Elevated troponin I level with hemoglobin based oxygen carrying solutions (HBOCs) as a priming solution despite improved left ventricular fu
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a Resident in Cardiothoracic Surgery, Loyola University, Chicago Stritch School of Medicine, 2160 S 1st Avenue, Maywood, IL 60153, USA
b Division of Cardiac Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
Abstract
Stroma free hemoglobin based oxygen-carrying solutions (HBOCs) have been shown to have the capability to transport oxygen, suggesting their use as a temporary blood substitute to maintain oxygenation of tissue. HBOCs might be the proper priming solution; however, elevated troponin associated with their application might be a major concern, particularly in patients with damaged myocardium. This study was performed in mongrel dogs (n=14). The animals underwent cardiac arrest with cardioplegic solution and aortic clamping using cardiopulmonary bypass (CPB). HBOC was used as a priming solution for CPB in the study group, and Lactated Ringer's in the control group. The extreme hemodilution in the study group was achieved by replacing more than 80% of the animal's blood with HBOC. A right heart bypass was performed to control the cardiac output. The hemodynamic parameters were measured with increasing cardiac output before and after CPB. At a cardiac output of 2500 ml/min, LAP (19±9 mmHg vs. 8.7±1.3 mmHg in the HBOCs group) and LVEDP (22±16 mmHg in the control group vs. 11±2.8 mmHg in the HBOC group) were significantly higher in control animals. The overall coronary sinus flow did not show any significant difference between both groups. The PO2 in the HBOCs group was slightly higher (534±10 mmHg vs. 494±71 mmHg) at 30 min after removal of aortic clamp compared to PO2 in control group. Post-ischemic troponin I level was increased in both groups, however, it was significantly higher in HBOCs group (49.64±48.58 ng/ml) compared to its level in control group (28.33±17.2 ng/ml). After the priming was completed and CPB was initiated, the hematocrit in the study group was 5.37±3.7% compared to 15±3.3% in the control group. However, the hemoglobin (Hb) in the study group remained higher throughout the experiment compared to control group, 8.34±1.55 g/dl vs. 5.37±1.04 g/dl, respectively. HBOC based priming permits cardiopulmonary bypass at a very low hematocrit with a better preservation of myocardium and adequate oxygen supply. However, elevated troponin I at the postischemic phase is a serious concern and its significance needs to be addressed before broad clinical application of HBOC.
Key Words: Artificial blood; LVEDP; LAP; Oxygen carrying
1. Introduction
When William Harvey first described the circulation of blood in 1616, scientists started thinking about replacing the blood by other liquids. Shortage in blood, infectious diseases like hepatitis and AIDS, ABO incompatibility, and the short shelf life of homologous blood have rekindled the intensive investigations to develop blood substitutes [1]. Further, priming of the cardiopulmonary bypass machine during cardiac surgical interventions with fresh whole blood is associated with an increased length of stay in the intensive care unit and increased perioperative fluid overload [2]. Because of the emergent nature of cardiac surgical interventions and elderly patient population, these patients are not proper candidates for autotransfusion.
The most physiologic blood substitutes are the hemoglobin-based oxygen carriers (HBOCs) containing modified human, mammalian, or recombinant hemoglobin [3]. The half life of HBOC is 16–30 h, therefore it can be used as priming solution in cardiopulmonary bypass (CPB) as a temporary oxygen carrier [4]. HBOC's low viscosity, oncotic pressure, and oxygen-carrying capacity compare favorably with blood [5], making it a proper temporary blood substitute to maintain oxygenation of tissue and preserve cardiac function [6].
2. Methods
A canine model was selected for this study. Fourteen mongrel dogs, 7 in each group with weight ranging from 18 to 22 kg, were studied. This study was approved by the Subcommittee for Animal Care in Massachusetts General Hospital. All animals used in this study were kept under conditions according to Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.
Ultrapurified polymerized bovine hemoglobin (Biopure, Cambridge, MA), used in this study, is a stroma free hemoglobin, which is prepared from bovine red blood cells by lysis, filtration, chromatography, and polymerization with glutaraldehyde [7]. After intubation and anesthesia with 1.5–2.5% isoflurane, arterial and venous catheters were inserted for hemodynamic measurements. A left thoracotomy was performed and the pericardium opened and suspended to form a cradle to support the heart. Micromanometer-tipped catheters were inserted in left atrium and ventricle for pressure measurements. Left carotid artery was cannulated as an arterial access for CPB. The right atrium and pulmonary artery were cannulated to isolate the right ventricle and study the left ventricular function by controlling the cardiac output. After cannulation of the right atrium, a catheter was inserted in the coronary sinus to measure the coronary sinus blood flow. Systemic anticoagulation was performed with 200 units/kg heparin. Lactated Ringer's was used as priming solution in the control group. In the study group, an extreme hemodilution with HBOC was performed and 2000 ml of canine's blood was stored in an extra reservoir. HBOC was used to replace the canine's blood as well as for priming of CPB. If additional volume was needed, HBOC was used in the study group and LR in the control group.
After reaching a steady state, arterial blood gas analysis (blood-gas analyzer model ABL 330, Radiometer, Copenhagen, Denmark) was performed and hemodynamic parameters were measured. Pre-ischemic left ventricular function curves were generated by increasing the cardiac output 500 ml/min stepwise to a maximum of 3500 ml. After the pre-ischemic measurements, cardiac output was adjusted to 1.75–2.25 l/min. The total cardiopulmonary bypass was initiated, the aorta was cross-clamped and systemic cooling to 24–26 °C was performed. The aorta was clamped and crystalloid potassium cardioplegia was infused in the aortic root (20 ml/kg). Antegrade cardioplegia was repeated 30 min later (10 ml/kg). Perfusion at 26 °C was maintained for 60 min at a flow rate of 75 ml/min/kg. The aortic cross clamp was removed after 60 min. The heart was electrically converted if spontaneous rhythm did not resume. After 40–50 min of recovery time and retransfusion of autologous blood (in HBOC group), the left ventricle function was studied and blood gas analysis and cardiac enzymes were measured.
3. Results
The left atrial pressure in the study group remained stable, however, it was elevated in control group (19±9 mmHg vs. 8.7±1.3 mmHg in the control and HBOC group at a cardiac output of 2500 ml/min, respectively (P<0.05). Table 1 shows the hemodynamic parameters at different phases of the study. Fig. 1 demonstrates the pre- and post-ischemic left atrial pressure (LAP) with increasing cardiac output. Left ventricular enddiastolic pressure (LVEDP) was increased in the post-ischemic phase in both groups; however, it was significantly higher in the control group (22±16 mmHg in HBOC group vs. 11±2.8 mmHg in control group, P<0.05, Fig. 2). Canines, which received HBOC for priming, were able to tolerate a high fluid challenge. The coronary sinus flow did not differ significantly between both groups throughout the experiment. Fig. 3 shows coronary sinus flow at different phases of study. The hemoglobin concentration in the study group remained higher compared to control group throughout the experiment, 8.34±1.55 g/dl vs. 5.37±1.04 g/dl, respectively. The high concentration of free hemoglobin in HBOC group explains the high measured Hb in study group despite a low hematocrit The hemotocrit in the study group was diluted down to 5.4%±3.7% and it remained in control group significantly higher, 15%±3.3%. The PO2 in HBOC group was slightly higher (534±10 mmHg 494±71, P<0.05) at 30 min after removal of aortic clamp and rewarming period (Table 2). The troponin I level after CPB was increased in both groups; however, it was significantly higher in HBOC group, 49.64±48.58 ng/ml, vs. 28.33± 17.2 ng/ml in the control group (P<0.05) (Fig. 4).
There was no significant difference in PO2 between both groups during CPB and after removal of aortic clamp, and it remained high to deliver a sufficient amount of oxygen to tissue in both groups. The PCO2 was only slightly higher in HBOC group during CPB and after removal of aortic clamp.
4. Discussion
The effect of HBOC on oxygen transport capacity under extreme hemodilution and the affinity of free hemoglobin to oxygen has been well studied [8]. Harringer et al. [8] demonstrated in a hemorrhagic shock model that replacement of blood with bovine hemoglobin could restore arterial PO2 and oxygen delivery. Polymerized bovine hemoglobin can maintain oxygenation in tissue and allow long-term survival of animals with hematocrit less than 3% [9]. A clinical trial with children suffering from sickle cell anemia supported the therapeutic effects of Hb solutions. These children received Hb solution up to 25% of their total blood volume. Their general condition improved, vaso-occulsive episodes decreased, and the children experienced less pain. The HBOCs were demonstrated to be as effective as blood transfusions and more effective than hetastarch to restore fetal oxygenation in pregnant ewes after hemorrhage [10].
Coronary perfusion is a predictor of proper myocardial oxygenation and perfusion [11]. Kasper et al. [12] demonstrated no significant differences in coronary sinus flow using HBOC or Lactated Ringer's. In our study there was no significant difference in coronary sinus flow between both groups. A decrease in regional blood flow is compensated by a more homogenous distribution of blood flow due to the lower viscosity of HBOC and its enhanced uploading of oxygen. The areas of low flow due to vasoconstriction caused by rewarming during weaning from CPB as well as atherosclerotic coronary vessels can be perfused and delivered with oxygen by HBOC owing to its low viscosity [12].
Hemoglobin has the ability to scavenge nitric oxide (NO) leading to vascular smooth muscle contraction [8,9]. The polymerized hemoglobin has a NO scavenging rate approximately 20- to 30-fold less than the previously used HBOCs and its effect on NO is minimal [13]. We previously demonstrated that the left ventricle function is preserved with HBOC [6]. LAP and LVEDP remained low in the HBOC group, while control animal were not able to tolerate the fluid overload, which led to increased LAP and LVEDP in the control animal; as a sign of failing left ventricular function. Figs. 1 and 2 compare the LAP and LVEDP in both groups with increasing cardiac output.
Elevated troponin level is suggestive of Ischemic events in myocardium. However, Filipovic et al. [14] demonstrated that postoperative elevation of cardiac troponin I is not always a predictor of major cardiac events. Ma et al. [15] examined the effects of HBOCs on clinical chemistry. They reported that HBOC concentrations up to 50 g/l cause no interference for immunoassays of troponin I. In our study, the postischemic troponin I level was increased in both groups, however, it was significantly higher in HBOCs group. We used high concentration of HBOC in this study (12 g/dl), which might explain falsely elevated troponin level, however, the interaction between HBOC and elevated troponin needs further investigation.
4.1. Limitation of the study
For this study, we used mongral dogs without any underlying cardiac disease. How far our results would apply to patients with CAD is not known. Another limitation of this study is the short period of time that the animals were exposed to HBOC. Preclinical studies could predict the clinical outcome as well as the adverse effects.
5. Conclusion
The results of this study demonstrate that HBOC has the capability to deliver a sufficient amount of oxygen to tissue. The relative low left atrial and left ventricular enddiastolic pressures in animals receiving HBOC is suggestive that using HBOC can preserve myocardial function. The clinical significance of elevated troponin with HBOC deserves further investigation. An elevated troponin level with possible ischemic event should be addressed before broad clinical application of HBOC.
Acknowledgements
This study was supported by a scholarship from German Heart Donation (Die Deutsche Herzstiftung).
References
Wahr JA, Anderson MM, Giacherio DA, Hallock L, Gawryl MS, Lansden C, Tremper KK. The effects of a blood-salvaging device on blood containing a hemoglobin-based oxygen carrier, HBOC-201. J Cardiothorac Vasc Anesth 1997; 11:10–12.
Mou SS, Giroir BP, Molitor-Kirsch EA, Leonard SR, Nikaidoh H, Nizzi F, Town DA, Roy LC, Scott W, Stromberg D. Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants. N Engl J Med 2004; 351:1635–1644.
Wohl JS, Cotter SM. Blood substitutes: oxygen-carrying acellular fluids. Vet Clin North Am Small Anim Pract 1995; 25:1417–1440.
Ning J, Chang TM. In vivo effects of stroma-free hemoglobin and polyhemoglobin on coagulation factors in rats. Int J Artif Organs 1990; 13:509–516.
Slanetz PJ, Lee R, Page R, Jacobs EE Jr, LaRaia PJ, Vlahakes GJ. Hemoglobin blood substitutes in extended preoperative autologous blood donation: an experimental study. Surgery 1994; 115:246–254.
Neragi-Miandoab S, Guerrero JL, Vlahakes GJ. Autologous blood sequestration using a double venous reservoir bypass circuit and polymerized hemoglobin prime. Asaio J 2002; 48:407–411.
Vlahakes GJ, Lee R, Jacobs EE Jr, LaRaia PJ, Austen WG. Hemodynamic effects and oxygen transport properties of a new blood substitute in a model of massive blood replacement. J Thorac Cardiovasc Surg 1990; 100:379–388.
Harringer W, Hodakowski GT, Svizzero T, Jacobs EE Jr, Vlahakes GJ. Acute effects of massive transfusion of a bovine hemoglobin blood substitute in a canine model of hemorrhagic shock. Eur J Cardiothorac Surg 1992; 6:649–654. discussion 654.
Lee R, Neya K, Svizzero TA, Vlahakes GJ. Limitations of the efficacy of hemoglobin-based oxygen-carrying solutions. J Appl Physiol 1995; 79:236–242.
Moon PF, Bliss SP, Posner LP, Erb HN, Nathanielsz PW. Fetal oxygen content is restored after maternal hemorrhage and fluid replacement with polymerized bovine hemoglobin, but not with hetastarch, in pregnant sheep. Anesth Analg 2001; 93:142–150.
Niemann JT, Rosborough JP, Ung S, Criley JM. Coronary perfusion pressure during experimental cardiopulmonary resuscitation. Ann Emerg Med 1982; 11:127–131.
Kasper SM, Walter M, Grune F, Bischoff A, Erasmi H, Buzello W. Effects of a hemoglobin-based oxygen carrier (HBOC-201) on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth Analg 1996; 83:921–927.
Resta TC, Walker BR, Eichinger MR, Doyle MP. Rate of NO scavenging alters effects of recombinant hemoglobin solutions on pulmonary vasoreactivity. J Appl Physiol 2002; 93:1327–1336.
Filipovic M, Jeger RV, Girard T, Probst C, Pfisterer M, Gurke L, Studer W, Seeberger MD. Predictors of long-term mortality and cardiac events in patients with known or suspected coronary artery disease who survive major non-cardiac surgery. Anaesthesia 2005; 60:5–11.
Ma Z, Monk TG, Goodnough LT, McClellan A, Gawryl M, Clark T, Moreira P, Keipert PE, Scott MG. Effect of hemoglobin- and Perflubron-based oxygen carriers on common clinical laboratory tests. Clin Chem 1997; 43:1732–1737.(Siyamek Neragi-Miandoab, )
b Division of Cardiac Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
Abstract
Stroma free hemoglobin based oxygen-carrying solutions (HBOCs) have been shown to have the capability to transport oxygen, suggesting their use as a temporary blood substitute to maintain oxygenation of tissue. HBOCs might be the proper priming solution; however, elevated troponin associated with their application might be a major concern, particularly in patients with damaged myocardium. This study was performed in mongrel dogs (n=14). The animals underwent cardiac arrest with cardioplegic solution and aortic clamping using cardiopulmonary bypass (CPB). HBOC was used as a priming solution for CPB in the study group, and Lactated Ringer's in the control group. The extreme hemodilution in the study group was achieved by replacing more than 80% of the animal's blood with HBOC. A right heart bypass was performed to control the cardiac output. The hemodynamic parameters were measured with increasing cardiac output before and after CPB. At a cardiac output of 2500 ml/min, LAP (19±9 mmHg vs. 8.7±1.3 mmHg in the HBOCs group) and LVEDP (22±16 mmHg in the control group vs. 11±2.8 mmHg in the HBOC group) were significantly higher in control animals. The overall coronary sinus flow did not show any significant difference between both groups. The PO2 in the HBOCs group was slightly higher (534±10 mmHg vs. 494±71 mmHg) at 30 min after removal of aortic clamp compared to PO2 in control group. Post-ischemic troponin I level was increased in both groups, however, it was significantly higher in HBOCs group (49.64±48.58 ng/ml) compared to its level in control group (28.33±17.2 ng/ml). After the priming was completed and CPB was initiated, the hematocrit in the study group was 5.37±3.7% compared to 15±3.3% in the control group. However, the hemoglobin (Hb) in the study group remained higher throughout the experiment compared to control group, 8.34±1.55 g/dl vs. 5.37±1.04 g/dl, respectively. HBOC based priming permits cardiopulmonary bypass at a very low hematocrit with a better preservation of myocardium and adequate oxygen supply. However, elevated troponin I at the postischemic phase is a serious concern and its significance needs to be addressed before broad clinical application of HBOC.
Key Words: Artificial blood; LVEDP; LAP; Oxygen carrying
1. Introduction
When William Harvey first described the circulation of blood in 1616, scientists started thinking about replacing the blood by other liquids. Shortage in blood, infectious diseases like hepatitis and AIDS, ABO incompatibility, and the short shelf life of homologous blood have rekindled the intensive investigations to develop blood substitutes [1]. Further, priming of the cardiopulmonary bypass machine during cardiac surgical interventions with fresh whole blood is associated with an increased length of stay in the intensive care unit and increased perioperative fluid overload [2]. Because of the emergent nature of cardiac surgical interventions and elderly patient population, these patients are not proper candidates for autotransfusion.
The most physiologic blood substitutes are the hemoglobin-based oxygen carriers (HBOCs) containing modified human, mammalian, or recombinant hemoglobin [3]. The half life of HBOC is 16–30 h, therefore it can be used as priming solution in cardiopulmonary bypass (CPB) as a temporary oxygen carrier [4]. HBOC's low viscosity, oncotic pressure, and oxygen-carrying capacity compare favorably with blood [5], making it a proper temporary blood substitute to maintain oxygenation of tissue and preserve cardiac function [6].
2. Methods
A canine model was selected for this study. Fourteen mongrel dogs, 7 in each group with weight ranging from 18 to 22 kg, were studied. This study was approved by the Subcommittee for Animal Care in Massachusetts General Hospital. All animals used in this study were kept under conditions according to Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.
Ultrapurified polymerized bovine hemoglobin (Biopure, Cambridge, MA), used in this study, is a stroma free hemoglobin, which is prepared from bovine red blood cells by lysis, filtration, chromatography, and polymerization with glutaraldehyde [7]. After intubation and anesthesia with 1.5–2.5% isoflurane, arterial and venous catheters were inserted for hemodynamic measurements. A left thoracotomy was performed and the pericardium opened and suspended to form a cradle to support the heart. Micromanometer-tipped catheters were inserted in left atrium and ventricle for pressure measurements. Left carotid artery was cannulated as an arterial access for CPB. The right atrium and pulmonary artery were cannulated to isolate the right ventricle and study the left ventricular function by controlling the cardiac output. After cannulation of the right atrium, a catheter was inserted in the coronary sinus to measure the coronary sinus blood flow. Systemic anticoagulation was performed with 200 units/kg heparin. Lactated Ringer's was used as priming solution in the control group. In the study group, an extreme hemodilution with HBOC was performed and 2000 ml of canine's blood was stored in an extra reservoir. HBOC was used to replace the canine's blood as well as for priming of CPB. If additional volume was needed, HBOC was used in the study group and LR in the control group.
After reaching a steady state, arterial blood gas analysis (blood-gas analyzer model ABL 330, Radiometer, Copenhagen, Denmark) was performed and hemodynamic parameters were measured. Pre-ischemic left ventricular function curves were generated by increasing the cardiac output 500 ml/min stepwise to a maximum of 3500 ml. After the pre-ischemic measurements, cardiac output was adjusted to 1.75–2.25 l/min. The total cardiopulmonary bypass was initiated, the aorta was cross-clamped and systemic cooling to 24–26 °C was performed. The aorta was clamped and crystalloid potassium cardioplegia was infused in the aortic root (20 ml/kg). Antegrade cardioplegia was repeated 30 min later (10 ml/kg). Perfusion at 26 °C was maintained for 60 min at a flow rate of 75 ml/min/kg. The aortic cross clamp was removed after 60 min. The heart was electrically converted if spontaneous rhythm did not resume. After 40–50 min of recovery time and retransfusion of autologous blood (in HBOC group), the left ventricle function was studied and blood gas analysis and cardiac enzymes were measured.
3. Results
The left atrial pressure in the study group remained stable, however, it was elevated in control group (19±9 mmHg vs. 8.7±1.3 mmHg in the control and HBOC group at a cardiac output of 2500 ml/min, respectively (P<0.05). Table 1 shows the hemodynamic parameters at different phases of the study. Fig. 1 demonstrates the pre- and post-ischemic left atrial pressure (LAP) with increasing cardiac output. Left ventricular enddiastolic pressure (LVEDP) was increased in the post-ischemic phase in both groups; however, it was significantly higher in the control group (22±16 mmHg in HBOC group vs. 11±2.8 mmHg in control group, P<0.05, Fig. 2). Canines, which received HBOC for priming, were able to tolerate a high fluid challenge. The coronary sinus flow did not differ significantly between both groups throughout the experiment. Fig. 3 shows coronary sinus flow at different phases of study. The hemoglobin concentration in the study group remained higher compared to control group throughout the experiment, 8.34±1.55 g/dl vs. 5.37±1.04 g/dl, respectively. The high concentration of free hemoglobin in HBOC group explains the high measured Hb in study group despite a low hematocrit The hemotocrit in the study group was diluted down to 5.4%±3.7% and it remained in control group significantly higher, 15%±3.3%. The PO2 in HBOC group was slightly higher (534±10 mmHg 494±71, P<0.05) at 30 min after removal of aortic clamp and rewarming period (Table 2). The troponin I level after CPB was increased in both groups; however, it was significantly higher in HBOC group, 49.64±48.58 ng/ml, vs. 28.33± 17.2 ng/ml in the control group (P<0.05) (Fig. 4).
There was no significant difference in PO2 between both groups during CPB and after removal of aortic clamp, and it remained high to deliver a sufficient amount of oxygen to tissue in both groups. The PCO2 was only slightly higher in HBOC group during CPB and after removal of aortic clamp.
4. Discussion
The effect of HBOC on oxygen transport capacity under extreme hemodilution and the affinity of free hemoglobin to oxygen has been well studied [8]. Harringer et al. [8] demonstrated in a hemorrhagic shock model that replacement of blood with bovine hemoglobin could restore arterial PO2 and oxygen delivery. Polymerized bovine hemoglobin can maintain oxygenation in tissue and allow long-term survival of animals with hematocrit less than 3% [9]. A clinical trial with children suffering from sickle cell anemia supported the therapeutic effects of Hb solutions. These children received Hb solution up to 25% of their total blood volume. Their general condition improved, vaso-occulsive episodes decreased, and the children experienced less pain. The HBOCs were demonstrated to be as effective as blood transfusions and more effective than hetastarch to restore fetal oxygenation in pregnant ewes after hemorrhage [10].
Coronary perfusion is a predictor of proper myocardial oxygenation and perfusion [11]. Kasper et al. [12] demonstrated no significant differences in coronary sinus flow using HBOC or Lactated Ringer's. In our study there was no significant difference in coronary sinus flow between both groups. A decrease in regional blood flow is compensated by a more homogenous distribution of blood flow due to the lower viscosity of HBOC and its enhanced uploading of oxygen. The areas of low flow due to vasoconstriction caused by rewarming during weaning from CPB as well as atherosclerotic coronary vessels can be perfused and delivered with oxygen by HBOC owing to its low viscosity [12].
Hemoglobin has the ability to scavenge nitric oxide (NO) leading to vascular smooth muscle contraction [8,9]. The polymerized hemoglobin has a NO scavenging rate approximately 20- to 30-fold less than the previously used HBOCs and its effect on NO is minimal [13]. We previously demonstrated that the left ventricle function is preserved with HBOC [6]. LAP and LVEDP remained low in the HBOC group, while control animal were not able to tolerate the fluid overload, which led to increased LAP and LVEDP in the control animal; as a sign of failing left ventricular function. Figs. 1 and 2 compare the LAP and LVEDP in both groups with increasing cardiac output.
Elevated troponin level is suggestive of Ischemic events in myocardium. However, Filipovic et al. [14] demonstrated that postoperative elevation of cardiac troponin I is not always a predictor of major cardiac events. Ma et al. [15] examined the effects of HBOCs on clinical chemistry. They reported that HBOC concentrations up to 50 g/l cause no interference for immunoassays of troponin I. In our study, the postischemic troponin I level was increased in both groups, however, it was significantly higher in HBOCs group. We used high concentration of HBOC in this study (12 g/dl), which might explain falsely elevated troponin level, however, the interaction between HBOC and elevated troponin needs further investigation.
4.1. Limitation of the study
For this study, we used mongral dogs without any underlying cardiac disease. How far our results would apply to patients with CAD is not known. Another limitation of this study is the short period of time that the animals were exposed to HBOC. Preclinical studies could predict the clinical outcome as well as the adverse effects.
5. Conclusion
The results of this study demonstrate that HBOC has the capability to deliver a sufficient amount of oxygen to tissue. The relative low left atrial and left ventricular enddiastolic pressures in animals receiving HBOC is suggestive that using HBOC can preserve myocardial function. The clinical significance of elevated troponin with HBOC deserves further investigation. An elevated troponin level with possible ischemic event should be addressed before broad clinical application of HBOC.
Acknowledgements
This study was supported by a scholarship from German Heart Donation (Die Deutsche Herzstiftung).
References
Wahr JA, Anderson MM, Giacherio DA, Hallock L, Gawryl MS, Lansden C, Tremper KK. The effects of a blood-salvaging device on blood containing a hemoglobin-based oxygen carrier, HBOC-201. J Cardiothorac Vasc Anesth 1997; 11:10–12.
Mou SS, Giroir BP, Molitor-Kirsch EA, Leonard SR, Nikaidoh H, Nizzi F, Town DA, Roy LC, Scott W, Stromberg D. Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants. N Engl J Med 2004; 351:1635–1644.
Wohl JS, Cotter SM. Blood substitutes: oxygen-carrying acellular fluids. Vet Clin North Am Small Anim Pract 1995; 25:1417–1440.
Ning J, Chang TM. In vivo effects of stroma-free hemoglobin and polyhemoglobin on coagulation factors in rats. Int J Artif Organs 1990; 13:509–516.
Slanetz PJ, Lee R, Page R, Jacobs EE Jr, LaRaia PJ, Vlahakes GJ. Hemoglobin blood substitutes in extended preoperative autologous blood donation: an experimental study. Surgery 1994; 115:246–254.
Neragi-Miandoab S, Guerrero JL, Vlahakes GJ. Autologous blood sequestration using a double venous reservoir bypass circuit and polymerized hemoglobin prime. Asaio J 2002; 48:407–411.
Vlahakes GJ, Lee R, Jacobs EE Jr, LaRaia PJ, Austen WG. Hemodynamic effects and oxygen transport properties of a new blood substitute in a model of massive blood replacement. J Thorac Cardiovasc Surg 1990; 100:379–388.
Harringer W, Hodakowski GT, Svizzero T, Jacobs EE Jr, Vlahakes GJ. Acute effects of massive transfusion of a bovine hemoglobin blood substitute in a canine model of hemorrhagic shock. Eur J Cardiothorac Surg 1992; 6:649–654. discussion 654.
Lee R, Neya K, Svizzero TA, Vlahakes GJ. Limitations of the efficacy of hemoglobin-based oxygen-carrying solutions. J Appl Physiol 1995; 79:236–242.
Moon PF, Bliss SP, Posner LP, Erb HN, Nathanielsz PW. Fetal oxygen content is restored after maternal hemorrhage and fluid replacement with polymerized bovine hemoglobin, but not with hetastarch, in pregnant sheep. Anesth Analg 2001; 93:142–150.
Niemann JT, Rosborough JP, Ung S, Criley JM. Coronary perfusion pressure during experimental cardiopulmonary resuscitation. Ann Emerg Med 1982; 11:127–131.
Kasper SM, Walter M, Grune F, Bischoff A, Erasmi H, Buzello W. Effects of a hemoglobin-based oxygen carrier (HBOC-201) on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth Analg 1996; 83:921–927.
Resta TC, Walker BR, Eichinger MR, Doyle MP. Rate of NO scavenging alters effects of recombinant hemoglobin solutions on pulmonary vasoreactivity. J Appl Physiol 2002; 93:1327–1336.
Filipovic M, Jeger RV, Girard T, Probst C, Pfisterer M, Gurke L, Studer W, Seeberger MD. Predictors of long-term mortality and cardiac events in patients with known or suspected coronary artery disease who survive major non-cardiac surgery. Anaesthesia 2005; 60:5–11.
Ma Z, Monk TG, Goodnough LT, McClellan A, Gawryl M, Clark T, Moreira P, Keipert PE, Scott MG. Effect of hemoglobin- and Perflubron-based oxygen carriers on common clinical laboratory tests. Clin Chem 1997; 43:1732–1737.(Siyamek Neragi-Miandoab, )