Free
Correspondence  |   February 2004
Alpha-stat Induced Alkalosis: Cause of Neuronal Apoptosis after Deep Hypothermic Perfusion
Author Affiliations & Notes
  • Tadaomi A. Miyamoto, M.D.
    *
  • * Kyoto University, Graduate School of Medicine, Kyoto, Japan.
Article Information
Correspondence
Correspondence   |   February 2004
Alpha-stat Induced Alkalosis: Cause of Neuronal Apoptosis after Deep Hypothermic Perfusion
Anesthesiology 2 2004, Vol.100, 455-456. doi:
Anesthesiology 2 2004, Vol.100, 455-456. doi:
To the Editor:—
We congratulate Ditsworth et al.  for the elegant biochemical demonstration of mechanisms triggering the apoptosis cascade to eventually cause neuronal death following deep hypothermic circulatory arrest (DHCA) in piglets. 1 
The authors dismissed the significantly elevated caspase-8 of the cardiopulmonary bypass (CPB) group (see their figure 5) and declined making any comments regarding it, but how do they explain it? We believe it is the key to interpreting the article in the proper perspective. It is indeed documented that ischemic damage, even though reversible, had occurred without arrest, corroborating numerous reports of the overlooked deleterious effects of α-stat cooling. If circulatory arrest was not induced and α-stat hypothermia was innocuous, one would not anticipate activation of caspase-8 or −3, the case of control animals without CPB.
The authors did not find postrewarming (adenosine triphosphate [ATP]) differences between the various groups. However, the issue is the ATP during cooling just before arrest and after the arrest just before rewarming, not after rewarming, because the described caspase-8 and −3 are activated by ischemia, during which time ATP is depleted.
We postulate that the arrest (ischemic) period was the final blow to activate the pathway of caspase-3 and to trigger the irreversible apoptosis cascade whose grounds had been conditioned by the hypothermia-induced Bohr effect (tissue hypoxia caused by the increased affinity of the oxyhemoglobin), aggravated by the α-stat alkalosis during induction of hypothermia to the point of caspase-8 activation. In the context of ischemia, apoptosis and necrosis must be a continuum, the fate depending on the extent of spared ATP stores;2 necrosis is found in the center of brain infarcts, and apoptosis in the surviving penumbra zone. Alkalosis within pH ranges of 7.0 to 8.0 depresses linearly creatine-kinase mediated phosphorylation (∼ P) reactions;3 the extremes of pH below 7 or above 8 at which linearity is maintained is not known. During deep α-stat hypothermia, the actual pH often exceeds far above 8.0; if sustained long enough the decreased synthesis will lead to ∼ P depletion even without arrest, manifested as significant elevation of caspase-8 in the CPB-only group. We postulate that ∼ is further consumed during the arrest to levels below the threshold limits for activation of caspase-3 and leading to the apoptosis cascade. If arrest time is limited, sufficient ∼ still remains for the recovery of ATP synthesis mechanisms on rewarming and oxygenation, leading to the recovery of postrewarming [ATP] levels similar to controls, thus preventing acute cellular death by necrosis. However, because the apoptosis cascade has been already activated, those cells are destined to die 8 to 72 h post-DHCA without involving ATP at that time.
Following is a brief account of some of the widely documented deleterious effects during α-stat cooling that, despite being significant, were dismissed (as with the caspase-8 in the CPB group in the authors’s study) because of the overwhelming findings of circulatory arrest:
  1. During cooling induction: (a) brain hypoxia, 4 worse with α-stat hypothermia than with pH-stat hypothermia 5; (b) brain lactate production 6; and (c) brain glutamate and nitric oxide release. 7 

  2. During or after rewarming: (d) brain production of hypoxanthine and xanthine. 8 

  3. Functional outcome: (e) the time required for electroencephalographic recovery on rewarming correlated with time to electrocerebral silence, and even minimal hypocarbia increased time to electrocerebral silence;9 (f) worse neurologic performance and worse brain histopathologic injury with longer pre-arrest CPB α-stat cooling duration. 10 

Cerebral oxygen needs below 18°C could theoretically  be met by the dissolved oxygen on which α-stat strategies rely, 11 but dissolved oxygen cannot satisfy requirements at temperatures higher than 18°C, at which the role of oxyhemoglobin (whose dissociation is carbon dioxide–dependent or pH-dependent) is greater. Significant brain lactate production starts during cooling well before arrest, 6 coinciding with brain hypoxia 4,5 and excitotoxicity. 7 Regardless of the temperature, the Ca2+extrusion pump is impaired by alkalosis. Alkalosis increases N  -methyl d-aspartate currents sensitizing to glutamate, 12,13 thus facilitating the intracellular Na+and Ca2+influx that cause cytotoxic edema, especially on reperfusion, which is minimized by acidosis. 14,15 Mild acidosis reduces glutamate neurotoxicity by decreasing the activation of N  -methyl d-aspartate receptors and, consequently, reducing Na+and Ca2+influx, thus minimizing oxygen-glucose deprivation excitotoxic and reperfusion neuronal injury. 12–16 
The issue is preserving the metabolic machinery integrity and ∼ P levels during cooling induction. For millions of years, nature 17 has exploited the protective hyperpolarizing effects of hypothermia due to increased Na+efflux 18 and increased Clconductance 19 of eucapnic ventilation–induced acidosis, which is equivalent to pH-stat perfusion management. Such a strategy maintains aerobic metabolism and integrity of energy requiring membrane pumps, regardless of age, 17 while fully taking advantage of metabolic depression and decreased release of excitatory aminoacids 20 induced by hypothermia.
Our contention that brain hypoxia (Bohr effect) develops with α-stat cooling severely enough to cause injury well before arrest induction has been corroborated by the authors’ elegant study. pH-stat management was demonstrated to be superior both functionally and histopathologically by the same group, 5,21 and it is regrettable that pH-stat–managed (CPB and DHCA) piglets were not included in this study, for we believe that caspase-8 in a CPB group and apoptosis in a DHCA group would have been prevented or greatly minimized. Supplementary intravenous taurine further potentiated, equivalent to 1.2°C, the protection afforded by pH-stat hypothermia. 22 
References
Ditsworth D, Priestley MA, Loepke AW, Ramamoorthy Ch, McCann J, Staple L, Kurth CD: Apoptotic neuronal death following deep hypothermic circulatory arrest in piglets. A nesthesiology 2003; 98: 1119–27Ditsworth, D Priestley, MA Loepke, AW Ramamoorthy, Ch McCann, J Staple, L Kurth, CD
Eguchi Y, Shimizu S, Tsujimoto Y: Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 1997; 57: 1835–40Eguchi, Y Shimizu, S Tsujimoto, Y
Lawson JWR, Veech RL: Effects of pH and free Mg2+on the Keqof the creatine kinase reaction and other phosphate hydrolyses and phosphate transfer reactions. J Biol Chem 1979; 254: 6526–37Lawson, JWR Veech, RL
Nollert G, Nagashima M, Bucerius J, Shin’oka T, Lidov HGW, du Plessis A, Jonas RA: Oxygenation strategy and neurologic damage after deep circulatory arrest: II. Hypoxic versus free radical injury. J Thorac Cardiovasc Surg 1999; 117: 1172–9Nollert, G Nagashima, M Bucerius, J Shin’oka, T Lidov, HGW du Plessis, A Jonas, RA
Kurth CD, O’Rourke MM, O’Hara IB: Comparison of pH-stat and alpha-stat cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets. A nesthesiology 1998; 89: 110–8Kurth, CD O’Rourke, MM O’Hara, IB
Rimpiläinen J, Pokela M, Kiviluoma K, Vainionpää V, Hirvonen J, Ohtonen P, Jäntti V, Anttila V, Heinonen H, Juvonen T: The N-methyl-D-aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: A study in the chronic porcine model. J Thorac Cardiovasc Surg 2001; 121: 957–70Rimpiläinen, J Pokela, M Kiviluoma, K Vainionpää, V Hirvonen, J Ohtonen, P Jäntti, V Anttila, V Heinonen, H Juvonen, T
Tseng EE, Brock MV, Kwon CC, Annanata M, Lange MS, Troncoso JC, Johnston MV, Baumgartner WA: Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest. Ann Thorac Surg 1999; 67: 371–6Tseng, EE Brock, MV Kwon, CC Annanata, M Lange, MS Troncoso, JC Johnston, MV Baumgartner, WA
Pesonen EJ, Peltola KI, Korpela RE, Sairanen HI, Leijala MA, Raivio KO, Andersson SH: Delayed impairment of cerebral oxygenation after deep hypothermic circulatory arrest in children. Ann Thorac Surg 1999; 67: 1765–70Pesonen, EJ Peltola, KI Korpela, RE Sairanen, HI Leijala, MA Raivio, KO Andersson, SH
Stecker MM, Cheung AT, Pochettino A, Kent GP, Patterson T, Weiss SJ, Bavaria JE: Deep hypothermic circulatory arrest: II. Changes in electroencephalogram and evoked potentials during rewarming. Ann Thorac Surg 2001; 71: 22–8Stecker, MM Cheung, AT Pochettino, A Kent, GP Patterson, T Weiss, SJ Bavaria, JE
Kurth CD, Priestley M, Golden J, McCann J, Raghupathi R: Regional patterns of neuronal death after deep hypothermic circulatory arrest in newborn pigs. J Thorac Cardiovasc Surg 1999; 118: 1068–77Kurth, CD Priestley, M Golden, J McCann, J Raghupathi, R
Dexter F, Hindman BJ: Theoretical analysis of cerebral venous blood hemoglobin’s oxygen saturation as an index of cerebral oxygenation during hypothermic cardiopulmonary bypass: a counter-proposal to the “luxury perfusion” hypothesis. A nesthesiology 1995; 83: 405–12Dexter, F Hindman, BJ
Schwiening CJ, Thomas RC: pH consequences of calcium regulation, in pH and brain function. Edited by Kaila K, Ranson B. New York, Wiley-Liss, 1998, pp 277–88
Giffard RG, Weiss JH, Choi DW: Extracellular alkalinity exacerbates injury of cultured cortical neurons. Stroke 1992; 23: 1817–21Giffard, RG Weiss, JH Choi, DW
Lascola CD, Kraig RP: Astroglial pH during and after global ischemia, in pH and brain function. Edited by Kaila K, Ranson B. New York, Wiley-Liss, 1998, pp 583–603
Giffard RG, Monyer H, Christine CW, Choi DW: Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 1990; 506: 339–342Giffard, RG Monyer, H Christine, CW Choi, DW
Ballanyi K, Kaila K: Activity-evoked changes in intracellular pH, in pH and brain function. Edited by Kaila K, Ranson B. New York, Wiley-Liss, 1998, pp 291–308
Lutz PL, Nilsson GE: The brain without oxygen. Austin, Landes Bioscience and Chapman & Hall, 1997, pp 103–88
Chapman RA, Suleiman MS, Rodrigo GC, Minezaki KK, Chatmara KR, Little CR, Mistry DK, Allen TJA: Intracellular taurine, intracellular sodium and defense against cellular damage, Ionic Channels and Effect of Taurine on the Heart. Edited by Noble D, Earm YE, Norwell, Boston, Kluwer Academic Publishers, 1993, pp 73–91
Ferroni S, Nobile M, Caprini M, Rapisarda C: pH modulation of an inward rectifier chloride current in cultured rat cortical astrocytes. Neuroscience 2000; 100: 431–8Ferroni, S Nobile, M Caprini, M Rapisarda, C
Nakashima K, Todd MM: Effects of hypothermia, pentobarbital, and isoflurane on postdepolarization aminoacid release during complete global cerebral ischemia. A nesthesiology 1996; 85: 161–8Nakashima, K Todd, MM
Priestley MA, Golden JA, O’Hara IB, McCann J, Kurth CD: Comparison of neurologic outcome after deep hypothermic circulatory arrest with alpha-stat and pH-stat cardiopulmonary bypass in newborn pigs. J Thorac Cardiovasc Surg 2001; 121: 336–43Priestley, MA Golden, JA O’Hara, IB McCann, J Kurth, CD
Ohno N, Miyamoto KH, Miyamoto TA: Taurine potentiates the efficacy of hypothermia. Asian Cardiovasc Thorac Ann 1999; 7: 267–71Ohno, N Miyamoto, KH Miyamoto, TA