing priming solut]on for cardlopulmonary bypass. Anesth Analg 72:428-434, 1991 2 Tuman KJ, McCarthy RJ, Najafi H, et al: Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 104 1510-1517, 1992 3. Zaidan JR, Klochany AI, Martin WM, et al Effect of thiopental on neurologic outcome following coronary artery bypass grafting Anesthesiology 74:406-411, 1991 4. Slogoff S, Reul GJ, Keats AS, et al: Role of perfuslon
pressure and flow m major organ dysfunction after cardlopulmonary bypass. Ann Thorac Surg 50'911-918, 1990 5 Shaw PJ, Bates D, Cartlidge NEF, et al Neurological complications of coronary artery bypass graft surgery: Six month follow-up study. Br Med J 293:165-167, 1986 6. Arts A, Solanes H, Camara ML, et al Arterial line filtration during cardlopulmonary bypass. J Thorac Cardiovasc Surg 91 526533, 1986 7 Shaw PJ, Bates D, Carthdge NEF, et al. Early intellectual dysfuncUon following coronary bypass surgery. Q J Med 58'59-68, 1986
CON: GLUCOSE-PRIMING SOLUTIONS
8. de Courten-Myers GM, Kleinholz M, Wagner KR, et al Fatal strokes in hyperglycemic cats. Stroke 20'1707-1715, 1989 9 Nedergaard M Transient focal lschemia in hyperglycemic rats IS associated with increased cerebral infarction Brain Research 408:79-85, 1987 10. Prado R, Ginsberg MD, Dietrich WD, et al' Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. J Cerebral Blood Flow Metab 8:186-192, 1988 11 Lanier WL, Stangland KJ, Scheithauer BW, et al' The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates Examination of a model. Anesthesiology 66:39-48, 1987 12 Nakaklmura K, Fleisher JE, Drummond JC, et al' Glucose administration before cardiac arrest worsens neurologIc outcome in cats Anesthesiology 72:1005-1011, 1990 13 Warner DS, Glonet TX, Todd MM, et al Insulin-induced normoglycemia improves IschemIc outcome In hyperglycemic rats. Stroke 23:1775-1781, 1992 14. Combs D J, Dempsey RJ, Maley M, et al Relationship between plasma glucose, brain lactate, and mtracellular pH during cerebral ischemia in gerbils. Stroke 21.936-942, 1990 15 Folbergrov~i J, Memezawa H, Smith M-L, et al' Focal and perlfocal changes in tissue energy state during middle cerebral artery occlusion in normo- and hyperglycemic rats. J Cerebral Blood Flow Metab 12'25-33, 1992 16 Wagner KR, Klelnholz M, de Courten-Myers GM, et al Hyperglycemic versus normoglycemlc stroke Topography of brain metabohtes, lntracellular pH, and infarct size J Cerebral Blood Flow Metab 12'213-222, 1992 17. Anderson RV, Slegman MG, Balaban RS, et al Hyperglycemia increases cerebral lntracellular acidosis during circulatory arrest Ann Thorac Surg 54:1126-1130, 1992 18 Wagner SR, Lanier WL Metabolism of glucose, glycogen, and high-energy phosphates during complete cerebral lschemia A comparison of normoglycemlc, chronically hyperglycemic diabetic, and acutely hyperglycemic nondiabetac rats Anesthesiology 81 15161526, 1994 19. Siesjo BK Pathophyslology and treatment of focal cerebral ischemla Part II' Mechanisms of damage and treatment J Neurosurg 77.337-354, 1992 20 Dietrich WD, Alonso O, Busto R' Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrain lschemia in rats Stroke 24.111-116, 1993 21 Blauth CI, Cosgrove DM, Webb BW, et al' Atheroembolism from the ascending aorta An emerging problem in cardiac surgery. J Thorac Cardiovasc Surg 103' 1104-1112, 1992 22 Katz ES, Tunick PA, Ruslnek H, et al Protruding aortic atheromas predict stroke In elderly patients undergoing cardiopulmonary bypass: Experience with intraoperatlve transesophageal echocardiography J Ain Coll Cardiol 20.70-77, 1992 23. D~ivila-Rom~in VG, Barzilal B, Waremg TH, et al' Atherosclerosis of the ascending aorta Prevalence and role as an independent predictor of cerebrovascular events In cardiac patients Stroke 25 2010-2016, 1994
607
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