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Is it justified to disregard the Bohr effect during alpha-stat hypothermia?
Ann Thorac Surg 2000;69:971– 82
occur in approximately 33% and 6% of cases, respectively [1]. However, its extension to the right side of the heart is rare. Although massive pulmonary embolism occurs relatively rarely, it can be a major hazard and has resulted in numerous deaths. In 1996 we reported a 60-year-old man as a case of successful management of massive pulmonary tumor embolism from renal cell carcinoma in The Annals of Thoracic Surgery [2]. Five years after the operation the patient is doing well without any sign of metastasis or local recurrence. The patient presented at a local hospital with flank pain and a progressively enlarging abdominal mass. Computed tomographic scan revealed a large enhanced mass, which was diagnosed as renal cell carcinoma in the left kidney and local extension to the infrahepatic inferior vena cava. Awaiting admission to our institute, the patient experienced sudden chest pain and severe shortness of breath at his home. He was admitted as an emergency patient to the local hospital and intubated. Computed tomographic scan on admission showed massive pulmonary emboli in the bilateral pulmonary artery, whereas part of the local extension to the inferior vena cava had disappeared. Radical nephrectomy and resection of the extended tumor in the inferior vena cava were performed in our institute in October 1994. Four days after the nephrectomy, tumor embolectomy of the bilateral pulmonary artery was performed through a median sternotomy using cardiopulmonary bypass with deep hypothermia and intermittent circulatory arrest. According to the TNM classification of renal call carcinoma UICC (International Union Against Cancer) 1997 [3], this case is classified as stage III (T3b, N0, M0). The histopathologic diagnosis was infiltrating type, papillary–alveolar type, granular cell subtype, G2⬎⬎G1, inf beta, pT3c (9.5 ⫻ 5 ⫻ 5 cm), pN0 (0/17), pV2c, ly (⫹). The cut end of the ureter was negative for cancer, and there was a tumor thrombus in the left testicular vein. The postoperative course was uneventful and the patient was discharged from the hospital 4 weeks after the operation. The patient was followed at our outpatient unit. At 5 years after the operation, although some scarring from the pulmonary infarcts was detected, no metastatic lesion was found on computed tomographic scan. As Javidan and associates [4] describe, the 5-year survival rates of renal cell carcinoma are 95% (stage I), 88% (stage II), 59% (stage III), and 20% (stage IV). Compared with other malignant tumors, the survival rate of renal cell carcinoma is relatively high. Our report described a patient who was rescued from the shock and survived long after the surgical management of massive pulmonary tumor embolism due to renal cell carcinoma. The pulmonary emboli should not be considered distant metastases as pulmonary embolism secondary to renal cell carcinoma does not always cause pulmonary metastasis. Masumori and associates [5] reported 2 patients with renal cell carcinoma in whom positive findings on lung perfusion imaging disappeared during follow-up. They suggest that the establishment of pulmonary metastasis requires not only mechanical trapping of carcinoma cells in the pulmonary microvasculature, but an invasive potential of the cells themselves (“seed”) and appropriate microenvironment (“soil”) for enhancing the local growth of cells [5]. Wagner and associates [6] also describe that pulmonary infarcts can “mimic” pulmonary metastases from renal cancer for the same reason. When there is a distant metastasis, it is classified as stage IV, so it is important not to diagnose pulmonary infarcts as pulmonary metastases. As renal cell carcinoma is not very sensitive to radiation therapy and anticancer agents, treatment of the original lesion and immedi© 2000 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
CORRESPONDENCE
973
ate removal of the pulmonary tumor thrombus should improve the long-term results of patients with renal cell carcinoma. Hiroshi Kubota, MD Department of Surgery Tokyo Metropolitan Police Hospital 2-10-41, Fujimi, Chiyodaku 102-8161 Tokyo, Japan Shinichi Takamoto, MD Yutaka Kotsuka, MD Department of Cardiothoracic Surgery University of Tokyo 113-8655 Tokyo, Japan Akira Furuse, MD Department of Cardiothoracic Surgery JR Tokyo General Hospital 151-8528 Tokyo, Japan
References 1. Marshall VF, Middleton RG, Holswade GR, Goldsmith EI. Surgery for renal cell carcinoma in the vena cava. J Urol 1970; 103:414–20. 2. Kubota H, Furuse A, Kotsuka Y, Yagyu K, Kawauchi M, Saito H. Successful management of massive pulmonary tumor embolism from renal cell carcinoma. Ann Thorac Surg 1996; 61:708–10. 3. Sobin LH, Wittekind Ch. International Union Against Cancer (UICC): TNM classification of malignant tumors, 5th ed. New York: Wiley-Liss, 1997:180–2. 4. Javidan J, Stricker HJ, Tamboli P, et al. Prognostic significance of the 1997 TNM classification of renal cell carcinoma. J Urol 1999;162:1277– 81. 5. Masumori N, Iwabe H, Kumamoto E. Studies on pulmonary metastasis of renal cell carcinoma–pulmonary embolism revealed by lung perfusion imaging and the metastasis. Nippon Hinyokika Gakkai Zasshi 1991;82:769–75. 6. Wagner JR, Merino MJ, Pass HI, Linehan WM, Walther MM. Pulmonary infarcts can mimic pulmonary metastases from renal cancer. J Urol 1997;158:1688–90.
Is It Justified to Disregard the Bohr Effect During Alpha-Stat Hypothermia? To the Editor: We read with great interest the timely and long overdue article by Parolari and colleagues, “Cardiopulmonary Bypass and Oxygen Consumption: Oxygen Delivery and Hemodynamics” [1]. The authors are to be congratulated for having clinically demonstrated beyond any doubt that O2 extraction is decreased during even mild to moderate hypothermic (28°C to 30°C) alpha-stat perfusion, which was attributed to redistribution of blood. They speculate that higher O2 delivery could possibly be obtained by manipulating the vascular resistance. It seems that the very cause was missed. The problem probably lies in the impaired O2 delivery caused by the increased O2 affinity of hemoglobin during hypothermia, aggravated by alkalosis to the point of developing tissular hypoxia (Bohr effect), which may result in redistribution of blood flow through the microvascular beds. The body fails to extract, ie, become hypoxic, because hemoglobin does not release the O2. Alpha-stat strategies during hypothermic perfusion have been preferred for 25 to 30 years against physiologic principles that have proved to be effective for millions of years. Nature has adapted to 0003-4975/00/$20.00
974
CORRESPONDENCE
temperature changes and prevented hypoxia through the evolutionary scale of the animal kingdom using hemoglobin as the pigment to carry O2 by increasing the O2 delivery capabilities and changing the paCO2 readily achieved by respiratory rate changes to maintain eucapnia, ie, pH-stat strategy. Indeed better cardiovascular function (hemodynamics) could be preserved during surface-induced hypothermia (without pump) down to 20°C in dogs [2] and down to 29°C in rabbits [3] by maintaining eucapnia (monitoring expiratory CO2 concentration and adjusting ventilation to obtain 5%) or minimal hypercapnia (5.5%) below 32°C. Alpha-stat results in alkalosis. Alkalinity further exacerbates the excessive CNS N-methyl D-aspartate (NMDA) receptor activation, or excitotoxicity induced by hypoxia, and sensitizes neurons to ischemic injury [4]. NMDA activation generates nitric oxide (NO) that may also cause neuronal injury [5]. The neuronal injury caused by Ca⫹⫹ influx, glutamate neurotoxicity, and oxygen-glucose deprivation is diminished by mild acidosis in cortical cultures [6] as well as in hippocampal neurons [7] by reduction of NMDA receptor activation. If O2 can not be delivered, extraction will decrease regardless of the vascular resistance manipulation, since in the mild to moderate hypothermia ranges, O2 delivery is still dependent on oxyhemoglobin rather than the physically dissolved O2. We concur with the authors on the need of improving O2 delivery during hypothermic perfusion, but suggest doing it by physiologic means. pH-stat strategies, obtained by maintaining the expiratory CO2 concentration eucapnic (5 to 5.5%, monitored at the gas outflow of the oxygenator, especially below 32°C by changing the O2 flow rate, which should also result in close to normoxia paO2 levels without increasing microbubbles) needs to be reappraised with studies, as careful as the one presented by the authors, to settle the long debated issue as to which strategy is better during hypothermic perfusion. Tadaomi-Alfonso Miyamoto, MD Research Department Kokura Memorial Hospital Kitakyushu-City, Japan Koho-Julio Miyamoto, MD, PhD Department of Physiology University of the Ryukyus School of Medicine Okinawa, Japan
References 1. Parolari A, Alamanni F, Gherli T, et al. Cardiopulmonary bypass and oxygen consumption: oxygen delivery and hemodynamics. Ann Thorac Surg 1999;67:1320–7. 2. Miyamoto TA, Hosoi N, Chiba T, Shibata S, Saito H, Wakusawa R. The effects of the “ideal pCO2” on the hemodynamics during surface induced hypothermia (in Japanese). Nihon Kyobu-Geka Gakkaishi (J Jap Assoc Thor Surg) 1970;18:45– 6. 3. Miyamoto TA, Miyamoto KJ, Ohno N. Objective assessment of CNS function within 6 hours of spinal cord ischemia in rabbits. J Anesthesia 1998;12:189–94. 4. Giffard RG, Weiss JH, Choi DW. Extracellular alkalinity exacerbates injury of cultured cortical neurons. Stroke 1992; 23:1817–21. 5. Tseng EE, Brock MV, Kwon ChC, et al. Increased intracerebral excitatory aminoacids and nitric oxide after hypothermic circulatory arrest. Ann Thor Surg 1999;67:371– 6. 6. 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– 42. 7. Tombaugh GC, Sapolsky RM. Mild acidosis protects hippocampal neurons from injury induced by oxygen and glucose deprivation. Brain Res 1990;506:343–5.
Ann Thorac Surg 2000;69:971– 82
Reply To the Editor: We thank Drs Miyamoto and Miyamoto for their comments on our paper entitled “Cardiopulmonary bypass and oxygen consumption: oxygen delivery and hemodynamics.” In their letter, they claim that the reduction in oxygen extraction rates during routine hypothermic cardiopulmonary bypass (CPB) with alpha-stat acid base management has to be ascribed to increased oxygen affinity for hemoglobin, resulting both from hypothermia and to the alkalotic environment of the alpha-stat acid base management. They also suggest, that the best method to improve oxygen transport to tissues in such conditions could be the use of a more acidotic protocol of acid base management (pH-stat), to facilitate the release of oxygen from hemoglobin. However, previous studies document no significant differences in oxygen consumption during moderately hypothermic perfusion with alpha-stat or pH-stat protocols [1, 2]. The behavior of the oxyhemoglobin dissociation curve did not change, and the values of P50 were very similar in the case of alpha-stat or pH-stat protocol use, because in these conditions the effect of hypothermia on the oxyhemoglobin dissociation is predominant over the Bohr effect [1]. In addition, a relative impairment in oxygen extraction, with respect to animal models, had previously been documented in anesthesized humans at normothermia [3], as well in acutely and chronically ill patients [4]. In these cases it cannot be ascribed to hypothermia nor to acid base management. Furthermore, another case of hypothermic (20°C) perfusion in humans, with the use of the alpha-stat method, documented oxygen extraction rates significantly higher, up to 55%, and in this case there was no impairment in oxygen extraction [5]. For the aforementioned reasons, we do not believe that the reduction in tissue capabilities of oxygen extraction, as documented in our study, should be ascribed to the pH management protocol, and the causes still need to be defined. However, the evidence of an impaired oxygen extraction that occurs during moderately hypothermic routine CPB should stimulate towards CPB protocols with lower vascular resistances and higher flow rates, so that the impairment of the tissues capability in oxygen extraction can, at least partially, be overcome. In addition, we can not share the statement that the use of alpha-stat acid-base management protocol results in alkalosis. When hypothermia ensues, alpha-stat allows arterial blood pH to rise as expected for a fluid (ie, the pH of water at 37°C is 6.8, whereas at 20°C it is 7.4) or for blood in a closed system [6]. Alpha-stat also allows the maintenance of the constancy of the fraction of dissociated imidazole groups versus total imidazole groups of histidine, which is the main protein buffer intra and extracellularly. So, with alpha-stat regulation, arterial blood pH remains close to the value that represents the biologic neutrality of blood at normothermia. Finally, we perfectly agree with Drs Miyamoto and Miyamoto on the need for additional studies to better define the pros and cons of the different protocols for acid-base management during routine hypothermic CPB. Francesco Alamanni, MD Alessandro Parolari, MD, PhD Patrizia Rubini, MD Paolo Biglioli, MD Department of Cardiac Surgery University of Milan Milan, Italy
References 1. Baraka AS, Baroody MA, Haroun ST, et al. Effect of ␣-stat versus pH-stat strategy on oxyhemoglobin dissociation and
occur in approximately 33% and 6% of cases, respectively [1]. However, its extension to the right side of the heart is rare. Although massive pulmonary embolism occurs relatively rarely, it can be a major hazard and has resulted in numerous deaths. In 1996 we reported a 60-year-old man as a case of successful management of massive pulmonary tumor embolism from renal cell carcinoma in The Annals of Thoracic Surgery [2]. Five years after the operation the patient is doing well without any sign of metastasis or local recurrence. The patient presented at a local hospital with flank pain and a progressively enlarging abdominal mass. Computed tomographic scan revealed a large enhanced mass, which was diagnosed as renal cell carcinoma in the left kidney and local extension to the infrahepatic inferior vena cava. Awaiting admission to our institute, the patient experienced sudden chest pain and severe shortness of breath at his home. He was admitted as an emergency patient to the local hospital and intubated. Computed tomographic scan on admission showed massive pulmonary emboli in the bilateral pulmonary artery, whereas part of the local extension to the inferior vena cava had disappeared. Radical nephrectomy and resection of the extended tumor in the inferior vena cava were performed in our institute in October 1994. Four days after the nephrectomy, tumor embolectomy of the bilateral pulmonary artery was performed through a median sternotomy using cardiopulmonary bypass with deep hypothermia and intermittent circulatory arrest. According to the TNM classification of renal call carcinoma UICC (International Union Against Cancer) 1997 [3], this case is classified as stage III (T3b, N0, M0). The histopathologic diagnosis was infiltrating type, papillary–alveolar type, granular cell subtype, G2⬎⬎G1, inf beta, pT3c (9.5 ⫻ 5 ⫻ 5 cm), pN0 (0/17), pV2c, ly (⫹). The cut end of the ureter was negative for cancer, and there was a tumor thrombus in the left testicular vein. The postoperative course was uneventful and the patient was discharged from the hospital 4 weeks after the operation. The patient was followed at our outpatient unit. At 5 years after the operation, although some scarring from the pulmonary infarcts was detected, no metastatic lesion was found on computed tomographic scan. As Javidan and associates [4] describe, the 5-year survival rates of renal cell carcinoma are 95% (stage I), 88% (stage II), 59% (stage III), and 20% (stage IV). Compared with other malignant tumors, the survival rate of renal cell carcinoma is relatively high. Our report described a patient who was rescued from the shock and survived long after the surgical management of massive pulmonary tumor embolism due to renal cell carcinoma. The pulmonary emboli should not be considered distant metastases as pulmonary embolism secondary to renal cell carcinoma does not always cause pulmonary metastasis. Masumori and associates [5] reported 2 patients with renal cell carcinoma in whom positive findings on lung perfusion imaging disappeared during follow-up. They suggest that the establishment of pulmonary metastasis requires not only mechanical trapping of carcinoma cells in the pulmonary microvasculature, but an invasive potential of the cells themselves (“seed”) and appropriate microenvironment (“soil”) for enhancing the local growth of cells [5]. Wagner and associates [6] also describe that pulmonary infarcts can “mimic” pulmonary metastases from renal cancer for the same reason. When there is a distant metastasis, it is classified as stage IV, so it is important not to diagnose pulmonary infarcts as pulmonary metastases. As renal cell carcinoma is not very sensitive to radiation therapy and anticancer agents, treatment of the original lesion and immedi© 2000 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
CORRESPONDENCE
973
ate removal of the pulmonary tumor thrombus should improve the long-term results of patients with renal cell carcinoma. Hiroshi Kubota, MD Department of Surgery Tokyo Metropolitan Police Hospital 2-10-41, Fujimi, Chiyodaku 102-8161 Tokyo, Japan Shinichi Takamoto, MD Yutaka Kotsuka, MD Department of Cardiothoracic Surgery University of Tokyo 113-8655 Tokyo, Japan Akira Furuse, MD Department of Cardiothoracic Surgery JR Tokyo General Hospital 151-8528 Tokyo, Japan
References 1. Marshall VF, Middleton RG, Holswade GR, Goldsmith EI. Surgery for renal cell carcinoma in the vena cava. J Urol 1970; 103:414–20. 2. Kubota H, Furuse A, Kotsuka Y, Yagyu K, Kawauchi M, Saito H. Successful management of massive pulmonary tumor embolism from renal cell carcinoma. Ann Thorac Surg 1996; 61:708–10. 3. Sobin LH, Wittekind Ch. International Union Against Cancer (UICC): TNM classification of malignant tumors, 5th ed. New York: Wiley-Liss, 1997:180–2. 4. Javidan J, Stricker HJ, Tamboli P, et al. Prognostic significance of the 1997 TNM classification of renal cell carcinoma. J Urol 1999;162:1277– 81. 5. Masumori N, Iwabe H, Kumamoto E. Studies on pulmonary metastasis of renal cell carcinoma–pulmonary embolism revealed by lung perfusion imaging and the metastasis. Nippon Hinyokika Gakkai Zasshi 1991;82:769–75. 6. Wagner JR, Merino MJ, Pass HI, Linehan WM, Walther MM. Pulmonary infarcts can mimic pulmonary metastases from renal cancer. J Urol 1997;158:1688–90.
Is It Justified to Disregard the Bohr Effect During Alpha-Stat Hypothermia? To the Editor: We read with great interest the timely and long overdue article by Parolari and colleagues, “Cardiopulmonary Bypass and Oxygen Consumption: Oxygen Delivery and Hemodynamics” [1]. The authors are to be congratulated for having clinically demonstrated beyond any doubt that O2 extraction is decreased during even mild to moderate hypothermic (28°C to 30°C) alpha-stat perfusion, which was attributed to redistribution of blood. They speculate that higher O2 delivery could possibly be obtained by manipulating the vascular resistance. It seems that the very cause was missed. The problem probably lies in the impaired O2 delivery caused by the increased O2 affinity of hemoglobin during hypothermia, aggravated by alkalosis to the point of developing tissular hypoxia (Bohr effect), which may result in redistribution of blood flow through the microvascular beds. The body fails to extract, ie, become hypoxic, because hemoglobin does not release the O2. Alpha-stat strategies during hypothermic perfusion have been preferred for 25 to 30 years against physiologic principles that have proved to be effective for millions of years. Nature has adapted to 0003-4975/00/$20.00
974
CORRESPONDENCE
temperature changes and prevented hypoxia through the evolutionary scale of the animal kingdom using hemoglobin as the pigment to carry O2 by increasing the O2 delivery capabilities and changing the paCO2 readily achieved by respiratory rate changes to maintain eucapnia, ie, pH-stat strategy. Indeed better cardiovascular function (hemodynamics) could be preserved during surface-induced hypothermia (without pump) down to 20°C in dogs [2] and down to 29°C in rabbits [3] by maintaining eucapnia (monitoring expiratory CO2 concentration and adjusting ventilation to obtain 5%) or minimal hypercapnia (5.5%) below 32°C. Alpha-stat results in alkalosis. Alkalinity further exacerbates the excessive CNS N-methyl D-aspartate (NMDA) receptor activation, or excitotoxicity induced by hypoxia, and sensitizes neurons to ischemic injury [4]. NMDA activation generates nitric oxide (NO) that may also cause neuronal injury [5]. The neuronal injury caused by Ca⫹⫹ influx, glutamate neurotoxicity, and oxygen-glucose deprivation is diminished by mild acidosis in cortical cultures [6] as well as in hippocampal neurons [7] by reduction of NMDA receptor activation. If O2 can not be delivered, extraction will decrease regardless of the vascular resistance manipulation, since in the mild to moderate hypothermia ranges, O2 delivery is still dependent on oxyhemoglobin rather than the physically dissolved O2. We concur with the authors on the need of improving O2 delivery during hypothermic perfusion, but suggest doing it by physiologic means. pH-stat strategies, obtained by maintaining the expiratory CO2 concentration eucapnic (5 to 5.5%, monitored at the gas outflow of the oxygenator, especially below 32°C by changing the O2 flow rate, which should also result in close to normoxia paO2 levels without increasing microbubbles) needs to be reappraised with studies, as careful as the one presented by the authors, to settle the long debated issue as to which strategy is better during hypothermic perfusion. Tadaomi-Alfonso Miyamoto, MD Research Department Kokura Memorial Hospital Kitakyushu-City, Japan Koho-Julio Miyamoto, MD, PhD Department of Physiology University of the Ryukyus School of Medicine Okinawa, Japan
References 1. Parolari A, Alamanni F, Gherli T, et al. Cardiopulmonary bypass and oxygen consumption: oxygen delivery and hemodynamics. Ann Thorac Surg 1999;67:1320–7. 2. Miyamoto TA, Hosoi N, Chiba T, Shibata S, Saito H, Wakusawa R. The effects of the “ideal pCO2” on the hemodynamics during surface induced hypothermia (in Japanese). Nihon Kyobu-Geka Gakkaishi (J Jap Assoc Thor Surg) 1970;18:45– 6. 3. Miyamoto TA, Miyamoto KJ, Ohno N. Objective assessment of CNS function within 6 hours of spinal cord ischemia in rabbits. J Anesthesia 1998;12:189–94. 4. Giffard RG, Weiss JH, Choi DW. Extracellular alkalinity exacerbates injury of cultured cortical neurons. Stroke 1992; 23:1817–21. 5. Tseng EE, Brock MV, Kwon ChC, et al. Increased intracerebral excitatory aminoacids and nitric oxide after hypothermic circulatory arrest. Ann Thor Surg 1999;67:371– 6. 6. 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– 42. 7. Tombaugh GC, Sapolsky RM. Mild acidosis protects hippocampal neurons from injury induced by oxygen and glucose deprivation. Brain Res 1990;506:343–5.
Ann Thorac Surg 2000;69:971– 82
Reply To the Editor: We thank Drs Miyamoto and Miyamoto for their comments on our paper entitled “Cardiopulmonary bypass and oxygen consumption: oxygen delivery and hemodynamics.” In their letter, they claim that the reduction in oxygen extraction rates during routine hypothermic cardiopulmonary bypass (CPB) with alpha-stat acid base management has to be ascribed to increased oxygen affinity for hemoglobin, resulting both from hypothermia and to the alkalotic environment of the alpha-stat acid base management. They also suggest, that the best method to improve oxygen transport to tissues in such conditions could be the use of a more acidotic protocol of acid base management (pH-stat), to facilitate the release of oxygen from hemoglobin. However, previous studies document no significant differences in oxygen consumption during moderately hypothermic perfusion with alpha-stat or pH-stat protocols [1, 2]. The behavior of the oxyhemoglobin dissociation curve did not change, and the values of P50 were very similar in the case of alpha-stat or pH-stat protocol use, because in these conditions the effect of hypothermia on the oxyhemoglobin dissociation is predominant over the Bohr effect [1]. In addition, a relative impairment in oxygen extraction, with respect to animal models, had previously been documented in anesthesized humans at normothermia [3], as well in acutely and chronically ill patients [4]. In these cases it cannot be ascribed to hypothermia nor to acid base management. Furthermore, another case of hypothermic (20°C) perfusion in humans, with the use of the alpha-stat method, documented oxygen extraction rates significantly higher, up to 55%, and in this case there was no impairment in oxygen extraction [5]. For the aforementioned reasons, we do not believe that the reduction in tissue capabilities of oxygen extraction, as documented in our study, should be ascribed to the pH management protocol, and the causes still need to be defined. However, the evidence of an impaired oxygen extraction that occurs during moderately hypothermic routine CPB should stimulate towards CPB protocols with lower vascular resistances and higher flow rates, so that the impairment of the tissues capability in oxygen extraction can, at least partially, be overcome. In addition, we can not share the statement that the use of alpha-stat acid-base management protocol results in alkalosis. When hypothermia ensues, alpha-stat allows arterial blood pH to rise as expected for a fluid (ie, the pH of water at 37°C is 6.8, whereas at 20°C it is 7.4) or for blood in a closed system [6]. Alpha-stat also allows the maintenance of the constancy of the fraction of dissociated imidazole groups versus total imidazole groups of histidine, which is the main protein buffer intra and extracellularly. So, with alpha-stat regulation, arterial blood pH remains close to the value that represents the biologic neutrality of blood at normothermia. Finally, we perfectly agree with Drs Miyamoto and Miyamoto on the need for additional studies to better define the pros and cons of the different protocols for acid-base management during routine hypothermic CPB. Francesco Alamanni, MD Alessandro Parolari, MD, PhD Patrizia Rubini, MD Paolo Biglioli, MD Department of Cardiac Surgery University of Milan Milan, Italy
References 1. Baraka AS, Baroody MA, Haroun ST, et al. Effect of ␣-stat versus pH-stat strategy on oxyhemoglobin dissociation and