There is a paucity of studies, clinical and experimental, attesting to the benefit of cerebral perfusion pressure (CPP) directed pressor therapy following traumatic brain injury (TBI). The current study evaluates this therapy in a swine model of TBI and hypotension. Forty-five anesthetized and ventilated swine received TBI followed by a 45% blood volume bleed. After 1 h, all animals were resuscitated with 0.9% sodium chloride equal to three times the shed blood volume. The experimental group (PHE) received phenylephrine to maintain CPP > 80 mm Hg; the control group (SAL) did not. Outcomes in the first phase (n = 33) of the study were as follows: cerebro-venous oxygen saturation (S cvO2), cerebro-vascular carbon dioxide reactivity (δScvO2), and brain structural damage (β-amyloid precursor protein [βAPP] immunoreactivity). In the second phase (n = 12) of the study, extravascular blood free water (EVBFW) was measured in the brain and lung. After resuscitation, intracranial and mean arterial pressures were >15 and >80 mm Hg, respectively, in both groups. CPP declined to 64 ± 5 mm Hg in the SAL group, despite fluid supplements. CPP was maintained at >80 mm Hg with pressors in the PHE group. PHE animals maintained better ScvO2 (p < 0.05 at 180, 210, 240, 270, and 300 min post-TBI). At baseline, 5% CO2 evoked a 16 ± 4% increase in ScvO2, indicating cerebral vasodilatation and luxury perfusion. By 240 min, this response was absent in SAL animals and preserved in PHE animals (p < 0.05). Brain EVBFW was higher in SAL animals; however, lung EVBFW was higher in PHE animals. There was no difference in βAPP immunoreactivity between the SAL and PHE groups (p > 0.05). In this swine model of TBI and hypotension, CPP directed pressor therapy improved brain oxygenation and maintained cerebro-vascular CO2 reactivity. Brain edema was lower, but lung edema was greater, suggesting a higher propensity for pulmonary complications.

The original purpose of this study was to compare initial resuscitation of hemorrhagic hypotension after traumatic brain injury (TBI) with saline and shed blood. Based on those results, the protocol was modified and saline was compared to a blood substitute, diaspirin cross-linked hemoglobin (DCLHb). Two series of experiments were performed in anesthetized and mechanically ventilated (FiO2 = 0.4) pigs (35-45 kg). In Series 1, fluid percussion TBI (6-8 ATM) was followed by a 30% hemorrhage. At 120 min post-TBI, initial resuscitation consisted of either shed blood (n = 7) or a bolus of 3x shed blood volume as saline (n = 13). Saline supplements were then administered to all pigs to maintain a systolic arterial blood pressure (SAP) of >100 mmHg and a heart rate (HR) of <110 beats/min. In Series 2, TBI (4-5 ATM) was followed by a 35% hemorrhage. At 60 min post-TBI, initial resuscitation consisted of either 500 mL of DCLHb (n = 6) or 500 mL of saline (n = 5). This was followed by saline supplements to all pigs to maintain a SAP of >100 mmHg and a HR of <110 beats/min. In Series 1, most systemic markers of resuscitation (e.g., SAP, HR, cardiac output, filling pressures, lactate, etc.) were normalized, but there were 0/7 vs. 5/13 deaths within 5 h (P = 0.058) with blood vs. saline. At constant arterial O2 saturation (SaO2), mixed venous O2 saturation (SvO2), cerebral perfusion pressure (CPP), and cerebral venous O2 saturation (ScvO2) were all higher, intracranial pressure (ICP) was lower, and CO2 reactivity was preserved with blood vs. saline (all P < 0.05). In Series 2, SAP, ICP, CPP, and lactate were higher with DCLHb vs. saline (all P < 0.05). Cardiac output was lower even though filling pressure was markedly elevated with DCLHb vs. saline (both P < 0.05). Neither SvO2 nor cerebrovascular CO2 reactivity were improved, and ScvO2 was lower with DCLHb vs. saline (P < 0.05). All survived at least 72 h with neuropathologic changes that included sub-arachnoid hemorrhage, midline cerebellar necrosis, and diffuse axonal injury. These changes were similar with DCLHb vs. saline. Thus, whole blood was more effective than saline for resuscitation of TBI, whereas DCLHb was no more, and according to many variables, less effective than saline resuscitation. These experimental results are comparable to those in a recent multicenter trial using DCLHb for the treatment of severe traumatic shock. Further investigations in similar experimental models might provide some plausible explanations why DCLHb unexpectedly increased mortality in patients.

No description available.

A fisiopatologia da pré-eclâmpsia não está completamente elucidada. No entanto, o aumento do estresse oxidativo e o comprometimento da atividade da sintase induzida do óxido nítrico (iNOS) têm sido envolvido nesse estado crítico. O aumento do estresse oxidativo com o aumento das espécies altamente reativas, incluindo o superóxido, pode formar o peroxinitrito. Verificamos o papel da sintase induzida do óxido nítrico e do estresse oxidativo no modelo experimental de pré-eclâmpsia caracterizado pela redução de pressão de perfusão uterina (RUPP). Este foi induzido em ratas wistar. Ratas grávidas do grupo RUPP tiveram a aorta clipada no 14° dia de gestação. Após uma incisão na linha média, um clipe de prata (0.203 mm) foi colocado em torno da aorta acima da bifurcação ilíaca; clipes de prata (0.100 mm) também foram colocados em ambos os ramos das artérias ovarianas direita e esquerda, que abastecem o útero. Ratas Sham operados (ratas grávidas controles) e RUPP foram tratadas com veículo ou subcutaneamente com 1 mg / kg de N-[3 - (aminometil)-benzil] acetamidina (1400W, inibidor da iNOS), durante 5 dias. Após o tratamento, a pressão arterial média foi verificada. Para determinarmos o estresse oxidativo foram avaliadas as concentrações plasmáticas de espécies reativas ao ácido tiobarbitúrico (TBARS), níveis do 8-isoprostano plasmático, atividade vascular da NADPH oxidase e produção de superóxido com dihidroetídeo. Além disso, utilizamos a técnica de imunohistoquímica para avaliar os níveis de nitrotirosina. A expressão vascular da iNOS foi verificada por western imunoblotting e concentrações de nitrito plasmático por quimiluminescência. Observamos um aumento da pressão arterial média em RUPP comparado com ratas grávidas controles e o tratamento com 1400W exerceu efeitos anti-hipertensivos. O tratamento com 1400W reduziu os níveis de 8-isoprostano, atividade vascular da NADPH oxidase e concentrações de EROs, expressão da iNOS e formação de peroxinitrito em RUPP 1400W em comparação com ratos não tratados RUPP. Nossos resultados sugerem que o 1400W atenua a hipertensão no modelo RUPP principalmente pela inibição da iNOS e formação de peroxinitrito. / The pathophysiology of preeclampsia (PE) is not entirely known. However, increased oxidative stress possibly leading to impaired nitric oxide (NO) activity has been implicated in this critical condition. The increased NO production associated with highly reactive oxygen species (ROS), including superoxide may generate peroxynitrite. We examined the role of inducible nitric oxide synthase (iNOS) and oxidative stress in the reduction uterine perfusion pressure (RUPP) in preeclampsia experimental model. RUPP was induced in wistar rats. Pregnant rats in the RUPP group had their aortic artery clipped at day 14 of gestation. After a midline incision, a silver clip (0.203 mm) was placed around the aorta above the iliac bifurcation; silver clips (0.100 mm) were also placed on branches of both the right and left ovarian arteries that supply the uterus. Sham-operated (pregnant control rats) and RUPP rats were treated with subcutaneous vehicle or 1 mg/kg of iNOS inhibitor (1400W) for 5 days. After the treatment the mean arterial pressure (MAP) was monitored. To evaluated oxidative stress we measured thiobarbituric acid-reactive species (TBARS) and 8-isoprostane levels in plasma, aortic NADPH oxidase activity, and production of superoxide with dihydroethidine. Futhermore, the immunohistochemical analysis assessed nitrotyrosine levels. The vascular iNOS expression was determinated by western imunoblotting and nitrite concentrations in plasma were measured by chemiluminescence. We found increased MAP in RUPP compared with pregnant control rats and 1400W treatment exerted antihypertensive effects. Treatment with 1400W decreased RUPP-induced higher systemic 8-isoprostane levels and vascular NADPH oxidase activity and attenuated ROS concentrations, iNOS expression and peroxynitrite formation in RUPP 1400W rats compared with untreated RUPP rats. Our results suggest that treatment with 1400W attenuates the development of hypertension in RUPP mainly due to inhibition of iNOS and decreased peroxynitrite formation.

A fisiopatologia da pré-eclâmpsia não está completamente elucidada. No entanto, o aumento do estresse oxidativo e o comprometimento da atividade da sintase induzida do óxido nítrico (iNOS) têm sido envolvido nesse estado crítico. O aumento do estresse oxidativo com o aumento das espécies altamente reativas, incluindo o superóxido, pode formar o peroxinitrito. Verificamos o papel da sintase induzida do óxido nítrico e do estresse oxidativo no modelo experimental de pré-eclâmpsia caracterizado pela redução de pressão de perfusão uterina (RUPP). Este foi induzido em ratas wistar. Ratas grávidas do grupo RUPP tiveram a aorta clipada no 14° dia de gestação. Após uma incisão na linha média, um clipe de prata (0.203 mm) foi colocado em torno da aorta acima da bifurcação ilíaca; clipes de prata (0.100 mm) também foram colocados em ambos os ramos das artérias ovarianas direita e esquerda, que abastecem o útero. Ratas Sham operados (ratas grávidas controles) e RUPP foram tratadas com veículo ou subcutaneamente com 1 mg / kg de N-[3 - (aminometil)-benzil] acetamidina (1400W, inibidor da iNOS), durante 5 dias. Após o tratamento, a pressão arterial média foi verificada. Para determinarmos o estresse oxidativo foram avaliadas as concentrações plasmáticas de espécies reativas ao ácido tiobarbitúrico (TBARS), níveis do 8-isoprostano plasmático, atividade vascular da NADPH oxidase e produção de superóxido com dihidroetídeo. Além disso, utilizamos a técnica de imunohistoquímica para avaliar os níveis de nitrotirosina. A expressão vascular da iNOS foi verificada por western imunoblotting e concentrações de nitrito plasmático por quimiluminescência. Observamos um aumento da pressão arterial média em RUPP comparado com ratas grávidas controles e o tratamento com 1400W exerceu efeitos anti-hipertensivos. O tratamento com 1400W reduziu os níveis de 8-isoprostano, atividade vascular da NADPH oxidase e concentrações de EROs, expressão da iNOS e formação de peroxinitrito em RUPP 1400W em comparação com ratos não tratados RUPP. Nossos resultados sugerem que o 1400W atenua a hipertensão no modelo RUPP principalmente pela inibição da iNOS e formação de peroxinitrito. / The pathophysiology of preeclampsia (PE) is not entirely known. However, increased oxidative stress possibly leading to impaired nitric oxide (NO) activity has been implicated in this critical condition. The increased NO production associated with highly reactive oxygen species (ROS), including superoxide may generate peroxynitrite. We examined the role of inducible nitric oxide synthase (iNOS) and oxidative stress in the reduction uterine perfusion pressure (RUPP) in preeclampsia experimental model. RUPP was induced in wistar rats. Pregnant rats in the RUPP group had their aortic artery clipped at day 14 of gestation. After a midline incision, a silver clip (0.203 mm) was placed around the aorta above the iliac bifurcation; silver clips (0.100 mm) were also placed on branches of both the right and left ovarian arteries that supply the uterus. Sham-operated (pregnant control rats) and RUPP rats were treated with subcutaneous vehicle or 1 mg/kg of iNOS inhibitor (1400W) for 5 days. After the treatment the mean arterial pressure (MAP) was monitored. To evaluated oxidative stress we measured thiobarbituric acid-reactive species (TBARS) and 8-isoprostane levels in plasma, aortic NADPH oxidase activity, and production of superoxide with dihydroethidine. Futhermore, the immunohistochemical analysis assessed nitrotyrosine levels. The vascular iNOS expression was determinated by western imunoblotting and nitrite concentrations in plasma were measured by chemiluminescence. We found increased MAP in RUPP compared with pregnant control rats and 1400W treatment exerted antihypertensive effects. Treatment with 1400W decreased RUPP-induced higher systemic 8-isoprostane levels and vascular NADPH oxidase activity and attenuated ROS concentrations, iNOS expression and peroxynitrite formation in RUPP 1400W rats compared with untreated RUPP rats. Our results suggest that treatment with 1400W attenuates the development of hypertension in RUPP mainly due to inhibition of iNOS and decreased peroxynitrite formation.

<p>Traumatic brain injury (TBI) is a major cause of death and disability. Intracranial secondary insults (e.g. intracranial haematoma, brain oedema) and systemic secondary insults (e.g. hypotension, hypoxaemia, hyperthermia) lead to secondary brain injury and affect outcome adversely. In order to minimise secondary insults and to improve outcome in TBI-patients, a secondary insult program and standardised neurointensive care (NIC) was implemented. The aim of this thesis was to describe patient outcome and to explore the occurrence and prognostic value of secondary insults after the implementation.</p><p>Favourable outcome was achieved in 79% and 6% died of the 154 adult TBI patients treated in the NIC unit 1996-97. In an earlier patient series from the department, 48% made a favourable outcome and 31% died. Hence, the outcome seems to have improved when NIC was standardised and dedicated to avoiding secondary insults. </p><p>Secondary insults counted manually from hourly recordings on surveillance charts did not hold any independent prognostic information. When utilising a computerised system, which enables minute-by-minute data collection, the proportion of monitoring time with systolic blood pressure > 160 mm Hg decreased the odds of favourable outcome independent of admission variables (odds ratio 0.66). Hyperthermia was related to unfavourable outcome. Hypertension was correlated to hyperthermia and may be a part of a hyperdynamic state aggravating brain oedema. </p><p>Increased proportion of monitoring time with cerebral perfusion pressure (CPP) < 60 mm Hg increased the odds of favourable outcome (odds ratio 1.59) in patients treated according to an intracranial pressure (ICP)-oriented protocol (Uppsala). In patients given a CPP-oriented treatment (Edinburgh), CPP <60 mm Hg was coupled to an unfavourable outcome. It was shown that pressure passive patients seem to benefit from an ICP-oriented protocol and pressure active patients from a CPP-oriented protocol. The overall outcome would improve if patients were given a treatment fit for their condition.</p>

Traumatic brain injury (TBI) is a major cause of death and disability. Intracranial secondary insults (e.g. intracranial haematoma, brain oedema) and systemic secondary insults (e.g. hypotension, hypoxaemia, hyperthermia) lead to secondary brain injury and affect outcome adversely. In order to minimise secondary insults and to improve outcome in TBI-patients, a secondary insult program and standardised neurointensive care (NIC) was implemented. The aim of this thesis was to describe patient outcome and to explore the occurrence and prognostic value of secondary insults after the implementation. Favourable outcome was achieved in 79% and 6% died of the 154 adult TBI patients treated in the NIC unit 1996-97. In an earlier patient series from the department, 48% made a favourable outcome and 31% died. Hence, the outcome seems to have improved when NIC was standardised and dedicated to avoiding secondary insults. Secondary insults counted manually from hourly recordings on surveillance charts did not hold any independent prognostic information. When utilising a computerised system, which enables minute-by-minute data collection, the proportion of monitoring time with systolic blood pressure &gt; 160 mm Hg decreased the odds of favourable outcome independent of admission variables (odds ratio 0.66). Hyperthermia was related to unfavourable outcome. Hypertension was correlated to hyperthermia and may be a part of a hyperdynamic state aggravating brain oedema. Increased proportion of monitoring time with cerebral perfusion pressure (CPP) &lt; 60 mm Hg increased the odds of favourable outcome (odds ratio 1.59) in patients treated according to an intracranial pressure (ICP)-oriented protocol (Uppsala). In patients given a CPP-oriented treatment (Edinburgh), CPP &lt;60 mm Hg was coupled to an unfavourable outcome. It was shown that pressure passive patients seem to benefit from an ICP-oriented protocol and pressure active patients from a CPP-oriented protocol. The overall outcome would improve if patients were given a treatment fit for their condition.

Title: Biomechanical aspects of the dynamics of intracranial pressure in traumatic brain injury Author: Ing. Martin Mayer e-mail: mayercz@seznam.cz Department: Department of Anatomy and Biomechanics Supervisor: doc. PaedDr. Karel Jelen, CSc. This PhD thesis "Biomechanical aspects of the dynamics of intracranial pressure in traumatic brain injury" is about the dynamics of intracranial pressure, particularly in relation to the external mechanical action of the patient. Severe head injury is the leading cause of death in patients under 35 years of age. Despite constantly-improving medical and nursing care only one third of patients, after recovery, regained the ability to live independently in the long term. Two-thirds of patients were severely disabled or died. The lifetime cost of such a patient who was not completely cured has been calculated to be $4,000,000. A significant consequence of craniocerebral injuries are secondary brain lesions, which among other means the rise in intracranial pressure (ICP), which can further exacerbate due to intracerebral or extracerebral causes. Therefore, the objective of the treatment is minimizing secondary injury, optimally at the phase of the primary lesion. However, realization of this requirement, about which we can say that is a conditio sine qua non, sometimes leads...

Title: Biomechanical aspects of the dynamics of intracranial pressure in traumatic brain injury Author: Ing. Martin Mayer e-mail: mayercz@seznam.cz Department: Department of Anatomy and Biomechanics Supervisor: doc. PaedDr. Karel Jelen, CSc. This PhD thesis "Biomechanical aspects of the dynamics of intracranial pressure in traumatic brain injury" is about the dynamics of intracranial pressure, particularly in relation to the external mechanical action of the patient. Severe head injury is the leading cause of death in patients under 35 years of age. Despite constantly-improving medical and nursing care only one third of patients, after recovery, regained the ability to live independently in the long term. Two-thirds of patients were severely disabled or died. The lifetime cost of such a patient who was not completely cured has been calculated to be $4,000,000. A significant consequence of craniocerebral injuries are secondary brain lesions, which among other means the rise in intracranial pressure (ICP), which can further exacerbate due to intracerebral or extracerebral causes. Therefore, the objective of the treatment is minimizing secondary injury, optimally at the phase of the primary lesion. However, realization of this requirement, about which we can say that is a conditio sine qua non, sometimes leads...

Diese kumulative Habilitation untersucht die Rolle des Renin-Angiotensin-Aldosteron-Systems (RAAS) bei chronischen und akuten Regelvorgänge im Salz-Wasser-Haushalt an wachen Hunden. Nach einer Einführung in die Methodik der Langzeitstudien werden zunächst die zirkardianen und ultradianen Veränderungen der Natriumausscheidung beschrieben, die wir bei den Hunden beobachten konnten. Es scheint, als sei das Natriumausscheidungsmuster bei Hunden das Resultat endogener Rhythmizität und exogen, reaktiver Prozesse. Beide Komponenten scheinen zur Aufrechterhaltung der Natriumhomöostase beizutragen. Bei der Infusion natriumretinierender Hormone wie Aldosteron und Angiotensin II verschob sich ein größerer Anteil der täglichen Natrium- und Wasserausscheidung in die Abend- und Nachtstunden. Wir haben dieses Phänomen als "Nachtverschiebung" bezeichnet. In Bilanzstudien über vier Tage wurde dann der Frage nachgegangen, ob das Ganz-Körper-(GK)-Natrium eine kontrollierte Variable ist. Wir konnten zeigen, dass zwei Faktoren bei der Kontrolle des GK-Natriums eine wesentliche Rolle spielen, die Aktivität des RAAS und der renale Perfusionsdruck. Ist nur eine dieser Komponenten gestört, kann sie durch die andere - was das Einstellen eines 24-Stunden Bilanzgleichgewichtes angeht - ausgeglichen werden, allerdings nur unter Inkaufnahme eines veränderten GK-Natriumbestands. Ebenfalls über vier Tage wurde die Bedeutung des NO (Stickoxid) für die langfristige Regelung des Natriumbestandes untersucht. Dabei wurde gefunden, dass die Plasma-Renin-Aktivität (PRA) während NO-Synthase-Inhibition durchweg niedriger als bei intaktem NO-System war. Der Aldosteron / PRA Quotient war unter NOS-Inhibition deutlich größer als in den jeweiligen Protokollen ohne NOS-Inhibition. In Kurzzeitstudien (3-4 Stunden) wurden wache Hunde während akuter Hypoxie, die akut mit einer Verminderung des Natrium- und Wasserbestandes einhergehen kann ("Höhendiurese"), sowie während kontrollierter maschineller Beatmung mit hohen positiv-end-exspiratorischen (PEEP) Drucken, die zur Natrium- und Wasserretention führen kann, untersucht. Unter Hypoxie zeigte sich, dass das in niedrigen Plasma-Konzentrationen als Adenosin-1-Rezeptorantagonist wirkende Theophyllin den Abfall der PRA und des Angiotensin II unter Hypoxie verhindern kann. Auf der anderen Seite fiel die Plasma-Aldosteron-Konzentration während Hypoxie unabhängig davon, ob Theophyllin infundiert wurde, wahrscheinlich wegen einer verminderten Aktivität der 18-Hydroxylase während Hypoxie. Die Untersuchungen unter PEEP-Beatmung ergaben u.a., dass bei bilateral denervierten, wachen Hunden, deren Natriumzufuhr normal ist, den Nierennerven keine wesentliche Rolle für die zu beobachtende Wasser- und Natriumretention während maschineller Beatmung zukommt. / This cumulative thesis investigates on conscious dogs the role of the renin-angiotensin-aldosterone system (RAAS) during chronic and acute challenges of salt and water homeostasis. After introducing the methods of long term studies in dogs, circadian and ultradian oscillations of sodium excretion are being described. We demonstrated, that the sodium excretion pattern in dogs is the result of endogenous rhythms and exogenous reactive processes. Both components seem to contribute to sodium homeostasis. When infusing sodium retaining hormones, such as aldosterone and angiotensin II, a greater share of the daily sodium and water excretion was shifted towards the evening and the night. This phenomenon was termed "night shift". In balance studies over four days it was investigated whether the total body sodium is a controlled variable. Two factors were identified to play a pivotal role in controlling total body sodium: the activity of the RAAS and renal perfusion pressure. If only one of these components is disturbed, the respective other component is able to equilibrate the 24 h sodium balance, but only on a different level of total body sodium. Also over a period of four days the significance of NO (nitric oxide) for the long-term regulation of sodium balance was investigated. Among others, it was found that compared to an intact NO system, the plasma-renin activity (PRA) was always lower during NO synthase (NOS) inhibition, and the aldosterone / PRA ratio was greater during NOS inhibition. In short-term studies (lasting 3-4 hours) awake dogs were studied during hypoxia - which is usually combined with a reduced total body sodium and water ("high altitude diuresis") - as well as during controlled mechanical ventilation with positive-end-expiratory pressure (PEEP) - which often leads to sodium and water retention. It was demonstrated that the decline in PRA and angiotensin II during hypoxia - which is a typical finding in conscious dogs - can be prevented by theophyllin, which acts as an adenosin-1-receptor antagonist in lower concentrations. On the other hand, plasma aldosterone concentration declined during hypoxia independent of whether theophyllin was infused or not, probably due to a reduced 18-hydroxylase activity during hypoxia. The PEEP studies demonstrated among others, that in bilaterally denervated conscious dogs - whose sodium intake was normal - the renal nerves play no substantial role for the water and sodium retention observed during PEEP ventilation.