Abstract Retrograde cerebral perfusion (RCP) techniques have been adopted in aortic arch surgery for clinical use. The clear benefits of RCP are that it reduces embolic injury and prolongs the permissible period of hypothermic circulatory arrest (HCA). At the same time, however, there is a great deal of evidence according to which RCP may be associated with an increased risk of fluid sequestration and cerebral edema. In the current study intermittent RCP was compared with continuous RCP and HCA alone to clarify if periodical RCP decreases fluid sequestration (I). HCA is an effective method of cerebral protection, but is associated with long cardiopulmonary bypass times, and coagulation disturbances. We tested the hypothesis that deep hypothermic RCP could improve cerebral outcome during moderate HCA (II and III). Glutamate excitotoxicity plays an important role in the development of ischemic brain injury. The purpose of the present study was to determine the efficacy of lamotrigine, a Na+ channel blocker, to mitigate cerebral injury after HCA (IV). A chronic porcine model was used in the present series of studies. Hemodynamic, electrophysiologic, and metabolic monitoring were performed until four hours after the instigation of rewarming. S-100β was measured up to 20 hours. Daily behavioral assessment performed until death or elective sacrifice on the seventh postoperative day. After continuous RCP the median fluid sequestration volume was 145 (0–250) ml compared with -50 (-100 - 0) ml after intermittent RCP (p = 0.04). In comparison of 15°C RCP to HCA alone during moderate 25°C hypothermia, 5/6 animals in the RCP group survived seven days compared with 2/6 in the HCA group (p = 0.04). The total histopathologic scores in the RCP(15°C) group were lower than those for the RCP(25°C) group during moderate 25°C hypothermia (p = 0.04). EEG bursts were recovered better in the RCP(15°C) group at 3 hours after the start of rewarming compared to HCA group (p = 0.05). The rate of EEG burst recovery was higher in lamotrigine treated animals compared to placebo treated animals after 4 hours during the rewarming (p = 0.02). Among the animals that survived for 7 days, the median behavioral score was higher in the lamotrigine group (8) compared with controls (7) (p = 0.02). The results indicate that intermittent RCP decreases the rate of fluid sequestration after continuous RCP. The cold RCP at moderate systemic hypothermia seems to provide a better neurological outcome than that with moderate temperature RCP, a finding suggesting that enhanced cranial hypothermia is the major beneficial factor of RCP. The Na+ channel blocker lamotrigine improves neurological outcome after a prolonged period of HCA. In conclusion, two refinements in the RCP concept are to administer it at low temperatures and if longer periods of perfusion are necessary, RCP should be applied intermittently.

Abstract Cessation of the blood circulation for some time during surgery of the aortic arch and repair of congenital heart defects is normally required to allow a bloodless operation field. Hypothermia is the most important mechanism for end-organ protection, particularly the brain, during such operations. Cardiopulmonary bypass is used for core cooling before total hypothermic circulatory arrest (HCA) or selective cerebral perfusion (SCP) are initiated. During hypothermic cardiopulmonary bypass, pH can be managed according to either pH- or alpha-stat principles. In the present work, the optimal pH management strategy for operations requiring HCA or SCP was explored. An experimental porcine model was used. Firstly, outcome was evaluated in a HCA model using either the α- or pH-stat perfusion strategy (I). Secondly, we sought to determine which acid-base management is more effective in attenuating ischemic brain injury during combined HCA and embolization conditions (II). In the third study, the impact of propofol anesthesia and α-stat perfusion strategy on outcome was explored (III). Finally, the acute effects of perfusion strategies in a SCP porcine were compared (IV). Hemodynamics, temperature, EEG (I-III), brain microdialysis, intracranial pressure (I-III), brain tissue oxygen partial pressure (I-III), and intravital microscopy (IV) were monitored intraoperatively. In the chronic studies, survival, postoperative neurologic recovery and brain histopathologic examination were evaluated (I-III). pH-stat strategy was associated with superior outcome compared to the α-stat strategy during a 75-minute period of deep HCA (I). In addition, despite the pH-stat strategy-related cerebral vasodilatation, this method provided better neuroprotection in a setting of cerebral particle embolization prior to a 25-minute period of deep HCA (II). Propofol anesthesia combined with α-stat perfusion strategy was observed to deteriorate the brain injury during HCA evaluated by key brain microdialysis parameters (III). Finally, when employing moderately hypothermic SCP, the differences between pH- and α-stat strategies in cerebral metabolism and microcirculation were minimal. These findings are clinically relevant since α-stat perfusion strategy is still the most commonly used acid-base perfusion strategy during hypothermic cardiopulmonary bypass in adults, and propofol one of the most used anesthetics in clinical practice. It is also noteworthy that the pH-stat strategy is not currently used in adults because of the perceived increased risk of atherosclerotic embolization. However, the advantage of pH-stat strategy over α-stat strategy could not be observed when employing SCP.

Abstract In the repair of complex congenital heart defects or in surgery of the aortic arch, normal circulation may be temporarily halted to ensure a clean, bloodless operation field. The brain is the organ most vulnerable to ischemic injury during this no-flow period, and the mortality and morbidity of these procedures today consists mostly of neurological complications. Hypothermia decreases the need for oxygen and other metabolites, and cooling the patient with an extracorporeal heart-lung machine can provide enough time to perform the necessary surgical procedures during a circulatory standstill. This procedure is referred to as hypothermic circulatory arrest (HCA). Sometimes the cerebral circulation can be maintained even if the rest of the body undergoes circulatory arrest, and this strategy, involving separate catheterization of brain-destined vessels, is referred to as selective cerebral perfusion (SCP). In this work, four separate brain protection strategies were evaluated. Two studies were performed on a surviving porcine model (I, II) to evaluate neurological recovery as well as cerebral metabolism and histopathology, and two were acute in design (III, IV), employing the modern technology of intravital microscopy to examine cerebral microcirculation. The first study (I) showed that the administration of hypertonic saline dextran (HSD) led to a decrease in intracranial pressure, improved brain metabolism, better neurological recovery and less histopathological injury of the brain tissue in association with HCA. In the second study (II) a novel pharmacological molecule, levosimendan, reduced the intracranial pressure during the operation, but no improvement in terms of cerebral metabolism, neurological recovery or histopathological brain injury was observed after HCA. In the third study (III), real-time intravital microscopy showed that in association with HCA, a leukocyte depleting filter (LDF) attached to the cardiopulmonary bypass circuit reduces the number of activated leukocytes in cerebral microcirculation. In the fourth study (IV), cerebral metabolism and microcirculation were similar during SCP independent of the acid-base management strategy. The results of this work suggest that HSD could be assessed in human trials, that levosimendan needs further studies to optimize its potential, that the LDF functions as designed and that the differences between the α- and the pH-stat acid-base management strategies with SCP did not differ in moderate hypothermia.

A técnica de \"Inflow Occlusion\" pode ser utilizada em cirurgias cardíacas quando se pretende manter o coração aberto apenas por alguns minutos, para realização de pequenos reparos. No entanto, a parada circulatória total, evento decorrente da técnica em questão, pode acarretar severas alterações metabólicas e neurológicas, sendo necessária monitorização trans e pósoperatória do paciente. Neste estudo foram utilizados 12 cães sem raça definida, os quais foram divididos em dois grupos, A e B, submetidos a 7 e 8 minutos de parada circulatória total, respectivamente, utilizando-se da técnica de \"Inflow Occlusion\". Tentou-se estabelecer normotermia dos animais durante os procedimentos cirúrgicos. Foram realizados exames hemogasométricos, e avaliações clínica e neurológica nos momentos preconizados. Alterações neurológicas transitórias foram observadas em ambos os grupos. Ocorreram dois óbitos transoperatórios no grupo B, e um animal do mesmo grupo apresentou cegueira permanente no período pós-operatório. Apesar da acidose metabólica observada durante os procedimentos, o pH, pressão parcial de dióxido de carbono no sangue arterial, e bicarbonato plasmático arterial de ambos os grupos, retornaram aos valores normais após trinta minutos da parada circulatória. Apesar das alterações observadas, é lícito afirmar que o \"Inflow Occlusion\" é seguro por até 7 minutos. Após este período, no entanto, é contra-indicado, segundo resultados obtidos e óbitos transoperatórios relatados. / \"Inflow Occlusion\" technique can be used in heart surgeries when heart is required to be opened just for few minutes, to allow quick repairs. However, circulatory arrest, event occasioned by this technique, can produce serious metabolic and neurologic consequences to the patient, and monitorization on trans, and postoperatory moments is well recommended. In this study, 12 mongrel dogs were used, and were divided into two groups, A and B, submmited to 7 and 8 minutes of total circulatory arrest, respectively, using \"Inflow Occlusion\" technique. Normothermia was tried during surgical procedures. Hemogasometric analysis, and clinical and neurological exams were made, each of them, on the moments established for the experiment. There were some transitory neurological problems related to both groups. There were two transoperatory deaths in group B and one case of permanent blindness in the same group, on postoperatory period. Despite metabolic acidosis occurred during procedures, pH values, arterial dioxide carbon parcial pressure, and arterial plasmatic bicarbonate related to both groups, returned to basal levels thirty minutes after surgery. Even occuring some hemogasometric and neurologic alterations, we can say that \"Inflow Occlusion\" is safe for periods up to 7 minutes. After this period of time, however, it is contraindicated, as seen after these results and because transoperatory deaths.

No description available.

A técnica de \"Inflow Occlusion\" pode ser utilizada em cirurgias cardíacas quando se pretende manter o coração aberto apenas por alguns minutos, para realização de pequenos reparos. No entanto, a parada circulatória total, evento decorrente da técnica em questão, pode acarretar severas alterações metabólicas e neurológicas, sendo necessária monitorização trans e pósoperatória do paciente. Neste estudo foram utilizados 12 cães sem raça definida, os quais foram divididos em dois grupos, A e B, submetidos a 7 e 8 minutos de parada circulatória total, respectivamente, utilizando-se da técnica de \"Inflow Occlusion\". Tentou-se estabelecer normotermia dos animais durante os procedimentos cirúrgicos. Foram realizados exames hemogasométricos, e avaliações clínica e neurológica nos momentos preconizados. Alterações neurológicas transitórias foram observadas em ambos os grupos. Ocorreram dois óbitos transoperatórios no grupo B, e um animal do mesmo grupo apresentou cegueira permanente no período pós-operatório. Apesar da acidose metabólica observada durante os procedimentos, o pH, pressão parcial de dióxido de carbono no sangue arterial, e bicarbonato plasmático arterial de ambos os grupos, retornaram aos valores normais após trinta minutos da parada circulatória. Apesar das alterações observadas, é lícito afirmar que o \"Inflow Occlusion\" é seguro por até 7 minutos. Após este período, no entanto, é contra-indicado, segundo resultados obtidos e óbitos transoperatórios relatados. / \"Inflow Occlusion\" technique can be used in heart surgeries when heart is required to be opened just for few minutes, to allow quick repairs. However, circulatory arrest, event occasioned by this technique, can produce serious metabolic and neurologic consequences to the patient, and monitorization on trans, and postoperatory moments is well recommended. In this study, 12 mongrel dogs were used, and were divided into two groups, A and B, submmited to 7 and 8 minutes of total circulatory arrest, respectively, using \"Inflow Occlusion\" technique. Normothermia was tried during surgical procedures. Hemogasometric analysis, and clinical and neurological exams were made, each of them, on the moments established for the experiment. There were some transitory neurological problems related to both groups. There were two transoperatory deaths in group B and one case of permanent blindness in the same group, on postoperatory period. Despite metabolic acidosis occurred during procedures, pH values, arterial dioxide carbon parcial pressure, and arterial plasmatic bicarbonate related to both groups, returned to basal levels thirty minutes after surgery. Even occuring some hemogasometric and neurologic alterations, we can say that \"Inflow Occlusion\" is safe for periods up to 7 minutes. After this period of time, however, it is contraindicated, as seen after these results and because transoperatory deaths.

Abstract During surgery of the aortic arch and pediatric heart surgery, the blood flow to the brain has to be interrupted at times to allow a bloodless operation field and adequate conditions for surgical repair. During this no-flow period the brain is exposed to a high risk of ischaemic injury, as it will become irreversibly damaged after 5 minutes of circulatory arrest at 37°C. Additional time can be gained by cooling the patient with an extracorporeal heart-lung machine, as hypothermia reduces the cerebral metabolic rate and allows longer safe periods of circulatory standstill. This method of cerebral protection, called hypothermic circulatory arrest (HCA), is widely used in clinical practice. Thus the brain becomes susceptible to ischaemic injury after 30 minutes of HCA at 15°C. Lower temperatures than this are not practicable, however, as they require longer periods of cardiopulmonary bypass, which may further aggravate cerebral injury. To ensure a better outcome for patients undergoing these operations, additional ways of protecting the brain are required. The present work focuses on neuroprotective biochemical and fluid therapy methods for use during HCA, employing a surviving porcine model. Fructose-1,6-bisphosphate (FDP), a high-energy intermediate of glycolysis, was examined for potential neuroprotective properties in two cerebral injury settings associated with HCA. First, FDP was administered before and after a 75-minute period of HCA at a brain temperature of 18°C. This led to better survival, neurological recovery and brain histopathological findings and had supportive effects on brain metabolism (I). Second, a 25-minute period of HCA along with an iatrogenic embolic load produced by microsphere injection was used to generate a massive ischaemic injury to the brain. In this setting FDP did not affect the neurological outcome but had a clear supportive impact on cerebral metabolism (II). In addition, cerebral histopathological samples taken during the first study were analysed by electron microscopy, which revealed significant preservation of the ultrastructure in the FDP-treated animals (III). Hypertonic saline dextran (HSD) is a novel fluid therapy method which has been shown to enhance the outcome after hypovolaemic shock with or without head injury and is potentially very effective in reducing ischaemia-reperfusion injury. Its administration led to a decrease in intracranial pressure, improved brain metabolism, faster and better recovery and less histopathologically observable morphological damage (IV). The findings indicate that both FDP and HSD have significant neuroprotective properties and should be assessed in humans as well.

Abstract Interruption of cerebral blood flow during hypothermic circulatory arrest (HCA) predisposes neurons to glutamate excitotoxicity. Reperfusion is followed by leukocyte infiltration, which results in an inflammatory reaction in the brain tissue. In the first study, the presynaptic glutamate release inhibitor lamotrigine (L) and the leukocyte-depleting filter (LF) were studied to determine if their combination could mitigate brain injury after HCA (I). The aim of the second study was to evaluate the possible neuroprotective effect of a 14-hour period of mild (32°C) hypothermia after HCA (II). Recent experimental research has demonstrated the neuroprotective properties of erythropoietin (EPO) and fructose-1,6-bisphosphate (FDP), whose effects during and after HCA were evaluated in the third and the fourth studies (III, IV). A chronic porcine model was used. The animals were randomly assigned to the study groups as follows: 8 animals in the L+LF group, 8 in the L group, and 8 in the control group (I); 10 animals in the hypothermia group and 10 in the normothermia group (II); 10 animals in the EPO group and 10 in the control group (III), and 12 animals in the FDP group and 12 in the control group (IV). Monitoring of hemodynamics, metabolism, temperature, electroencephalogram (EEG), brain microdialysis, intracranial pressure (II-IV), and brain tissue oxygen (II-IV) was carried out. A daily behavioral assessment was performed until death or until elective sacrifice on the seventh postoperative day, after which the brain was prepared for a histopathologic examination. The results of these studies indicate that lamotrigine has a neuroprotective effect during HCA. This is observed in terms of EEG burst recovery, behavioral and histopathologic outcome, and brain microdialytic findings. The combined use of lamotrigine and leukocyte filtration may further improve survival. A 14-hour period of mild hypothermia after HCA is associated with a poor outcome. However, it may preserve its efficacy when used for no longer than 4 hours. Administration of EPO before HCA proved ineffective in reducing mortality or brain histopathologic injury. Findings from brain microdialysis, brain tissue oxygen tension, and neuronal apoptosis, however, suggest that the drug has neuroprotective properties. Administration of FDP before and after HCA is associated with better survival, behavioral outcome, and brain histopathologic scores. The metabolic and brain microdialytic findings also suggest that this drug has supportive effects on myocardial and brain metabolism.

Abstract Ischaemic cerebral injury follows a well attested sequence of events including three phases, i.e. depolarization, biochemical cascade and reperfusion injury. Glutamate excitotoxicity plays an important role in the development of ischaemic brain injury following prolonged hypothermic circulatory arrest (HCA), and leukocyte infiltration and a cytokine-mediated inflammatory reaction are known to play a pivotal role in the reperfusion phase. The aim of this series of experimental studies was to develop biochemical and reperfusion-related strategies to improve brain protection. We tested the hypotheses that the Na+ channel blocker lamotrigine (I) or the N-Methyl-D-Aspartate-receptor antagonist memantine (III) could improve the cerebral outcome after HCA and studied whether a leukocyte-depletion filter (L-DF; LeukoGuard LG6®, Pall Biomedical, Portsmouth, U.K) could mitigate brain injury (II). The aim of the fourth study was to find out whether lamotrigine combined with the leukocyte-depleting filter can potentiate cerebral protection (IV). A chronic porcine model was used, in which haemodynamic, electrophysiological, metabolic and temperature monitoring were performed for four hours after the instigation of rewarming and S-100β measured up to 20 hours. Cytokines were measured, microdialysis was performed, and daily behavioural assessments were made until death or elective sacrifice on the seventh postoperative day, upon which a histopathological analysis of the brain was carried out. The rate of EEG burst recovery was higher in the lamotrigine-treated animals, the median being 40% of the baseline compared with 17% in the placebo group at 4 hours after the start of rewarming (p = 0.02) and 80% compared with 20% at 4 hours (p = 0.01). Complete behavioural recovery was seen in 5/8 of cases (63%) after lamotrigine administration, compared with 1/8 (13%) in the placebo group (p = 0.02). The median behavioural score among the animals that survived for 7 days was higher in the lamotrigine group (8) than in the controls (7) (p = 0.02). Mortality was 2/10 in the L-DF group and 5/10 in the controls, the median behavioural score on day 7 being higher in the L-DF group (8.5 vs. 3.5 p = 0.04). The median of the total histopathological score was 6.5 in the L-DF group and 15.5 in the control group (p = 0.005). In the memantine group 5/10 animals survived seven days, as compared with 9/10 in the placebo group, and the median behavioural score on day 7 was 3.5 compared with 7.5 in the placebo group (p = 0.39). The median of the total histopathological score was 16 in the memantine group and 14 in the placebo group (p = 0.25). In the LD-F + lamotrigine group 7/8 animals survived for seven days, as compared with 4/8 in the lamotrigine only group and 3/8 among the controls. EEG burst recovery 7 hours after the start of rewarming was highest in the LDF + lamotrigine group, the median being 94% (p = 0.024 vs. controls), compared with 81% in the lamotrigine group and 64% in the control group. The median behavioural score on day 7 was 9 in the LD-F + lamotrigine group (p = 0.004 vs. controls), 4 in the lamotrigine group and 0 in the control group, while the median of total histopathological score was 14 (p = 0.046 vs controls), 14.5 (p = 0.062 vs. controls) and 21, respectively. The control group had the highest intracerebral lactate, glutamate and glycerol levels after HCA. In conclusion, the results indicate that the NA+ channel blocker lamotrigine improves the neurological outcome after a prolonged period of HCA but that the NMDA receptor antagonist memantine does not have this property in the present setting. The leukocyte-depleting filter mitigates brain injury after a prolonged period of HCA, and lamotrigine can potentiate this effect.

abstract: Aortic aneurysms and dissections are life threatening conditions addressed by replacing damaged sections of the aorta. Blood circulation must be halted to facilitate repairs. Ischemia places the body, especially the brain, at risk of damage. Deep hypothermia circulatory arrest (DHCA) is employed to protect patients and provide time for surgeons to complete repairs on the basis that reducing body temperature suppresses the metabolic rate. Supplementary surgical techniques can be employed to reinforce the brain's protection and increase the duration circulation can be suspended. Even then, protection is not completely guaranteed though. A medical condition that can arise early in recovery is postoperative delirium, which is correlated with poor long term outcome. This study develops a methodology to intraoperatively monitor neurophysiology through electroencephalography (EEG) and anticipate postoperative delirium. The earliest opportunity to detect occurrences of complications through EEG is immediately following DHCA during warming. The first observable electrophysiological activity after being completely suppressed is a phenomenon known as burst suppression, which is related to the brain's metabolic state and recovery of nominal neurological function. A metric termed burst suppression duty cycle (BSDC) is developed to characterize the changing electrophysiological dynamics. Predictions of postoperative delirium incidences are made by identifying deviations in the way these dynamics evolve. Sixteen cases are examined in this study. Accurate predictions can be made, where on average 89.74% of cases are correctly classified when burst suppression concludes and 78.10% when burst suppression begins. The best case receiver operating characteristic curve has an area under its convex hull of 0.8988, whereas the worst case area under the hull is 0.7889. These results demonstrate the feasibility of monitoring BSDC to anticipate postoperative delirium during burst suppression. They also motivate a further analysis on identifying footprints of causal mechanisms of neural injury within BSDC. Being able to raise warning signs of postoperative delirium early provides an opportunity to intervene and potentially avert neurological complications. Doing so would improve the success rate and quality of life after surgery. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2020