左旋精氨酸对犬深低温停循环脑氧代谢的影响

目的 利用犬深低温停循环(DHCA)动物模型,研究左旋精氨酸(L-arg)预处理对DHCA不同时期犬脑氧代谢及超微结构的影响.方法 健康成年杂种犬15只,分为3组,即对照组;L-arg预处理组:停循环前60min给予L-arg100mg/kg预处理;联合处理组:停循环前60min给予L-arg100mg/kg、7-硝基吲唑(7-Ni)25mg/kg联合处理,每组各5只.按临床方法建立体外循环转流降温至鼻咽部温18℃停循环,90min后恢复循环复温.分别于停循环前30min、停循环时(0min)、停循环45min、停循环90min、复温再灌注60min抽取颈静脉、颈动脉血测颈静脉血氧饱和度(SjvO2)、一氧化氮(NO).实验犬处死时颈动脉灌注4%多聚甲醛固定,取脑皮质、海马行透射电镜观察脑组织超微结构.结果 L-arg预处理和联合处理均可增加血浆N0含量、提高DHCA期SjvO2,改善脑氧代谢,减轻脑超微结构损害.停循环前血浆NO与停循环后SjvO2呈正相关(r=0.679,P=0.005).结论 DHCA前给予L-arg预处理有较好的脑保护效果.     

Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs

We previously found mild hypothermia (34-36 degrees C), induced before cardiac arrest, to improve neurologic outcome. In this study we used a reproducible dog model to evaluate mild hypothermia by head cooling during arrest, continued with systemic cooling (34 degrees C) during recirculation and for 1 h after arrest. In four groups of dogs, ventricular fibrillation (no flow) of 12.5 min at 37.5 degrees C was reversed with cardiopulmonary bypass and defibrillation in less than or equal to 5 min, and followed by controlled ventilation to 20 h and intensive care to 96 h. In Study A we resuscitated with normotension and normal hematocrit; Control Group A-I (n = 12) was maintained normothermic, while Treatment Group A-II (n = 10) was treated with hypothermia. In Study B we resuscitated with hypertension and hemodilution. Control Group B-I (n = 12) was maintained normothermic (6 of 12 were not hemodiluted), while Treatment Group B-II (n = 10) was treated with hypothermia. Best overall performance categories (OPCs) achieved between 24 and 96 h postarrest were in Group A-I: OPC 1 (normal) in 0 of 12 dogs, OPC 2 (moderate disability) in 2, OPC 3 (severe disability) in 7, and OPC 4 (coma) in 3 dogs. In Group A-II, OPC 1 was achieved in 5 of 10 dogs (p less than 0.01), OPC 2 in 4 (p less than 0.001), OPC 3 in 1, and OPC 4 in 0 dogs. In Group B-I, OPC 1 was achieved in 0 of 12 dogs, OPC 2 in 6, OPC 3 in 5, and OPC 4 in 1 dog. In Group B-II, OPC 1 was achieved in 6 of 10 dogs (p less than 0.01), OPC 2 in 4 (p less than 0.05), and OPC 3 or 4 in 0 dogs. Mean neurologic deficit and brain histopathologic damage scores showed similar significant group differences. Morphologic myocardial damage scores were the same in all four groups. We conclude that mild brain cooling during and after insult improves neurologic outcome after cardiac arrest.     

Hypertension with hemodilution prevents multifocal cerebral hypoperfusion after cardiac arrest in dogs.

BACKGROUND: Improved neurological outcome with postarrest hypertensive hemodilution in an earlier study could be the result of more homogeneous cerebral perfusion and improved O2 delivery. We explored global, regional, and local cerebral blood flow by stable xenon-enhanced computed tomography and global cerebral metabolism in our dog cardiac arrest model. METHODS: Ventricular fibrillation cardiac arrest of 12.5 minutes was reversed by brief cardiopulmonary bypass, followed by life support to 4 hours postarrest. We compared control group I (n = 5; mean arterial blood pressure, 100 mm Hg; hematocrit, greater than or equal to 35%) with immediately postarrest reflow-promoted group II (n = 5; mean arterial blood pressure, 140-110 mm Hg; hypervolemic hemodilution with plasma substitute to hematocrit, 20-25%). RESULTS: After initial hyperemia in both groups, during the "delayed hypoperfusion phase" at 1-4 hours postarrest, global cerebral blood flow was 51-60% of baseline in group I versus 85-100% of baseline in group II (p less than 0.01). Percentages of brain tissue voxels with no flow, trickle flow, or low flow were lower (p less than 0.01) and mean regional cerebral blood flow values were higher in group II (p less than 0.01). Global cerebral oxygen uptake recovered to near baseline values at 3-4 hours postarrest in both groups. Postarrest arterial O2 content, however, in hemodiluted group II was 40-50% of that in group I. Thus, the O2 uptake/delivery ratio was increased (worsened) in both groups at 2-4 hours postarrest. CONCLUSIONS: After prolonged cardiac arrest, immediately induced moderate hypertensive hemodilution to hematocrit 20-25% can normalize cerebral blood flow patterns (improve homogeneity of cerebral perfusion), but does not improve cerebral O2 delivery, since the flow benefit is offset by decreased arterial O2 content. Individualized titration of hematocrit or hemodilution with acellular O2 carrying blood substitute (stroma-free hemoglobin or fluorocarbon solution) would be required to improve O2 uptake/delivery ratio.     

Moderate hypothermia after cardiac arrest of 17 minutes in dogs. Effect on cerebral and cardiac outcome

Moderate hypothermia (30 degrees C) induced before circulatory arrest is known to improve neurologic outcome. We explored, for the first time in a reproducible dog outcome model, moderate hypothermia induced during reperfusion after cardiac arrest (resuscitation). In three groups of six dogs each (N = 18), normothermic ventricular fibrillation cardiac arrest (no blood flow) of 17 minutes was reversed by cardiopulmonary bypass--normothermic in control group I (37.5 degrees C) and hypothermic to 3 hours in groups II (32 degrees C) and III (28 degrees C). Defibrillation was achieved in less than or equal to 5 minutes and partial bypass was continued to 4 hours, controlled ventilation to 20 hours, and intensive care to 96 hours. All 18 dogs survived. Electroencephalographic activity returned significantly earlier in groups II and III. Mean +/- SD best neurologic deficit between 48 and 96 hours was 44 +/- 8% in group I, 38 +/- 12% in group II, and 35 +/- 7% in group III (differences not significant). Best overall performance category 2 (good outcome) between 48 and 96 hours was achieved in none of the six dogs in group I and in four of the 12 dogs in the combined hypothermic groups II and III (difference not significant). Mean +/- SD brain total histologic damage score was 130 +/- 22 in group I, 93 +/- 28 in group II (p = 0.05), and 80 +/- 26 in group III (p = 0.03). Gross myocardial damage was greater in groups II and III than in group I--numerically higher overall and significantly higher in group III for the right ventricle alone (p = 0.02). Moderate hypothermia after prolonged cardiac arrest may or may not improve cerebral outcome slightly and can worsen myocardial damage.     

Neuropathologic aspects of hypothermic circulatory arrest in newborn dogs

Summary A model of hypothermic circulatory arrest with recovery has been developed in the newborn dog. Eleven puppies were anesthetized with halothane, paralyzed and artificially ventilated with 70% nitrous oxide –30% oxygen to paO₂>60 mm Hg, paCO₂=33–42 mm Hg and pHa=7.35–7.42. Animals were surface cooled to 20°C, following which cardiac arrest was effected with i.v. KCl. Dogs remained asystolic without ventilation for 1.0, 1.5 or 1.75. Resuscitation was accomplished with closed-chest compression, mechanical ventilation, i.v. epinephrine and NaHCO₃, and rewarming to 37°C. Thereafter, the puppies were allowed to recover from anesthesia and maintained for either 18–22 h (n=9) or 72 h (n=2), at which time they underwent perfusion-fixation of their brains for pathologic analysis. Of the total, four out of four puppies arrested for 1.0 h exhibited no brain damage, including one recovered for 72 h; whereas one out of three and four out of four puppies arrested for 1.5 and 1.75 h, respectively, showed brain damage predominantly of the cerebral cortex but also of the basal ganglia and amygdaloid nucleus. The hippocampus was spared, even in a 1.75-h-arrested animal which was maintained for 72 h. No differences in pre- or post-arrest systemic blood pressure, heart rate, or acid-base balance were observed between the brain damaged and undamaged animals except for the single damaged animal arrested for 1.5 h, for which the blood pressure prior to cardiac arrest and during recovery was the lowest of all survivors. We conclude that newborn dogs undergoing hypothermic circulatory arrest for 1.0–1.5 h and which are fully recoverable without systemic hypotension exhibit no brain damage, whereas puppies arrested for 1.75 h exhibit brain damage entirely on the basis of global cerebral ischemia arising during the cardiac arrest. The experimental model has relevance to newborn human infants undergoing hypothermic circulatory arrest for the operative correction of congenital heart defects and should be useful for studying mechanisms of cellular injury in brain and other organs during prolonged ischemia.     

Method for preservation of water content during prolonged storage of cerebral tissue

We set out to determine whether prolonged freezing of samples of cerebral tissue would alter specific gravity measurements. Our goal was to devise a method to prevent tissue water evaporation during transportation and storage of human cerebral samples in order to allow accurate measurements of specific gravity and water content at a delayed time. Control cerebral samples from healthy and water-intoxicated anaesthetized adult mice were immediately immersed in a gravimetric column for fresh specific gravity measurements. Cerebral samples from the same animals were also preserved by rapid freezing in liquid nitrogen, followed by deep-freeze storage at -80 degrees C for up to 7 days. The mean specific gravity and standard error of 65 non-oedematous and 18 oedematous fresh cerebral samples was 1,0483 +/- 2 x 10(-4) and 1,0433 +/- 5 x 10(-4), respectively. Freezing for 1 h to 7 days resulted in no significant alteration of specific gravity for 109 non-oedematous and 27 oedematous samples (P greater than 0.05). We describe a rapid freezing technique that is practical for transportation and storage of experimental or surgical cerebral specimens. Our findings indicate that storage of cerebral samples in liquid nitrogen, with or without subsequent deep-freezing, preserves water content of normal and oedematous cerebral tissue, thereby allowing accurate measurements at a later time.     

Deferoxamine improves early postresuscitation reperfusion after prolonged cardiac arrest in rats.

The no-reflow phenomenon and delayed hypoperfusion after transient cardiac arrest (CA) impede postischemic recovery. Activation of lipid peroxidation (LPO) after ischemia and reperfusion is considered one of the mechanisms responsible for such abnormalities. The present study investigates the influence of iron-dependent LPO inhibitor deferoxamine (DFO) on the cerebral perfusion after prolonged CA and resuscitation. Fourteen male Sprague-Dawley rats were subjected to 17 minutes of CA, induced by esmolol (an ultrashort-acting beta-blocker) and apnea, followed by resuscitation by retrograde intraaortic infusion of oxygenated donor blood mixed with a resuscitation cocktail inside a vertical-bore 9.4-T magnetic resonance imaging (MRI) magnet. Animals were randomized double-blindly into two groups to receive DFO or saline, respectively. Cerebral perfusion was measured by MRI continuously using the arterial spin-labeling method before, during, and after CA. All animals were successfully resuscitated in 1.36 +/- 0.04 minutes with well-controlled arrest time (17.99 +/- 0.03 minutes) in both groups. Deferoxamine significantly increased cerebral perfusion in hippocampus, thalamus, hypothalamus, and amygdala, but not in cortex, during the first 20 minutes of reperfusion. In the DFO-treated group, the neurologic deficit score was significantly better (400 +/- 30 vs. 250 +/- 47, out of 500 as the best, P < 0.05) and weight loss was significantly less (33 +/- 6 vs. 71 +/- 19 g, P < 0.05) 5 d after arrest. The finding supports the notion that early reperfusion immediately after resuscitation is important for long-term outcome and that LPO may be involved in microvascular disorders during the reperfusion, particularly in the brain after prolonged cardiac arrest and resuscitation.     

Clipping of cerebral aneurysm under hypothermic cardiac arrest and simultaneous coronary artery bypass grafting: case report

This report describes a case where joint neurological and cardiac surgery teams cooperated to perform simultaneous procedures of clipping a complex internal carotid artery under hypothermic cardiac arrest and coronary artery bypass grafting. A 69 year old man was evaluated for complaints of double vision, pain behind his right eye, and progressively worsening headaches. Examination showed bilateral upgoing toes and difficulty performing a tandem gait. The patient had a history of myocardial infarction. Brain MRI showed a 1.6 cm diameter, partially thrombosed aneurysm of the right internal carotid artery and posterior communicating artery. Cardiac catheterisation showed critical coronary artery disease of the distal segment of the right coronary artery with 90% stenosis of the midcircumflex artery and an ejection fraction of 40%. After initial exposure of the aneurysm, the cardiac team instituted hypothermic cardiac arrest (21 degree C). The aneurysmal sac was collapsed and dissected from the surrounding perforators. An encircling fenestrated clip was applied and a small part of the neck of the aneurysm was further clipped with straight clips. The cardiac surgery team performed the coronary artery bypass grafting procedure. The patient recovered fully, returned to his normal activities, and is functioning independently.     

Neurological outcome of prolonged coma survivors of out-of-hospital cardiac arrest.

Nine adult survivors of out-of-hospital presumed cardiogenic cardiac arrest, who remained unresponsive for longer than their third hospital day and who eventually were discharged from the acute care hospital, are reported. Their neurological outcome fell into three distinct categories: (a) a persistent vegetative state, (b) able to follow some simple commands but requiring total nursing care, and (c) able to perform most activities of daily living but unemployable because of marked organic deficits.     

Return of neuronal functions after prolonged cardiac arrest

Cardiociculatory and respiratory arrest of 30 min was produced in normothermic cats by electrical ventricular fibrillation and tracheal occlusion. Resuscitation after cardiac arrest was attempted by open-chest manual heart massage and electrical fibrillation combined with pharmacological treatment of postischemic hypotension. In 8 out of 15 animals spontaneous heart action with systolic arterial blood pressure above 80 mm Hg returned. In these 8 cats cerebral blood flow was temporarily increased and signs of neuronal functions returned: the evoked pyramidal response started to reappear after 5 min, the cortical evoked potentials after 40 min, and spontaneous electrocortical activity after 45 min. Within 6 h the pyramidal response returned to 100%, the evoked potential to 75% and the EEG to 60% of their control amplitudes. In the cats in which systolic blood pressure was below 80 mm Hg, cerebral blood flow was not increased, and signs of functional recovery did not return or returned only transitorily. It is concluded that, with the techniques used, the return of neuronal functions after cardiac arrest is limited by the vulnerability of the heart and not that of the brain.     

Amelioration of brain damage after 12 minutes' cardiac arrest in dogs.

To determine the efficacy of cerebral microcirculation promoting therapy in postischemic brain failure, 11 dogs awakening from methohexital sodium anesthesia were subjected to 12 minutes of reversible circulatory arrest by ventricular fibrillation. Physiological variables were controlled for six hours after resuscitation, and the dogs were observed for seven days. Six dogs without the special postresuscitative therapy did not awaken, and either died within 36 hours or remained comatose for seven days. In five dogs, a combination of the following measures was applied: (1) mean arterial pressure was raised to 150 to 180 mm Hg with norepinephrine for six hours; (2) heparinization; (3) rapid intra-aortic injection of dextran 40 (10 ml/kg body weight); and (4) normovelemic hemodilution with dextran 40 to a hematocrit reading of 25% to 30%. All five treated dogs awakened within 24 hours and appeared normal on the seventh day. Therapy enhanced constriction of pupils and normalization of the electroencephalogram (P less than .05). Postischemic neurological deficit is at least partially due to impaired reperfusion and can be ameliorated or prevented by blood flowing-promoting therapy.     

Hypothermic-induced electrocerebral silence, prolonged circulatory arrest, and cerebral protection during cardiovascular surgery

Certain cardiovascular operations require cardiopulmonary bypass and prolonged circulatory arrest to provide an adequate operative field. Profound hypothermia is induced to protect brain function during these periods without cerebral perfusion. Because peripheral body temperatures may not be valid indicators of brain temperature, we conducted this study to establish an alternative, more reliable, method of determining the appropriate level of hypothermia. We measured peripheral body temperatures from 3 sites (rectum, nasopharynx, and esophagus) at the onset of hypothermic-induced electrocerebral silence (ECS) in the intraoperative electroencephalogram (EEG) of 56 adults undergoing cardiovascular procedures. The EEG in most patients showed a characteristic progression of changes from its normal resting state during cooling. Gradual depression and slowing of background rhythms was followed by generalized, periodic, slow-wave transients, prolongation of the intervals between the transients, and then the onset of ECS. In cases in which the slow-wave transients did not appear, the initial depression and slowing of background activity gradually progressed to ECS. No consistent relationship was found between peripheral body temperatures at various sites and the onset of ECS. Using EEG-guided hypothermia, there was low morbidity and mortality. These data suggest that ECS is a safe and reliable guide for determining the appropriate level of hypothermia during cardiovascular procedures.     

Visual evoked potentials during hypothermia and prolonged circulatory arrest.

Visual evoked potentials were recorded in eight children during hypothermia and circulatory arrest. The potentials were lost in all children recorded in late arrest. The evoked potential is a more sensitive indicator of CNS stress as provoked by combined hypothermia and hypoxia than is the EEG. EEG activity persisted in six of the eight children in this series even during circulatory arrest. The EEG had been seen to do the same in more than half of a larger series of children recorded at that stage. The results suggest that evoked potentials may be a sensitive indicator of early impairment of cerebral function and may demonstrate useful change sooner than the EEG. The examination may be useful in following children with illnesses producing hypoxia or anoxia. The N1 component was as easily and as frequently identifiable as the P2 component. Under the stress of this procedure, the latency of the P2 component became more variable than the N1 peak. The results suggest the N1 component may be as useful and perhaps more useful than the P2 wave in following the effect of some CNS stresses in children.     

犬心脏骤停后脑缺血的病理变化

目的：本文旨在观察心肺脑复苏过程中脑缺血的病理变化。方法：16条成年健康杂种犬，随机分为两组，以同法诱颤后复苏，A组诱颤后5分钟而B组诱颤后10分钟开始复苏，复苏成功后，立即取血、脑脊液标本进行脑型肌酸激酶同功酶（CK－BB）检查，72小时后取脑组织标本进行光、电镜检查。结果：A组脑型肌酸激酶同功酶明显低于B组，且其病理改变也明显轻微。结论：心脏骤停后脑复苏成功与否与时间密切相关，时间短则脑病理改变较轻。     

Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in dogs

Lipid peroxidation reactions during reperfusion after cardiac arrest may contribute to postischemic cerebral hypoperfusion, which in turn can contribute to permanent neurological dysfunction. We designed this study to determine whether the aminosteroid U74006F, a putative inhibitor of lipid peroxidation, mitigates cerebral multifocal hypoperfusion after cardiac arrest. We used our established dog model of ventricular fibrillation cardiac arrest (no blood flow) of 12.5 minutes, reperfusion by cardiopulmonary bypass of less than or equal to 5 minutes, and control of extracerebral variables during 4 hours postarrest. Cerebral blood flow was monitored by the stable xenon computed tomography method. Changes in cerebral oxygen consumption were obtained from mean blood flow values of coronal slices and the cerebral arteriovenous (sagittal sinus) oxygen content difference. A treatment group (n = 5) received U74006F starting with reperfusion (1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose 4.5, 7.5, or 14.5 mg/kg). The U74006F-treated group showed the same postarrest transient hyperemia and protracted hypoperfusion in terms of global (computed tomography slice), regional, and local (multifocal) cerebral blood flow values and the same global cerebral oxygen consumption pattern as a concurrent control group (n = 5). At 1-4 hours postarrest, in both groups there was mismatching of global cerebral oxygen consumption, which reached baseline values, in relation to global cerebral blood flow and oxygen delivery, which remained at 50% of baseline. We conclude that treatment with U74006F after prolonged cardiac arrest causes no deleterious side effects and does not seem to alter multifocal postarrest cerebral blood flow and oxygen consumption.     

Spindle activity in children during cardiac surgery and hypothermic cardiopulmonary bypass.

Hypothermia has marked effects on the electrical activity of the brain, which has been shown in animals as well as in humans. The aim of this study was to investigate EEG spindle activity in children during cardiac surgery and hypothermic cardiopulmonary bypass. The authors obtained intraoperative 21-channel EEG recordings in 36 children (mean age, 22 months; range, 6 days to 69 months) with congenital heart disease. Bipolar EEG derivations were analyzed visually for rhythmic spindle activity based on morphology, frequency, duration, and amplitude. Linear regression analysis for duration, frequency, and amplitude versus rectal temperature was performed in each individual. Spindle activity was observed in 17 children (16 children < 12 months of age). Progressive slowing of spindle frequency with decreasing rectal temperature was found (mean decrease, 0.54 +/- 0.31 Hz/ degrees C). Spindle duration increased on average by 0.69 +/- 0.39 second/ degrees C during cooling procedures. Spindle amplitude did not show any correlation to changes in rectal temperature. The current study demonstrates spindle activity during hypothermic cardiopulmonary bypass with temperature-dependent spindle modifications of frequency and duration. Although the temperature-dependent changes in this study confirm temperature coefficients of other EEG studies, the reasons for the clear age relationship and the "nature" of these spindles remain unknown.     

Hypertension with or without hemodilution after cardiac arrest in dogs

We studied blood flow-promoting therapies after cardiac arrest in 18 dogs. Our model consisted of ventricular fibrillation (no blood flow) lasting 12.5 minutes, controlled reperfusion with cardiopulmonary bypass and defibrillation within 5 minutes, controlled intermittent positive-pressure ventilation to 20 hours, and intensive care to 96 hours. Group I (control, n = 6) dogs were reperfused under conditions of normotension (mean arterial blood pressure 100 mm Hg) and normal hematocrit (greater than or equal to 35%). Group II (n = 6) and III (n = 6) dogs were treated with norepinephrine at the beginning of reperfusion to induce hypertension for 4 hours. In addition, group III dogs received hypervolemic hemodilution to a hematocrit of 20% using dextran 40. There were no differences in the time to recovery of electroencephalographic activity among groups. All six group I dogs remained severely disabled; in groups II and III combined, six of the 12 dogs achieved good outcome (p less than 0.01). Some regional histopathologic damage scores at 96 hours were better in groups II and/or III than in group I (neocortex: p less than 0.05 group II different from group I; hippocampus: p less than 0.01 both groups II and III different from group I). Total histopathologic damage scores were similar among the groups. A hypertensive bout with a peak mean arterial blood pressure of greater than or equal to 200 mm Hg beginning 1-5 minutes after the start of reperfusion was correlated with good outcome (p less than 0.01). Our results support the use of an initial bout of severe hypertension, but not the use of delayed hemodilution.     

Cortical brain microdialysis and temperature monitoring during hypothermic circulatory arrest in humans

OBJECTIVES—Critical vascular surgery of the brainor the heart occasionally requires total cessation of the circulatorysystem. Profound hypothermia is used to protect the brain fromischaemic injury. This study explores the use of microdialysis tomeasure metabolic indices of ischaemia: glutamate, lactate, and pH, andcerebral temperature during profound hypothermia and circulatory arrest.
METHODS—Effluent from a microdialysis catheterplaced in the cerebral cortex of three patients undergoing completecirculatory arrest was continuously sampled. Samples were pooled over10 minute periods and glutamate and lactate concentrations weremeasured postoperatively. Brain temperature and pH were measured online intraoperatively. Electroencephalography and monitoring ofsomatosensory evoked potentials and brainstem auditory evokedpotentials were simultaneously carried out.
RESULTS—Patient 1 had normal glutamate andlactate. PH was 6.75 to 6.85 and increased to 6.9 after warming ensued.Patient 2 had raised glutamate and lactate during most measurements.The glutamate concentrations peaked at 305 µM/l at the start of themeasurements and fell below 20 µM/l after warming. The lactateconcentrations peaked at 680 µM/l before cooling, rose to 1040 µM/lduring the cooling process, decreased to 212 µM/l during circulatoryarrest, and rose again to 620 µM/l after warming. The pH started at7.06and continued a downward course until stabilising at a pH of 6.5after circulatory arrest. Patient 3 had a transient, mild increase inglutamate and lactate during the cooling and warming period. pH wasstable throughout.
CONCLUSION—Microdialysis combinedwith temperature and pH measurements of the cerebral cortexpromises to be an important tool in detecting cerebral ischaemia.Further studies are needed to validate our findings and test thefeasibility of modifying ischaemic changes.