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Background: Previously, we had shown that elevation of cerebral perfusion pressure, using pressors, improved short-term outcomes after traumatic brain injury and hemorrhagic shock in swine. The current study evaluates outcomes after resuscitation with diaspirin cross-linked hemoglobin (DCLHb)-a hemoglobin-based oxygen carrier with pressor activity-in the same swine model of traumatic brain injury and hemorrhagic shock. Methods: Anesthetized and ventilated swine received traumatic brain injury via cortical fluid percussion (6-8 atm) followed by 45% blood volume hemorrhage. One hour later, animals were randomized to either a control group (SAL) resuscitated with normal saline equal to three times shed blood volume or to one of two experimental groups resuscitated with DCLHb. The two experimental groups consisted of a low-dose group, resuscitated with 250 mL of DCLHb (Hb1), and a high-dose group, resuscitated with 500 mL of DCLHb (Hb2). Animals were observed for 210 minutes postresuscitation. Outcomes evaluated were cerebral oxygenation by measuring partial pressure and saturation of oxygen in cerebrovenous blood; cerebral function by evaluating the preservation and magnitude of cerebrovascular carbon dioxide reactivity; and brain structural damage by semiquantitatively assessing beta amyloid precursor protein positive axons. Results: Postresuscitation, cerebral perfusion pressure was higher in the DCLHb groups (p < 0.05, Hb1 and Hb2 vs. SAL), and intracranial pressure was lower in the Hb2 group (p < 0.05 vs. SAL). Cerebrovenous oxygen level was similar in all groups (p > 0.05). At baseline, 5% carbon dioxide evoked a 16 ± 1% increase in cerebrovenous oxygen saturation, indicating vasodilatation. At 210 minutes, this response was nearly absent in SAL (4 ± 4%) (p < 0.05 vs. baseline) and Hb1 (1 ± 5%), but was partially preserved in Hb2 (9 ± 5%). There was no intergroup difference in beta amyloid precursor protein positive axons. Five of 20 SAL and 0 of 13 DCLHb animals developed brain death (flat electroencephalogram) (p = 0.05, SAL vs. DCLhb). Postresuscitation, DCLHb animals maintained higher mean pulmonary arterial pressure (28 ± 1 mm Hg, SAL; 42 ± mm Hg, Hb1; 45 ± 1 mm Hg, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL) and lower cardiac output (3.9 ± 1.6 L/min, SAL; 2.6 ± 0.1 L/min, Hb1; 2.7 ± 0.1 L/min, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL). Three Hb2 animals died as a result of cardiac failure, and one SAL animal died as a result of irreversible shock. Conclusion: In this swine model of traumatic brain injury and hemorrhagic shock, resuscitation with DCLHb maintained a higher cerebral perfusion pressure. Low-dose DCLHb (minimal increase in oxygen carriage) failed to significantly improve short-term outcome. With high-dose DCLHb (significant improvement in oxygen carriage), intracranial pressure was lower and cerebrovascular carbon dioxide reactivity was partially preserved; however, this was at the cost of poorer cardiac performance secondary to high afterload.

<p>During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P>40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P>40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.</p>

The neurological wake-up test, NWT, is a clinical monitoring tool that can be used to evaluate the level of consciousness in patients with traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) during neurocritical care (NCC). Since patients with severe TBI or SAH are often treated with mechanical ventilation and sedation, the NWT requires that the continuous sedation is interrupted. However, interruption of continuous sedation may induce a stress response and the use of the NWT in NCC is controversial. The effects of the NWT on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were evaluated in 21 patients with TBI or SAH. Compared to baseline when the patients were sedated with continuous propofol sedation, the NWT resulted in increased ICP and CPP (p&lt;0.05). Next, the effects of the NWT on the stress hormones adrenocorticotrophic hormone (ACTH), cortisol, epinephrine and norepinephrine were evaluated in 24 patients. Compared to baseline, the NWT caused a mild stress response resulting in increased levels of all evaluated stress hormones (p&lt;0.05). To compare the use of routine NCC monitoring tools, the choice of sedation and analgesia and the frequency of NWT in Scandinavian NCC units, a questionnaire was used. The results showed that all 16 Scandinavian NCC units routinely use ICP and CPP monitoring and propofol and midazolam were primary choices for patient sedation in an equal number of NCC units. In 2009, the NWT was not routinely used in eight NCC units whereas others used the test up to six times daily. Finally, intracerebral microdialysis (MD), brain tissue oxygenation (PbtiO2) and jugular bulb oxygenation (SjvO2) were used in 17 TBI patients to evaluate the effect of the NWT procedure on focal neurochemistry and cerebral oxygenation. The NWT did not negatively alter interstitial markers of energy metabolism or cerebral oxygenation. In conclusion, the NWT induced a mild stress response in patients with TBI or SAH that did not result in a detectable, significant secondary insult to the injured brain. These results suggest that the NWT may safely be used as a clinical monitoring tool in the NCC of severe TBI and SAH in a majority of patients.

During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P&gt;40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P&gt;40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.

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.

<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...