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J Thorac Cardiovasc Surg 1996;112:1610-1621
© 1996 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Received for publication May 6, 1996 Revisions requested July 1, 1996; revisions received August 5, 1996 Accepted for publication August 7, 1996. Address for reprints: Richard A. Jonas, MD, Department of Cardiovascular Surgery, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
Abstract
Background: Various degrees of hemodilution are currently in clinical use during deep hypothermic circulatory arrest to counteract deleterious rheologic effects linked with brain injury by previous reports. Material and methods: Seventeen piglets were randomly assigned to three groups. Group I piglets (n = 7) received colloid and crystalloid prime (hematocrit < 10%), group II piglets (n = 5) received blood and crystalloid prime (hematocrit 20%), group III piglets (n = 5) received blood prime (hematocrit 30%). All groups underwent 60 minutes of deep hypothermic circulatory arrest at 15º C. with continuous magnetic resonance spectroscopy and near-infrared spectroscopy Neurologic recovery was evaluated for 4 days (neurologic deficit score 0, normal, to 500, brain death; overall performance category 1, normal, to 5, brain death). Neurohistologic score (0, normal, to 5+, necrosis) was assessed after the animals were euthanized on day 4.
Results: Group I had significant loss of phosphocreatine and intracellular acidosis during early cooling (phosphocreatine in group I, 86.3% ± 26.8%; group II, 117.3% ± 8.6%; group III, 110.9% ± 2.68%; p = 0.0008; intracellular pH in group I, 6.95 ± 0.18; group II, 7.28 ± 0.04; group III, 7.49 ± 0.04; p = 0.0048). Final recovery was the same for all groups. Cytochrome aa3 was more reduced in group I during deep hypothermic circulatory arrest than in either of the other groups (group I, -43.6 ± 2.6; group II, -16.0 ± 5.2; group III, 1.3 ± 3.1; p< 0.0001). Neurologic deficit score was best preserved in group III (p< 0.05 group II vs group III) on the first postoperative day, although this difference diminished with time and all animals were neurologically normal after 4 days. Histologic assessment was worst among group I in neocortex area (group I, 1.33 ± 0.3; group II, 0.22 ± 0.1; group III, 0.40 ± 0.2, p < 0.05, group I vs group II; p = 0.0287, group I vs group III).
Conclusion: Extreme hemodilution during cardiopulmonary bypass may cause inadequate oxygen delivery during early cooling. The higher hematocrit with a blood prime is associated with improved cerebral recovery after deep hypothermic circulatory arrest. (J THORAC CARDIOVASC SURG 1996;112:1610-21)
Hemodilution has been widely applied for hypothermic cardiopulmonary bypass (CPB) for many years. It was first introduced to decrease homologous blood use,
1 thereby avoiding the "homologous blood syndrome." 2 Later, the effects of hemodilution in counteracting the deleterious rheologic consequences of deep hypothermia, such as increased viscosity and red cell rigidity, came to be considered important in minimizing brain injury associated with deep hypothermic circulatory arrest (DHCA). 3 However, hemodilution reduces the oxygen carrying capacity of blood. In combination with the leftward shift of the oxyhemoglobin dissociation curve induced by hypothermia, which may be further exacerbated by an alkaline pH strategy such as alpha-stat, hemodilution may critically limit oxygen delivery to neurons and other cells. 4
Until recently, it was not possible to directly examine the adequacy of oxygen delivery to neurons during CPB. Both clinical and laboratory studies have used surrogate end points, such as gross evidence of neurologic injury or measurement of cerebral blood flow or cerebral metabolic rate. Recent developments in magnetic resonance spectroscopy (MRS) and near infra-red spectroscopy (NIRS) 5 now allow more direct investigation of the adequacy of oxygen delivery to cerebral cells and the ability of cells to synthesize and maintain high-energy phosphates. We developed a piglet survival model of DHCA that includes simultaneous MRS and NIRS, followed by evaluation of neurologic status for 4 days and ending with the sacrifice and histologic assessment of the animal. We used the model in this study to evaluate the neurologic effects of perfusate hematocrit during DHCA under conditions similar to those used clinically.
Consistent with a lack of firm data from the past on which to base a strategy for hematocrit manipulation during DHCA is the observation that widely disparate protocols have evolved at different centers undertaking high volumes of neonatal and infant cardiac operations. 6 At Loma Linda University, a blood-free prime is routinely applied for neonatal DHCA, resulting in a hematocrit less than 10%. 7 Colloid osmotic pressure is elevated by means of albumin. At Children's Hospital in Boston, a mixture of whole blood (not packed cells) and crystalloid solution is used for the prime to achieve an hematocrit of 20% during CPB. 8 No colloid other than the plasma in the whole blood is added. At Marie-Lannelongue in Paris, a blood-only prime is used to achieve an hematocrit greater than 30%. 9 Our study examines the adequacy of cerebral protection afforded by these three hemodilution protocols.
METHODS
Experimental preparation
Seventeen 5-week-old Yorkshire piglets, weight 6.2 to 8.8 kg (mean 7.9 kg), were anesthetized with intraperitoneal sodium methohexital (45 mg/kg) and intubated with a 5 mm cuffed endotracheal tube. Each animal was ventilated at a peak inspiratory pressure of 20 cm H2O, an inspired oxygen fraction of 0.21, and a rate of 12 breaths/min, by means of a pressure control ventilator (Healthdyne model 105; Healthdyne Technologies, Marietta, Ga.) to achieve a normal pH and arterial carbon dioxide tension. After an intravenous bolus of fentanyl (25 µg/kg) and pancuronium (0.5 mg/kg), anesthesia was maintained by a continuous infusion of fentanyl (25 µg
kg-1hr-1), midazolam (0.2 mgkg-1hr-1), and pancuronium (0.2 mg/kg), throughout the entire experiment except during the period of circulatory arrest. Esophageal temperature was recorded continuously until extubation. Before operation, a 3.0 cm diameter surface coil for MRS was sutured on the scalp overlying the cerebral hemispheres, and a pair of fiberoptic optodes for NIRS were applied to the head over the frontal lobes with an interoptode distance of 3 cm. The superficial left femoral artery was cannulated for arterial blood pressure monitoring and blood gas sampling. The right femoral artery was exposed for the CPB arterial cannula. A right anterolateral thoracotomy was performed in the third intercostal space to expose the right atrium for venous cannulation.
After systemic heparinization (300 IU/kg), an 8F Bio-Medicus arterial cannula (Medtronic Bio-Medicus, Minneapolis, Minn.) and 24F venous cannula (Bard, Inc., USCI Division, Billerica, Mass.) were inserted into the right femoral artery and right atrium, respectively. The animal was then placed in a MRS horizontal-bore superconducting 4.7 magnet (Oxford Research System, Oxford, England) and subjected to CPB and DHCA, as determined by the protocol (Fig. 1).
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All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication No. 86-23, revised in 1985).
Experimental groups
Piglets were randomly assigned to three groups. Group I (n = 7, extreme hemodilution) received colloid and crystalloid priming with a hematocrit lower than 10%. The prime consisted of 800 ml Normosol R, pH 7.4 (Abbott Laboratories, North Chicago, Ill.), and 400 ml Hetastarch (Hespan; Du Pont Companies, Wilmington, Del.). Group II (n = 5) was moderately hemodiluted with 400 ml blood and 800 ml crystalloid solution (Normosol R, pH 7.4) with a hematocrit of 20%. Group III (n = 5, no hemodilution) was prepared with 1200 ml whole-blood prime and a hematocrit of 30%.
CPB technique
The circuit consisted of a roller pump (Cardiovascular Instrument Corp., Wakefield, Mass.), membrane oxygenator (VPCML plus; COBE Cardiovascular, Inc., Arvada, Colo.), and sterile tubing (Olson Medical Sales, Inc., Ashland, Mass.), with a 40 µm arterial filter (Pediatric extracorporeal blood filter; PALL Biomedical, Inc., East Hills, N.Y.). The pump prime was determined by the experimental protocols described previously. Cefazolin sodium (25 mg/kg), methylprednisolone sodium succinate (30 mg/kg), furosemide (0.25 mg/kg), and sodium bicarbonate (10 ml) were added to the prime. Full bypass flow was set at 100 mlkg-1min-1. After cannulation and connection of the CPB circuit, animals were placed in the magnet bore for measurement of baseline MRS and NIRS data. CPB was then commenced and animals were immediately cooled to an esophageal temperature of 15º C during a 40-minute period by the pH-stat strategy. Phentolamine mesylate (0.2 mg/kg) was administered before cooling. Ventilation was stopped after the establishment of CPB.
On reperfusion, furosemide (0.25 mg/kg), mannitol (0.5 g/kg), phentolamine (0.2 mg/kg), and sodium bicarbonate (10 ml) were administered into the pump. The animal was warmed to a temperature of 35º C during a 45-minute period, maintaining a flow rate of 100 mlkg-1min-1. The heart was defibrillated as necessary at 25º C. Fresh whole blood from a donor pig, drawn on the day of operation, was transfused into the pump as required to increase hematocrit to at least 25% in all groups during rewarming. In addition, ultrafiltration with a hemoconcentrator (Hemocor HPH 400; Minntech Corp., Minneapolis, Minn.) was performed during reperfusion in group I to achieve this hematocrit. Ventilation was restarted 10 minutes before weaning from CPB with an inspired oxygen fraction of 1.0. The animal was then weaned from CPB and decannulated outside the bore. Intravenous protamine was administered when the animal was in hemodynamically stable condition. After decannulation, the animal was repositioned in the bore for a further 3 hours of MRS and NIRS data collection.
Postoperative management
All animals remained sedated, paralyzed, mechanically ventilated, and monitored continuously for 12 hours after operation, at which time chest tubes were removed, infusions were discontinued, and the animals were weaned from ventilation and extubated. Hemodynamic stability was observed in all animals, and none required postoperative inotropic or vasopressor support.
Data collection
Spectroscopy
Details of MRS 10 and NIRS 11 have been described previously elsewhere.
Biochemical analysis
Blood samples were taken on the day after the operation. Aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatine kinase (CK), and total bilirubin were measured.
Other evaluations
Details of methods employed for neurologic and behavioral evaluations (neurologic deficit score [NDS] and overall performance category [OPC]) and for histologic evaluations have been described previously elsewhere. 12,13
Statistical analysis
All results were expressed as mean (± standard error of the mean) and analyzed by a statistical analysis software package (Stat-View version 4.5, Abacus Concepts, Berkeley, Calif.). Analysis of variance and Bonferroni test were used to analyze the MRS data, NIRS data, enzyme deficits, and NDSs among and between groups. Kruskal-Wallis and Mann-Whitney tests were used for analysis of the OPC and histologic score. A p value less than 0.05 was considered statistically significant.
RESULTS
Experimental conditions
The experimental conditions for each group are shown in Table I. Animals were similar in size, and there were no differences in hematocrit among groups before operation. During the cooling, arrest, and rewarming phases of CPB, there were no statistical differences in esophageal temperature among groups. During the cooling phase, hematocrit was set according to protocol, but there were no differences among groups after rewarming and on the first postoperative day. The mean perfusion pressure and calcium concentration changed with the hematocrit level during cooling and were therefore highest in group 3 and lowest in group 1 (p < 0.0001). The osmolarity of the pump prime was significantly lower in group I, but there were no significant differences among groups after rewarming and discontinuation of CPB.
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Cerebral high-energy phosphates and intracellular pH (pHi)
During the cooling phase a significant decrease in phosphocreatine (PCr) in group I was noted during the initial 10 and 20 minutes, whereas PCr increased in groups II and III (Fig. 2). An increase in pHi was noted in group III, whereas pHi significantly decreased during cooling in group I. During the circulatory arrest period, the adenosine triphosphate (ATP) signal was highest in group III and lowest in group I. PCr and pHi did not show any significant differences among groups during DHCA. During the rewarming phase, group III showed more rapid recovery of ATP, PCr, and pHi than in groups I and II. After discontinuation of CPB bypass, group III maintained higher levels of ATP, PCr, and pHi than did groups I and II. Three hours after CPB, however, there were no significant differences among groups with respect to PCr and pHi, although group III showed a significantly higher ATP level than did group I.
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Table II). Levels of CK, AST, ALT, LDH, ALP, and total bilirubin tended to be lowest in group III.
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Table II). On postoperative day 1, both the NDS and OPC in group III were significantly better than those in group II (p = 0.0965 for NDS, p = 0.0194 for OPC). On postoperative 2, the NDS in group III remained significantly better than that in group II (p = 0.0492). The NDS was generally worse in group I than group III, although this difference did not reach statistical significance. By postoperative days 3 and 4, most animals had recovered and showed normal performance, with no neurologic deficit.
Neuropathologic results
As in previous studies, neuropathologic damage was evaluated primarily by the presence of hypereosinophilic shrunken neurons with karyorrhectic nuclei, suggestive of recent hypoxic ischemic injury (Fig. 4). The patterns of injury followed those seen in the previous studies. Injury occurred primarily in the lateral frontal and parietal neocortex. A lesser degree of damage was present in the caudate nucleus; in one instance, a focal ischemic lesion of grade 2 was present in the hippocampal dentate gyrus. No damage that could be ascribed to hypoxic or ischemic injury was noted in the diencephalon, brain stem, or cerebellum. Rare, scattered perivascular vacuolated lesions were noted, but these were not systematically recorded and their significance remains unclear at present. The hypoxic or ischemic injury was most pronounced in group I and was negligible in groups II and III (Fig. 5).
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In this study, a blood-free prime resulting in a hematocrit lower than 10% was associated with evidence of inadequate oxygen delivery to cerebral cells, as suggested by reduced cytochrome aa3 byNIRS during the cooling phase on CPB before DHCA. Furthermore, cerebral PCr and pHi fell significantly during cooling with severe hemodilution. Histologic assessment revealed neuronal necrosis after 4 days. In contrast, a hematocrit greater than 30 was associated with increased mitochondrial oxygen availability during cooling. In addition, oxyhemoglobin was markedly above baseline at the onset of DHCA, followed by a continuous decline during DHCA. This suggests that red blood cells continue to deliver oxygen throughout the arrest period; that is, hemoglobin may act as a reservoir of oxygen through 1 hour of DHCA. In contrast, oxyhemoglobin remained at baseline through cooling with a hematocrit lower than 10%. During DHCA, it appears that the oxygen reservoir is exhausted after approximately 30 minutes when the hematocrit is 20% or lower than 10%. The findings with oxyhemoglobin are reinforced by the reciprocal changes observed with deoxyhemoglobin, as measured by NIRS.
The least evidence of neurologic injury was observed in the animals with the highest hematocrits. The greatest histologic damage was seen in the animals with the lowest hematocrits.
The findings of this study are consistent with previous work from this laboratory, which suggested that a more alkaline pH strategy (alpha-stat) during cooling before DHCA with moderate hemodilution (hematocrit 20%) is associated with a greater degree of mitochondrial hypoxia, delayed recovery of cerebral high-energy phosphates, and worse neurodevelopmental outcome than is a more acidotic strategy (pH-stat). 11,14 In the setting of deep hypothermia with severe or moderate hemodilution, this study suggests that hematocrit critically limits oxygen delivery. A more alkaline pH strategy further limits oxygen delivery through its effect on oxyhemoglobin dissociation.
It is interesting to speculate why the neurologic recovery of the moderate hemodilution group was delayed relative to the highest and lowest hematocrit groups. The moderate hemodilution group had no colloid added to the prime, whereas the severe hemodilution group had hetastarch added to model the addition of albumin, as is done clinically by the Loma Linda group. The colloid osmotic pressure was thus almost certainly higher in groups I and III than in group II. This may have been associated with more cerebral as well as generalized body edema in group II, which may have resulted in worse neurologic and general performance scores. We are currently undertaking a study that will separate the effects of red blood cell and colloid hemodilution. This should help to define the relative importances of the inadequate oxygen delivery demonstrated by the intraoperative MRS and NIRS and of postoperative edema in determining postoperative outcome.
There has been a long-standing controversy regarding the optimal degree of hemodilution during hypothermic CPB. 15,16 Kawashima, Yamamoto, and Manabe 17 and Michenfelder and Theye 18 found that oxygen delivery was limited by a hematocrit lower than 20%. A lower hematocrit resulted in acidosis. In 1976, Koster and coworkers 19 demonstrated the beneficial effects of hemodilution on cerebral blood flow. In studies of three experimental groups with various degrees of hemodilution on CPB at hematocrits of 40%, 25%, and 15%, they concluded that hemodilution enhanced cerebral blood flow and maintained oxygen delivery to the brain in the dog. After 60 minutes of arrest, there was significant cerebral hyperemia during reperfusion, especially in the hemodilution group. This finding has been substantiated by many other investigators. 20-22 It can be argued, however, that there is a serious limitation to studies that derive inferences from cerebral blood flow and metabolic rate determined by oxygen consumption in any setting where oxyhemoglobin dissociation is shifted leftward, as is the case with hypothermic CPB, particularly profoundly hypothermic CPB. There are even more important limitations to the many studies that have examined the question of optimal hematocrit with non-CPB models. 21 In these models, hemodilution is always compensated for by a marked increase in cardiac output, usually also associated with an increase in cerebral blood flow. It is not clear whether the increases in cardiac output and cerebral blood flow are related to the decrease in viscosity caused by hemodilution or if there is an important component of hypoxic stress (flow-metabolism coupling in the case of the brain) that drives the increase in flow. In any event, cardiac output is fixed in the patient receiving CPB. Furthermore, the flow rate that is traditionally used at normothermia (2 to 2.5 Lmin-1m-2) would be considered a low cardiac output state in a normothermic person with a normal hematocrit. This could not be considered a flow rate that might compensate for the effects of hemodilution. Nevertheless, clinical experience suggests that hemodilution to a hematocrit between 20% and 30% in the adult undergoing continuous mildly or moderately hypothermic CPB is not associated with neurologic injury, 6 although comprehensive neuropsychometric testing has only recently been widely employed. One multiinstitutional study of adults found that lower hematocrit was associated with a postoperative decrease in cognitive score. 23
The effects of deep hypothermia on microvascular circulation are complex and include red blood cell aggregation and arteriovenous shunting. 24 The role of hemodilution in reversing these effects was reviewed by Cooper and Elliott. 4 Edmunds and associates 25 suggested that the presence of microinfarction observed from sections of the brain taken from animals subjected to DHCA was related to the presence of blood within the brain during the period of DHCA. In a study in our laboratory with a blood-free solution (Hypothermosol; Cryomedical Sciences, Rockville, Md.) in the cerebral circulation during DHCA, however, outcome as determined by NIRS and by neurologic score was inferior to outcome with blood perfusate. 13 This study revealed no histologic evidence of microinfarcts. Most previous studies of microcirculatory disturbance in the setting of DHCA predate more recent interest in endothelial and white blood cell activation and its relationship to ischemia. 26 Future studies should focus on the role of upregulation of adhesion molecules in contributing to microcirculatory disturbance after DHCA. The role of red blood cell aggregation may have been overemphasized.
This is the first study from our laboratory that has combined MRS and NIRS with postoperative neurologic evaluation and histologic assessment in the same animals. We hoped to identify changes in intraoperative MRS and NIRS parameters that best predicted neurologic and histologic outcomes, and we therefore calculated Pearson coefficients. Although no definite predictors were identified, it is interesting to note the trends in r and p values. For example, for ATP at DHCA 60 minutes versus NDS on day 1, p was 0.98; for cytochrome aa3 at DHCA 60 minutes versus NDS on day 1, p was 0.2; for pH at DHCA 60 minutes versus NDS on day 1, p was 0.12. The lack of statistically significant predictors is perhaps not surprising in light of the small numbers and the fact that DHCA time was limited to minimize mortality, rather than being extended to achieve severe neurologic injury as has been done in some previous studies from our laboratory.
In conclusion, extreme hemodilution results in evidence of inadequate oxygen delivery during the initial cooling phase and during DHCA. Whole-blood priming is associated with optimal preservation of mitochondrial redox state, optimal preservation of high-energy phosphates, and subsequently better early neurologic and histologic scores. The improved cerebral recovery with higher hematocrit after DHCA might in part be explained by greater oxygen availability and therefore preservation of high-energy phosphate metabolism. However, the effects of cerebral edema, low perfusion pressure, and low colloid oncotic pressure related to hemodilution could also be important. Further studies are underway to explore these variables.
Appendix: Discussion
Dr. Steven R. Gundry (Loma Linda, Calif.)
I congratulate you on designing a complex experimental model to once again look at the outcomes of various protocols for circulatory arrest. The fact that you were able to carry out this experiment successfully in a large number of piglets reflect your skills as surgeons and as managers of a bypass circuit.
You have attempted to compare three clinical protocols that are in use at Loma Linda, Boston, and Paris by means of three distinct methods of hemodilution or priming with whole blood. You have come to a remarkable conclusion in that you have concluded that your own protocol was not the winner, and you, the authors, are to be congratulated on admitting that. A review of the details of your perfusion mechanism, however, suggests that your conclusions are correct but your method of arriving at the conclusions may in fact be incorrect, and that you set yourself up to make the high hematocrit group win.
Specifically, I have these comments. You note in your article that the aortic cannula was placed in the femoral artery. This is far removed from the brain and completely opposite to the method used clinically, where the aortic cannula and thus the perfusate visit the brain first rather than last. This ensures that the brain is the last organ to be cooled in your model, rather than the first, as is done clinically.
Next, I noticed that your cooling occurs during a 40-minute period, and you specifically relate in your article that you used the entire 40 minutes to reach the cooling temperature. This implies that for most of the 40-minute cooling period the two groups with very low hemoglobin do in fact have very low oxygen-carrying capacity during periods of relative warmth of the brain. Your conclusions are therefore correct that during a prolonged, slow cooling period, the two groups that have the least oxygen carrying capacity and the slowest cooling of the brain would lose in this protocol, and that is exactly what you prove. Clinical protocols are exactly the opposite. The brain cannula is nearby and the brain is cooled rapidly, at Loma Linda specifically during a 10-minute period. Work by Schell and colleagues at Duke has shown fairly conclusively that rapid cooling of the brain results in much better brain metabolism after these short cooling periods compared with a long period for cooling of the brain.
Finally, I noticed that your group I was primed with hetastarch. Schell and colleagues at Duke have shown repeatedly that hetastarch undergoes viscosity changes at low temperatures. Specifically, hetastarch is not used in a priming solution at Loma Linda or at any other institution that I know of for circulatory arrest. I think that the fact that two animals out of the group I group died of hypotension suggests that this model was not tolerated systemically, either with the heart or any other organ, much less the brain; thus you set this model up to lose.
I have two questions. Do you believe that a more clinically relevant cannulation and cooling period would have changed your results, and perhaps that your own method of cooling would then have prevailed?
Second, do you think that the fact that two animals in group I died of hypotension suggests that the hetastarch, which is not used in any clinical protocol, may have been the reason for some of your findings?
I again congratulate you on a difficult study, but I think examination of your protocol shows what you might expect—a lot of blood with warm temperatures is better than no blood at warm temperatures.
Dr. Shin'oka. Thank you, Dr. Gundry. In response to the first issue, regarding the site of arterial cannulation, we do not agree that femoral cannulation would bias the result against the low-hematocrit groups. In fact, we believe it possible that the bias would be in the opposite direction, for the following reason. The fundamental problem in the low-hematocrit groups is that there is inadequate oxygen carrying capacity in the early phase of cooling, as demonstrated by reduction in the cytochrome aa3 signal and fall in PCr level. This is because of inadequate oxygen delivery from a low-hematocrit perfusate when the brain is still warm and the perfusate is cold. The more gradual cooling of the brain that results from femoral cannulation should, if anything, decrease this problem in the low-hematocrit groups.
Regarding the cooling duration of 40 minutes, we believe that the same issue applies here. In other words, a longer cooling duration allows any oxygen debt incurred in the early phase of cooling to be "paid off." We suspect that if a shorter cooling duration had been employed, the differences between the groups would have been exaggerated.
Finally, regarding the use of hetastarch, we have been interested in the work of Zikria and Oz at Columbia University regarding the biophysical properties of hetastarch when used during CPB and especially during DHCA. The group at Columbia uses hetastarch routinely in their CPB prime. They have demonstrated that not only is the use of hetastarch not deleterious during deep hypothermic circulatory arrest in the piglet model but in fact it is associated with a marked decrease in postoperative edema. Our inference from the deaths of two animals in the very low–hematocrit group, with no deaths in the other two groups, is therefore, that this is more likely related to inadequate oxygen delivery not only to the brain but also to other organs including the heart. We believe that the marked reduction of the cytochrome aa3 signal in the low-hematocrit group as well as the fall in PCr is convincing evidence that extreme hemodilution results in inadequate oxygen availability during the early phases of cooling on CPB.
Footnotes
From the Department of Cardiovascular Surgery, Children's Hospital, and Department of Surgery, Harvard Medical School, Boston,a the Department of Pathology, Children's Hospital, and Department of Pathology, Harvard Medical School, Boston,b the Department of Anesthesia and Intensive Care, Children's Hospital, and Department of Anesthesia, Harvard Medical School, Boston,c and the Department of Neurology, Children's Hospital and Department of Neurology, Harvard Medical School, Boston, Mass.d 
Read at the Seventy-sixth Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif., April 28–May 1, 1996.
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E. Hickey, T. Karamlou, J. You, and R. M. Ungerleider Effects of Circuit Miniaturization in Reducing Inflammatory Response to Infant Cardiopulmonary Bypass by Elimination of Allogeneic Blood Products Ann. Thorac. Surg., June 1, 2006; 81(6): S2367 - S2372. [Abstract] [Full Text] [PDF]
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C. Thuys, S. Horton, M. Bennett, and S. Augustin New technology increases perioperative haemoglobin levels for paediatric cardiopulmonary bypass: what is the benefit? Perfusion, January 1, 2006; 21(1): 39 - 44. [Abstract] [PDF]
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G. Amir, C. Ramamoorthy, R. K. Riemer, V. M. Reddy, and F. L. Hanley Neonatal Brain Protection and Deep Hypothermic Circulatory Arrest: Pathophysiology of Ischemic Neuronal Injury and Protective Strategies Ann. Thorac. Surg., November 1, 2005; 80(5): 1955 - 1964. [Abstract] [Full Text] [PDF]
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K. Karkouti, G. Djaiani, M. A. Borger, W. S. Beattie, L. Fedorko, D. Wijeysundera, J. Ivanov, and J. Karski Low Hematocrit During Cardiopulmonary Bypass is Associated With Increased Risk of Perioperative Stroke in Cardiac Surgery Ann. Thorac. Surg., October 1, 2005; 80(4): 1381 - 1387. [Abstract] [Full Text] [PDF]
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V. Anttila, I. Hagino, D. Zurakowski, Y. Iwata, L. Duebener, H. G.W. Lidov, and R. A. Jonas Specific Bypass Conditions Determine Safe Minimum Flow Rate Ann. Thorac. Surg., October 1, 2005; 80(4): 1460 - 1467. [Abstract] [Full Text] [PDF]
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I. Hagino, V. Anttila, D. Zurakowski, L. F. Duebener, H. G.W. Lidov, and R. A. Jonas Tissue oxygenation index is a useful monitor of histologic and neurologic outcome after cardiopulmonary bypass in piglets J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 384 - 392. [Abstract] [Full Text] [PDF]
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R. A. Jonas Hematocrit trial J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1200 - 1200. [Full Text] [PDF]
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J. T. Strauch, D. Spielvogel, P. L. Haldenwang, N. Zhang, D. Weisz, C. A. Bodian, N. A. Tatton, and R. B. Griepp Cooling to 10{degrees}C and treatment with Cyclosporine A improve cerebral recovery following prolonged hypothermic circulatory arrest in a chronic porcine model Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 74 - 80. [Abstract] [Full Text] [PDF]
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T. Sakamoto, D. Zurakowski, L. F. Duebener, H. G. W. Lidov, G. L. Holmes, R. J. Hurley, P. C. Laussen, and R. A. Jonas Interaction of temperature with hematocrit level and pH determines safe duration of hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., August 1, 2004; 128(2): 220 - 232. [Abstract] [Full Text] [PDF]
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S. S. L. Tsui, J. M. Schultz, I. Shen, and R. M. Ungerleider Postoperative hypoxemia exacerbates potential brain injury after deep hypothermic circulatory arrest Ann. Thorac. Surg., July 1, 2004; 78(1): 188 - 196. [Abstract] [Full Text] [PDF]
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G. Pardi, M. M. Ferrari, F. Iorio, F. Acocella, V. Boero, N. Berlanda, A. Monaco, C. Reato, F. Santoro, and I. Cetin The effect of maternal hypothermic cardiopulmonary bypass on fetal lamb temperature, hemodynamics, oxygenation, and acid-base balance J. Thorac. Cardiovasc. Surg., June 1, 2004; 127(6): 1728 - 1734. [Abstract] [Full Text] [PDF]
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V. Anttila, I. Hagino, D. Zurakowski, H. G. W. Lidov, and R. A. Jonas Higher bypass temperature correlates with increased white cell activation in the cerebral microcirculation J. Thorac. Cardiovasc. Surg., June 1, 2004; 127(6): 1781 - 1788. [Abstract] [Full Text] [PDF]
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T. Sakamoto, G. D. A. Nollert, D. Zurakowski, J. Soul, L. F. Duebener, J. Sperling, M. Nagashima, G. Taylor, A. J. duPlessis, and R. A. Jonas Hemodilution elevates cerebral blood flow and oxygen metabolism during cardiopulmonary bypass in piglets Ann. Thorac. Surg., May 1, 2004; 77(5): 1656 - 1663. [Abstract] [Full Text] [PDF]
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 H. Shimura, M. Masuda, M. Imamaki, and M. Miyazaki Evaluation of cerebral pathologic changes and long-term behavioral disorder after deep hypothermic circulatory arrest in dogs Interactive CardioVascular and Thoracic Surgery, December 1, 2003; 2(4): 466 - 471. [Abstract] [Full Text] [PDF]
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R. A. Jonas, D. Wypij, S. J. Roth, D. C. Bellinger, K. J. Visconti, A. J. du Plessis, H. Goodkin, P. C. Laussen, D. M. Farrell, J. Bartlett, et al. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1765 - 1774. [Abstract] [Full Text] [PDF]
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D. C. Bellinger, D. Wypij, A. J. duPlessis, L. A. Rappaport, R. A. Jonas, G. Wernovsky, and J. W. Newburger Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: The Boston Circulatory Arrest Trial J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1385 - 1396. [Abstract] [Full Text] [PDF]
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D. Shum-Tim, C. I. Tchervenkov, E. Laliberte, A.-M. Jamal, T. Nimeh, C.-Y. Luo, B. Bittira, and A. Philip Timing of steroid treatment is important for cerebral protection during cardiopulmonary bypass and circulatory arrest: minimal protection of pump prime methylprednisolone Eur. J. Cardiothorac. Surg., July 1, 2003; 24(1): 125 - 132. [Abstract] [Full Text] [PDF]
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R. H. Habib, A. Zacharias, T. A. Schwann, C. J. Riordan, S. J. Durham, and A. Shah Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: Should current practice be changed? J. Thorac. Cardiovasc. Surg., June 1, 2003; 125(6): 1438 - 1450. [Abstract] [Full Text] [PDF]
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R. Pretre and M. I. Turina Deep Hypothermic Circulatory Arrest Card. Surg. Adult, January 1, 2003; 2(2003): 401 - 412. [Full Text]
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C. Hagl, N. Khaladj, D. J. Weisz, N. Zhang, L. J. Guo, C. A. Bodian, D. Spielvogel, and R. B. Griepp Impact of high intracranial pressure on neurophysiological recovery and behavior in a chronic porcine model of hypothermic circulatory arrest Eur. J. Cardiothorac. Surg., October 1, 2002; 22(4): 510 - 516. [Abstract] [Full Text] [PDF]
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J. M. Forbess, K. J. Visconti, D. C. Bellinger, R. J. Howe, and R. A. Jonas Neurodevelopmental outcomes after biventricular repair of congenital heart defects J. Thorac. Cardiovasc. Surg., April 1, 2002; 123(4): 631 - 639. [Abstract] [Full Text] [PDF]
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T. Sakamoto, D. Zurakowski, L. F. Duebener, S.'i. Hatsuoka, H. G.W. Lidov, G. L. Holmes, U. A. Stock, P. C. Laussen, and R. A. Jonas Combination of alpha-stat strategy and hemodilution exacerbates neurologic injury in a survival piglet model with deep hypothermic circulatory arrest Ann. Thorac. Surg., January 1, 2002; 73(1): 180 - 189. [Abstract] [Full Text] [PDF]
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A. Undar, T. Masai, S.-Q. Yang, H. C Eichstaedt, M. C. McGarry, W. K Vaughn, J. Goddard-Finegold, and C. D Fraser Jr Global and regional cerebral blood flow in neonatal piglets undergoing pulsatile cardiopulmonary bypass with continuous perfusion at 25{degrees}C and circulatory arrest at 18{degrees}C Perfusion, December 1, 2001; 16(6): 503 - 510. [Abstract] [PDF]
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 L. F. Duebener, T. Sakamoto, S.-i. Hatsuoka, C. Stamm, D. Zurakowski, B. Vollmar, M. D. Menger, H.-J. Schafers, and R. A. Jonas Effects of Hematocrit on Cerebral Microcirculation and Tissue Oxygenation During Deep Hypothermic Bypass Circulation, September 18, 2001; 104 (2009): I-260 - I-264. [Abstract] [Full Text] [PDF]
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T. Sakamoto, S.'i. Hatsuoka, U. A. Stock, L. F. Duebener, H. G. W. Lidov, G. L. Holmes, J. S. Sperling, M. Munakata, P. C. Laussen, and R. A. Jonas Prediction of safe duration of hypothermic circulatory arrest by near-infrared spectroscopy J. Thorac. Cardiovasc. Surg., August 1, 2001; 122(2): 339 - 350. [Abstract] [Full Text] [PDF]
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C. Hagl, N. A. Tatton, D. J. Weisz, N. Zhang, D. Spielvogel, H. H. Shiang, C. A. Bodian, and R. B. Griepp Cyclosporine A as a potential neuroprotective agent: a study of prolonged hypothermic circulatory arrest in a chronic porcine model Eur. J. Cardiothorac. Surg., June 1, 2001; 19(6): 756 - 764. [Abstract] [Full Text] [PDF]
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M. A. Priestley, J. A. Golden, I. B. O'Hara, J. McCann, and C. D. Kurth Comparison of neurologic outcome after deep hypothermic circulatory arrest with alpha-stat and pH-stat cardiopulmonary bypass in newborn pigs J. Thorac. Cardiovasc. Surg., February 1, 2001; 121(2): 0336 - 343. [Abstract] [Full Text] [PDF]
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P. Sekaran, M. Ehrlich, C. Hagl, M. L. Leavitt, R. Jacobs, J. N. McCullough, and E. Bennett-Guerrero A Comparison of Complete Blood Replacement With Varying Hematocrit Levels on Neurological Recovery in a Porcine Model of Profound Hypothermic (<5{degrees}C) Circulatory Arrest Anesth. Analg., February 1, 2001; 92(2): 329 - 334. [Abstract] [Full Text] [PDF]
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J. M. Pearl, D. W. Thomas, G. Grist, J. Y. Duffy, and P. B. Manning Hyperoxia for management of acid-base status during deep hypothermia with circulatory arrest Ann. Thorac. Surg., September 1, 2000; 70(3): 751 - 755. [Abstract] [Full Text] [PDF]
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R. Sharma, S. K. Choudhary, M. R. Mohan, M. V. Padma, S. Jain, M. Bhardwaj, A. Bhan, U. Kiran, N. Saxena, and P. Venugopal Neurological evaluation and intelligence testing in the child with operated congenital heart disease Ann. Thorac. Surg., August 1, 2000; 70(2): 575 - 581. [Abstract] [Full Text] [PDF]
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T. Watanabe and Y. Shimazaki Reply Ann. Thorac. Surg., August 1, 2000; 70(2): 690 - 691. [Full Text] [PDF]
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S Dittrich, A Schuth, H Aurich, J vonLoeper, C Grosse-Siestrup, and P E Lange Haemodilution improves organ function during normothermic cardiopulmonary bypass: investigations in isolated perfused pig kidneys Perfusion, May 1, 2000; 15(3): 225 - 229. [Abstract] [PDF]
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A. Undar, W. K Vaughn, and J. H Calhoon The effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on blood viscoelasticity and cerebral blood flow in a neonatal piglet model Perfusion, March 1, 2000; 15(2): 121 - 128. [Abstract] [PDF]
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T. Shin’oka, G. Nollert, D. Shum-Tim, A. du Plessis, and R. A. Jonas Utility of near-infrared spectroscopic measurements during deep hypothermic circulatory arrest Ann. Thorac. Surg., February 1, 2000; 69(2): 578 - 583. [Abstract] [Full Text] [PDF]
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R. Berryessa, R. Wiencek, J. Jacobson, D. Hollingshead, K. Farmer, and G. Cahill Practical techniques Vacuum-assisted venous return in pediatric cardiopulmonary bypass Perfusion, January 1, 2000; 15(1): 63 - 67. [Abstract] [PDF]
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C. D. Kurth, M. Priestley, J. Golden, J. McCann, and R. Raghupathi REGIONAL PATTERNS OF NEURONAL DEATH AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST IN NEWBORN PIGS J. Thorac. Cardiovasc. Surg., December 1, 1999; 118(6): 1068 - 1077. [Abstract] [Full Text] [PDF]
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K. J. Visconti, D. P. Bichell, R. A. Jonas, J. W. Newburger, and D. C. Bellinger Developmental Outcome After Surgical Versus Interventional Closure of Secundum Atrial Septal Defect in Children Circulation, November 9, 1999; 100 (2009): II-145 - II-150. [Abstract] [Full Text] [PDF]
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G. Nollert, M. Nagashima, J. Bucerius, T. Shin'oka, H. G. W. Lidov, A. d. Plessis, and R. A. Jonas OXYGENATION STRATEGY AND NEUROLOGIC DAMAGE AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST. II. HYPOXIC VERSUS FREE RADICAL INJURY J. Thorac. Cardiovasc. Surg., June 1, 1999; 117(6): 1172 - 1179. [Abstract] [Full Text] [PDF]
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T. Shin'oka, M. Nagashima, G. Nollert, D. Shum-Tim, P. C. Laussen, H. G. W. Lidov, A. d. Plessis, and R. A. Jonas A NOVEL SIALYL LEWIS X ANALOG ATTENUATES CEREBRAL INJURY AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST J. Thorac. Cardiovasc. Surg., June 1, 1999; 117(6): 1204 - 1211. [Abstract] [Full Text] [PDF]
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T. Shin'oka, D. Shum-Tim, P. C. Laussen, S. M. Zinkovsky, H. G. W. Lidov, A. d. Plessis, and R. A. Jonas Effects of Oncotic Pressure and Hematocrit on Outcome After Hypothermic Circulatory Arrest Ann. Thorac. Surg., January 1, 1998; 65(1): 155 - 164. [Abstract] [Full Text] [PDF]
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