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J Thorac Cardiovasc Surg 1999;118:938-945
© 1999 Mosby, Inc.
CARDIOPULMONARY SUPPORT AND PHYSIOLOGY |
From the Departments of Surgerya and Anaesthesiologyb and the Laboratory of Clinical Neurophysiology,c Oulu University Hospital, and the Department of Forensic Medicine,d University of Oulu, Oulu, Finland.
Address for reprints: Tatu Juvonen, MD, PhD, Department of Surgery, Oulu University Hospital, FIN 90220 Oulu, Finland.
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Abstract |
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Introduction |
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1,2 The permissible period of hypothermic circulatory arrest (HCA) is limited, however, and low temperatures are associated with prolonged cooling and rewarming times and subsequent coagulation disturbances. 3,4 Retrograde cerebral perfusion (RCP) was introduced as a treatment for massive air embolism during cardiopulmonary bypass (CPB) in 1980. 5 In 1982, Lemole and colleagues 6 reported the use of intermittent RCP during the repair of a dissected thoracic aorta. Intermittent and continuous RCP were introduced by Ueda and colleagues 7 as methods of cerebral protection during surgery of the aortic arch. Since then, RCP has become very popular, especially in the field of aortic surgery. In previous studies it has been shown that RCP can improve neurologic outcome after prolonged HCA. 8 Imamaki and colleagues 9 have reported the use of cold RCP (10°C) in 2 patients undergoing aortic arch replacement. Good results have been reported after the use of the same kind of strategy in the surgical treatment of type A aortic dissections. 10 Moshkovitz and colleagues 11 in Toronto used cold RCP (10°C) during systemic hypothermia of 22°C to 28°C, demonstrating that this method is safe for up to 30 minutes of HCA. They reported excellent outcomes after the use of this technique in 104 patients operated on for disease of the proximal aorta. Despite these findings, there is still controversy regarding the safety of this method in a clinical setting. In this experimental study we tested the efficacy of deep hypothermic RCP for improved cerebral outcomes during moderate HCA.
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Methods |
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Preoperative management.
All animals received humane care in accordance 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, National Research Council, and published by the National Academy Press, revised 1996. The study was approved by the Research Animal Care and Use Committee of the University of Oulu.
Anesthesia and hemodynamic monitoring.
Anesthesia was induced with ketamine hydrochloride (10 mg/kg intramuscularly) and midazolam (1 mg/kg intramuscularly), and muscular paralysis was maintained with pancuronium bromide (0.1 mg/kg intravenously). After endotracheal intubation, the animals were maintained on positive pressure ventilation with 100% oxygen; anesthesia was maintained with isoflurane (1.1%-1.2%). The arterial catheter was positioned in the left femoral artery. A Swan-Ganz catheter (CritiCath, 7-F; Ohmeda GmbH & Co, Erlangen, Germany) was placed through the femoral vein to allow blood sampling and pressure monitoring in the pulmonary artery and for recording of cardiac output. Temperature probes were placed in the esophagus and rectum, and a 10-Ch nelaton catheter (Braun Melsungen AG, Melsungen, Germany) was placed in the urinary bladder to monitor urine output.
Electroencephalography monitoring.
Cortical electrical activity was registered from 4 stainless steel screw electrodes (5 mm in diameter) implanted in the skull over the parietal and frontal areas of the cortex by using a digital electroencephalography (EEG) recorder (Nervus, Island) and an amplifier (Magnus EEG 32/8, Island). Sampling frequency was 1024 Hz, with a bandwidth of 0.03 to 256 Hz. All EEG recordings are referenced to a frontal screw electrode, which, together with a ground screw electrode, is implanted over the frontal sinuses. Continuous EEG activity was recorded for 10 minutes after achievement of anesthesia before the cooling period (baseline) and after HCA until 4 hours after the beginning of rewarming. During general anesthesia, the EEG showed a burst-suppression pattern. Thus the recovery of the EEG was measured by the EEG burst ratio. The burst ratio was calculated as the summation of burst lengths divided by the length of the recording.
CPB.
Through a right thoracotomy in the fourth intercostal space, the heart and great vessels were exposed, the right mammarian artery and azygos vein were ligated, and the hemiazygos vein was snared. The superior vena cava (SVC) was mobilized. A membrane oxygenator (Midiflow D 705; Dideco, Mirandola, Italy) was primed with 1 L of Ringer acetate and heparin (5000 IU). After heparinization (300 IU/kg), the ascending aorta was cannulated with a 16F arterial cannula, and the right atrial appendage was cannulated with a single 24F atrial cannula. Nonpulsatile CPB was initiated at a flow rate of 100 mL · kg–1 · min–1, and afterward the flow was adjusted to maintain a perfusion pressure of 50 mm Hg. A cannula was positioned into the left ventricle for decompression of the left heart during CPB. A heat exchanger was used for core cooling. The pH was maintained by using alpha-stat principles at 7.40 ± 0.05 with an arterial PCO2 of 4.0 to 5.0 kPa uncorrected for temperature. All measurements were performed at 37°C.
The cooling period of 45 minutes was carried out to attain a rectal temperature of 25°C. Cardiac arrest was induced by injecting potassium chloride (1 mEq/kg) into the aortic cannula, and topical cardiac cooling was then begun and maintained throughout the aortic crossclamp period. The ascending aorta was crossclamped just proximal to the aortic cannula.
Experimental protocol.
After cooling to 25°C and crossclamping the aorta, the animals underwent a 45-minute interval of HCA with the head packed in ice or 5 minutes of HCA after 40 minutes of RCP (15°C) also with the head packed in ice and as dictated by the randomization protocol.
Preparations for RCP involved inserting a 14F cannula into the SVC, advancing it as cranially as possible, snaring it in place, and connecting it to the arterial line with a Y connector. The inferior vena cava (IVC) was not occluded. Retrograde flow was slowly increased and regulated to attain an SVC pressure of 20 mm Hg. In the RCP group perfusate returning from the upper body to the ascending aorta was drained to the collecting chamber and returned to the pump once its volume had been measured. The amount of sequestered fluid was also measured.
After 45 minutes, rewarming was initiated, the SVC and the left ventricular vent cannulas were removed, and the snared hemiazygos vein was released. Weaning from CPB occurred approximately 60 minutes after the start of rewarming with administration of furosemide (40 mg), mannitol (15.0 g), methylprednisolone (80 mg), and lidocaine (40-150 mg). Cardiac support was provided by dopamine. Animals were kept in isoflurane anesthesia until the following morning, extubated, and moved into a recovery room.
During the experiments, hemodynamic and metabolic measurements were recorded at 5 different time points as follows: (1) at baseline, after the Swan-Ganz catheter was positioned; (2) at the end of cooling (25°C) immediately before institution of the intervention; (3) during rewarming at 30°C; (4) 2 hours after the start of rewarming; and (5) 4 hours after the start of rewarming.
Postoperative evaluation.
Postoperatively, all the animals were evaluated daily by blinded observers using a species-specific quantitative behavioral score, as reported earlier. 12 The assessment quantified mental status (0, comatose; 1, stuporous; 2, depressed; and 3, normal), appetite (0, refuses liquids; 1, refuses solids; 2, decreased; and 3, normal), and motor function (0, unable to stand; 1, unable to walk; 2, unsteady gait; and 3, normal). Numerical summing of these functions provides a final score: the maximum (score of 9) reflects apparently normal neurologic function, whereas lower values indicate substantial neurologic damage. A score of 8 means that the animals were able to stand unassisted and were likely to recover fully.
Each surviving animal was electively killed on day 7 after surgery. The entire brain was immediately harvested and weighed for subsequent histologic analysis.
Histopathologic analysis.
During autopsy, the brain was excised immediately, and the hemispheres were separated. One half was immersed in 10% neutral formalin and allowed to fix for 2 weeks en bloc. After fixing, 3-mm thick coronal samples were taken from the frontal lobe, thalamus (including the adjacent cortex), and hippocampus (including the adjacent brain stem, and temporal cortex), and sagittal samples were taken from the posterior brain stem (medulla oblongata and pons) and cerebellum. The pieces were fixed in fresh formalin for another week. After the fixation, the samples were processed as follows: rinsing in water for 20 minutes, immersion in 70% ethanol for 2 hours, immersion in 94% ethanol for 4 hours, and immersion in absolute ethanol for 9 hours. Thereafter the pieces were kept for 1 hour in absolute ethanol-xylene mixture and 4 hours in xylene and embedded in warm paraffin for 6 hours. The samples were sectioned at 6 µm and stained with hematoxylin-eosin stain. The sections of the brain samples of each animal were screened by a single experienced senior pathologist (J. H.) who was unaware of the experimental design and the identity and fate of individual animals. Each section was carefully investigated for the presence or absence of any hypoxic or other damage.
Visual estimation of the injuries in the sampled regions was made as follows: 0, no morphologic damage identified; 1, edema, occasional dark neurons, or both; 2, numerous dark neurons (often also shrunk) and eosinophilic or dark-shrunk cerebellar Purkinje cells or hemorrhages; 3, clearly infarctive foci with neoformation of capillaries.
To allow semiquantitative comparisons between the animals, a total histologic score was calculated by adding all the regional scores. A score of more than 4 means that the animal had a distinct brain injury.
Other measurements.
Systemic arterial and venous blood samples were obtained to determine pH, PO2, PCO2, oxygen saturation, oxygen content, and hematocrit, hemoglobin, and glucose levels (Ciba-Corning 288 Blood Gas System; Ciba-Corning Diagnostic Corp, Medfield, Mass). Lactate was analyzed by using a YSI 1500 (Yellow Springs Instrument Co, Yellow Springs, Ohio). Temperatures were recorded at intervals throughout the study.
Statistical analysis.
Summary statistics for continuous or ordinal variables are expressed as the median with 25th and 75th percentiles or means with standard deviation of means. In the figures values are shown as medians with interquartile range. Statistical significance was determined by an independently sampled 1-tailed t test for equality of means between the treatment groups. If t-test assumptions (normality or equality of variances) did not hold, the analysis was performed by using the corresponding nonparametric test (Mann-Whitney U test). Statistical significance was determined longitudinally by 2-way analysis of variance. If significant differences were found by the analysis of variance, relevant pairwise comparisons were performed, and the significance levels were reported. Comparisons between each time point and baseline were done by a set of paired t tests or Wilcoxon signed-rank tests. Normality was tested first, and if it failed, the analysis was performed by using the corresponding nonparametric test (Wilcoxon).
However, the levels of statistical significance should be interpreted with caution, given the large number of statistical tests performed. Analyses were performed by using a standard commercially available statistical program (SPSS Inc, Chicago, Ill).
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Results |
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Comparability of experimental groups.
The mean weight of the animals in the HCA group was 26 ± 2 kg (SD), and that in the RCP group was 26 ± 2 kg (P = .9). The mean CPB cooling time in the HCA group was 45 ± 2 minutes, and that in the RCP group was 45 ± 1 minutes (P = 1.0). Warming time in the HCA group was 59 ± 12 minutes, and that found in the RCP group was 56 ± 6 minutes (P = .6). Rectal temperature measurements(Fig 1) showed some drift upward from baseline in both groups during HCA, but there were no significant differences between the groups.
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). The oxygen extraction was significantly higher in the HCA group at the beginning of rewarming. A similar difference, although not significant, was seen over the period of rewarming. The oxygen consumption did not differ significantly between the groups(Table II).
Morbidity and mortality rates.
All animals were stable during the surgical procedures and survived to at least postoperative day 1. Seven (69%) of the 12 animals survived 7 days after surgery and were electively killed. In the RCP group, 5 (83%) of 6 animals survived 7 days compared with 2 (33%) of 6 in the HCA group (P = .04).
Behavioral outcome.
The results of behavioral scoring for both groups are shown inFig 2. A score of 8 and 9 indicate an essentially complete neurologic recovery. Animals who died early were given a score of zero beginning at the time of death. Complete behavioral recovery was seen in 4 (67%) of 6 animals after RCP compared with only 1 (17%) of 6 in the HCA group. At day 7, there was a significant difference in behavioral scores between the groups (P = .04).
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Discussion |
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In this study both groups had decreased pH levels after intervention, and 2 hours after the start of rewarming, the HCA group was significantly more acidotic. The venous lactate levels increased significantly during cooling and after intervention in both of the groups, and these levels remained significantly higher in the HCA group. The oxygen extraction rate was found to be higher in the HCA group during rewarming. We assume that this is a result of the ability of RCP to provide at least minimal tissue oxygenation. On the other hand, the cold RCP is able to reduce tissue oxygen metabolism, and decreased oxygen extraction could be a result of more effective cooling in this group. Previous studies have shown that RCP does not provide nutritive flow to the brain and that its most important benefit is its cooling effect, 13 with a subsequent decrease in the metabolic rate.
This model was originally designed to study the strategies for brain protection during aortic arch surgery. Most surgeons in this field of adult cardiac surgery choose the alpha-stat protocol for acid base management, and therefore this protocol was used in this study. In the alpha-stat strategy blood gases are regulated to remain pH neutral at normal body temperature, resulting in a relatively alkaline environment during hypothermia, and cerebral autoregulation is fairly well preserved. Cerebral blood flow is reduced more or less in concert with diminishing cerebral oxygen requirements. pH-Stat management, in turn, requires adding carbon dioxide to gas mixtures to correct the blood for body temperature. This more acidic environment promotes cerebral vasodilatation, and cerebral blood flow quickly exceeds that required for the maintenance of cerebral metabolic requirements, resulting in what has been termed luxury perfusion. The advantage of pH-stat management is that it allows more rapid cooling and rewarming as a result of vasodilatation, and therefore many pediatric cardiac surgeons prefer this method. But the inherited problem related to pH-stat protocol is that this strategy may expose the brain for increased embolic load because of vasodilatation, the absence of autoregulation of the cerebral blood flow. 14
RCP has been enthusiastically adopted for aortic arch surgery to increase the permissible period of HCA and to flush out cerebral emboli. There exists a substantial amount of clinical reports supporting these expectations. 14,15 These hypotheses were recently tested in 2 studies. 8,12 Snaring the IVC provided a more efficient means of flushing out of cerebral emboli but was related to subsequent brain edema. 12,15 In the second study RCP with the IVC open enhanced cerebral protection during 90 minutes of HCA at 20°C, but once again was associated with a high rate of fluid sequestration. 8 In the current study the median sequestration volume was only 190 mL. The major difference between these studies, which used the same animal model, was the site of venous pressure recordings. In previous studies pressure was monitored in the sagittal sinus, 8,12 whereas the SVC was the site of pressure readings in our current study.
There exists a substantial amount of data suggesting that RCP-related cerebral injury occurs during the reperfusion phase. 12 In that study almost complete recovery of brain stem–evoked responses were seen shortly after the beginning of rewarming in animals that had undergone RCP, but this activity diminished over the following few hours. In terms of EEG recovery, a similar trend was seen in the present study, as depicted inFig 4. EEG activity recovered much faster after RCP compared with HCA, with this difference being highest 2
hours after the start of rewarming. After that time point, however, a striking drawback was seen in the RCP group, a finding emphasizing the previously set hypothesis that RCP exposes the brain to reperfusion injury. 16 This phenomenon is most likely related to a high rate of fluid sequestration and subsequent development of brain edema during and after RCP. This has been documented by other investigators as well. 17-19
The results of this study suggest that cold continuous RCP during moderate HCA provides better cerebral protection compared with HCA alone, and it may not be necessary to cool the whole body by CPB to deep hypothermia. The advantages of this technique are the shortened cooling and rewarming CPB times. 11 Enhanced CPB time was associated with an increased risk of stroke and increased mortality rate in a large clinical series of patients undergoing aortic arch surgery with RCP. 20 This is of particular importance in elderly patients who have impaired autoregulation of cerebral blood flow, predisposing their brain to an embolic load during CPB. In addition, during CPB, platelet dysfunction occurs and prolonged CPB time increases the risk of bleeding complications. 21 Deep hypothermia decreases the activity of the enzymes involved in platelet activation pathways and reduces the enzymatic activity of clotting factors on coagulation activation. This ultimately leads to a retardation of fibrin-platelet clot generation. These phenomena are compounded by the presence of heparin, which may significantly contribute to a bleeding tendency. 3
In conclusion, this study showed that cold RCP during moderate HCA seems to improve neurologic outcome compared with moderate HCA with the head packed in ice. The model is one of severe injury, and even with the beneficial effects demonstrated in the RCP group, these are not results that would be at all acceptable in the clinical situation. In addition, present findings shed more light on the hypothesis that RCP itself may have some potential for harm. Accordingly, careful attention must be paid on its implementation. Further studies are needed to determine the mechanisms of RCP-related cerebral injury, which most likely occurs during reperfusion.
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Acknowledgments |
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Supported by grants from Oulu University Hospital and the Finnish Heart Foundation and Ingegerd and Viking Olov Björk Scholarship for Cardiothoracic Research (Dr Juvonen).
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This article has been cited by other articles:
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  D. Harrington, C. H. Wong, and R. S. Bonser Neurological Complications of Aortic Surgery Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2002; 6(1): 7 - 16. [Abstract] [PDF]
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W. A. L. Soong, S. Uysal, and D. L. Reich Cerebral Protection During Surgery of the Aortic Arch Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2001; 5(4): 286 - 292. [Abstract] [PDF]
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 D. L. Reich, S. Uysal, M. A. Ergin, and R. B. Griepp Retrograde cerebral perfusion as a method of neuroprotection during thoracic aortic surgery Ann. Thorac. Surg., November 1, 2001; 72(5): 1774 - 1782. [Abstract] [Full Text] [PDF]
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 J. Rimpilainen, M. Pokela, K. Kiviluoma, V. Anttila, V. Vainionpaa, J. Hirvonen, P. Ohtonen, A. Mennander, E. Remes, and T. Juvonen Leukocyte filtration improves brain protection after a prolonged period of hypothermic circulatory arrest: A study in a chronic porcine model J. Thorac. Cardiovasc. Surg., December 1, 2000; 120(6): 1131 - 1140. [Abstract] [Full Text] [PDF]
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V. Anttila, J. Rimpilainen, M. Pokela, K. Kiviluoma, M. Makiranta, V. Jantti, V. Vainionpaa, J. Hirvonen, and T. Juvonen Lamotrigine improves cerebral outcome after hypothermic circulatory arrest: A study in a chronic porcine model J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 247 - 255. [Abstract] [Full Text] [PDF]
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J. M. Murkin Central Nervous System Complications in Cardiac Surgery: Retrograde Cerebral Perfusion, Pressure, Pulsatility, Temperature, and pH Management During Cardiopulmonary Bypass Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 2000; 4(2): 65 - 69. [Abstract] [PDF]
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V. Anttila, M. Pokela, K. Kiviluoma, M. Makiranta, J. Hirvonen, and T. Juvonen Is maintained cranial hypothermia the only factor leading to improved outcome after retrograde cerebral perfusion? An experimental study with a chronic porcine model J. Thorac. Cardiovasc. Surg., May 1, 2000; 119(5): 1021 - 1029. [Abstract] [Full Text] [PDF]
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