Prospective study: Long-term outcome at 12-15 years after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) have poor outcome. Studies on outcome beyond 1 year post-aSAH are few, and late recovery is poorly investigated, initiating this prospective outcome study on patients 12-15 years after an aSAH. We hypothesized to find; functional improvement > 1 year post-ictus; increased long-term mortality in aSAH patients vs matched controls, and finally to present; predictors of long-term favorable outcome (GOS 4-5). METHODS: We prospectively investigated patients, admitted 2000-2003 to the Sahlgrenska University Hospital, 1 year post-ictus using Glasgow Outcome Scale (GOS). The patients were revalidated 12-15 years post-aSAH by structured-telephone interviews (GOS), followed by statistical analysis. RESULTS: A total of 158 patients were included, (women n = 114, men n = 44), with a mean age of 55 years at aSAH. Patients treated with surgical clipping had lower mortality. At the follow-up 12-15 years post-aSAH, all 103 survivors (65.2%) were categorized as having; good recovery (39.9%), moderate disability (15.2%), or severe disability (10.1%). Within the patient cohort, 23.6% improved GOS over time. Fifty-five patients died, median at 4 years post-ictus. aSAH patients had 3.5 times increased mortality 12-15 years post-ictus vs matched controls (P < .0001). Patients with favorable outcome at 1 year (67.3%, n = 101) had similar survival probability as control patients. Prognostic indicators of long-term favorable outcome were low age and high GOS at 1-year follow-up, (AUCROC, 0.79). CONCLUSIONS: Individual functional improvement was found >1 year post-ictus. Patients with favorable outcome at 1 year had similar long-term life expectancy as the general population. Indicators of long-term favorable prognosis were low age at ictus and high GOS at 1-year follow-up.

A prospective outcome study observing patients with severe traumatic brain injury over 10-15 years.

BACKGROUND: Severe traumatic brain injury (sTBI) can be divided into primary and secondary injuries. Intensive care protocols focus on preventing secondary injuries. This prospective cohort study was initiated to investigate outcome, including mortality, in patients treated according to the Lund Concept after a sTBI covering 10-15 years post-trauma. METHODS: Patients were included during 2000-2004 when admitted to the neurointensive care unit, Sahlgrenska University Hospital. Inclusion criteria were: Glasgow coma scale score of ≤8, need for artificial ventilation and intracranial monitoring. Glasgow Outcome Scale (GOS) was used to evaluate outcome both at 1-year and 10-15 years post-trauma. RESULTS: Ninety-five patients, (27 female and 68 male), were initially included. Both improvement and deterioration were noted between 1- and 10-15 years post-injury. Mortality rate (34/95) was higher in the studied population vs. a matched Swedish population, (Standard mortality rate (SMR) 9.5; P < 0.0001). When dividing the cohort into Good (GOS 4-5) and Poor (GOS 2-3) outcome at 1-year, only patients with Poor outcome had a higher mortality rate than the matched population (SMR 7.3; P < 0.0001). Further, good outcome (high GOS) at 1-year was associated with high GOS 10-15 years post-trauma (P < 0.0001). Finally, a majority of patients demonstrated symptoms of mental fatigue. CONCLUSION: This indicates that patients with severe traumatic brain injury with Good outcome at 1-year have similar survival probability as a matched Swedish population and that high Glasgow outcome scale at 1-year is related to good long-term outcome. Our results further emphasise the advantage of the Lund concept.

Apolipoprotein E polymorphism in aneurysmal subarachnoid haemorrhage in West Sweden.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality despite novel treatments. Genetic variability may explain outcome differences. Apolipoprotein E (ApoE) is a glycoprotein with a major role in brain lipoprotein metabolism. It has three isoforms encoded by distinct alleles: APOEε2, APOEε3 and APOEε4. The APOEε4 allele is associated with Alzheimer's disease and worse outcome after traumatic brain injury and ischaemic stroke. This prospective blinded study explored the influence of the APOEε4 polymorphism on the risk of aSAH, risk of cerebral vasospasm (CVS) and 1-year neurological outcome. METHODS: The APOΕε4 polymorphism was analysed in 147 patients with aSAH. Allele and genotype frequencies were compared to those found in a gender- and area-matched control group of healthy individuals (n = 211). Early CVS was identified and treated according to neurointensive care unit (NICU) guidelines. Neurological deficit(s) at admittance and at 1-year follow-up visit was recorded. Neurological outcome was assessed by the National Institute of Health Stroke Scale, Barthel Index and the Extended Glasgow Outcome Scale. RESULTS: APOEε4 and non-APOEε4 allele frequencies were similar in aSAH patients and healthy individuals. The presence of APOEε4 was not associated with the development of early CVS. We could not find an influence of the APOE polymorphism on 1-year neurological outcome between groups. Subgroup analyses of patients treated with surgical clipping vs endovascular coiling did not reveal any associations. CONCLUSIONS: The APOEε4 polymorphism has no major influence on risk of aSAH, the occurrence of CVS or long-term neurological outcome after aSAH.

In-hospital C-reactive protein predicts outcome after aneurysmal subarachnoid haemorrhage treated by endovascular coiling.

BACKGROUND: This study aimed to examine prospectively whether the inflammatory marker C-reactive protein (CRP) increases in patients with aneurysmal subarachnoid haemorrhage (aSAH) treated by endovascular coiling and investigate whether CRP could be used as prognostic factor for long-term neurological outcome. METHODS: This single-hospital study comprised 98 consecutive patients with confirmed aSAH treated by endovascular coiling. Admission status was classified according to the World Federation of Neurosurgical Societies (WFNS) Scale and initial cerebral computed tomography according to Fisher scale. CRP was analysed on days 0, 1, 2, 3, 4, 6 and 8 after the initial bleed. A neurological follow up was performed 1 year later according to the Extended Glasgow Outcome Scale (GOSE) for overall outcome and National Institute of Health Stroke Scale (NIHSS) for focal deficit. RESULTS: CRP values increased from normal to peak at 53 mg/l at day 3-4 and then declined, without normalising, at day 8. Patients with a higher increase in CRP had a poorer neurological outcome after 1 year. CRP during the first week had a stronger correlation to outcome (r = 0.417) and NIHSS (r = 0.449) than initial clinical status (WFNS; r = 0.280 and 0.274) and radiology (Fisher scale; r = 0.137 and 0.158). CRP increase indicated a risk of poor outcome (GOSE) (P < 0.001) and permanent loss of neurological function (NIHSS) (P < 0.001). Logistic regression analysis suggested that elevated CRP already on day 2 is an independent prognostic marker for outcome. CONCLUSION: Early CRP values can perhaps be used as a prognostic factor for long-term neurological outcome prediction after endovascular treatment of aSAH.

Apolipoprotein E polymorphism and gender difference in outcome after severe traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is one of the most common causes of death and dismal outcome among children and young adults. The morbidity and mortality differ but more aggressive monitoring and more designated neuro intensive care units have improved the results. Studies have demonstrated a connection between apolipoprotein E (APOE) genotype and outcome after TBI, but few are prospective and none is from northern Europe. APOE has three alleles: epsilon2, epsilon3 and epsilon4. METHODS: A total of 96 patients with Glasgow coma score (GCS) < or =8 were prospectively and consecutively included. APOE genotypes were all analyzed at the same laboratory from blood samples by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: All patients were assessed at 1 year with Glasgow outcome scale extended (GOSE), National Institute of Health Stroke Scale (NIHSS) and the Barthel daily living index. The genotype was available in all patients. Twenty-six patients expressed APOE epsilon4 while 70 patients did not. Outcome demonstrated that patients with APOE epsilon4 had worse outcome vs. those lacking this allele. When subdividing patients into gender, males with APOE epsilon4 did worse, a difference not detected among female patients. CONCLUSIONS: APOE epsilon4 correlated to worse outcome in TBI patients. We also found that males with APOE epsilon4 had poor outcome while females did not. Thus, the results indicate that genetic polymorphism may influence outcome after TBI.

Serum levels of S100B, S100A1B and S100BB are all related to outcome after severe traumatic brain injury.

OBJECTIVES: S100B is an established marker of brain damage. Used in the context as a biochemical marker, S100B denotes a measurement of all S100 proteins, including at least one S100B monomer, i.e. the sum of the two dimers S100A1B and S100BB. Almost all published studies are based on this "sum concentration". However, the brain specificity of S100B has been questioned and increased serum levels have also been reported after trauma without head injury. Since the S100B monomer dominates in the brain, we hypothesised that the S100BB dimer should be better related to outcome after severe traumatic brain injury than S100A1B or the "sum concentration". METHODS: Daily serum samples were collected from 59 patients with severe traumatic brain injury. Three different ELISA methods were used for measurements of S100B, S100A1B and S100BB respectively. Outcome was assessed after one year and categorised according to the Glasgow Outcome Scale. RESULTS: Serum levels of S100B, S100A1B and S100BB followed the same temporal course, with early maximum and rapidly decreasing values over the first days after the trauma. Maximum serum concentrations of each of the parameters were increased in the patient group with an unfavourable outcome compared with those with a favourable outcome (p = 0.01, 0.006 and 0.004, respectively). CONCLUSION: Both S100A1B and S100BB were related to outcome after severe traumatic brain injury. Even though this study is small, it seems unlikely that separate analyses of the dimers are of any advantage compared with measuring S100B alone.

Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury.

OBJECTIVE: We investigated if tau, microtubular binding protein, in serum and ventricular CSF (vCSF) in patients with severe traumatic brain injury (TBI) during the initial posttraumatic days correlated to 1-year outcome. METHODS: Patients with severe TBI (n = 39, Glasgow Coma Scale score 2,126 pg/mL on days 2 to 3 discriminated between dead and alive (sensitivity of 100% and a specificity of 81%). A vCSF total tau level of >702 pg/mL on days 2 to 3 discriminated between bad (GOSE 1 to 4) and good (GOSE 5 to 8) outcome (sensitivity of 83% and a specificity of 69%). Patients with GOSE 1 (dead) had higher vCSF total tau levels on days 2 to 3 (p < 0.001) vs both surviving patients (GOSE 2 to 8) and those with NPH. Total tau was not detected in serum throughout the study. CONCLUSION: The increase in ventricular CSF (vCSF) total tau probably reflects axonal damage, known to be a central pathologic mechanism in traumatic brain injury (TBI). These results suggest that vCSF total tau may be an important early biochemical neuromarker for predicting long-term outcome in patients with a severe TBI.

Prone position in mechanically ventilated patients with reduced intracranial compliance.

BACKGROUND: Prone position has been used for several years to treat acute lung insufficiency, but in previous studies patients with unstable intracranial pressure (ICP) are mostly excluded. The aim of this study was to investigate if prone position is a safe and useful treatment in patients with reduced intracranial compliance. METHODS: A consecutive, prospective pilot study of 11 patients admitted to the neuro intensive care unit (NICU) due to traumatic brain injury or intracerebral haemorrhage. ICP, cerebral perfusion pressure (CPP), heart rate (HR), mean arterial blood pressure (MABP), arterial partial pressure of oxygen (PaO(2)), arterial partial pressure of carbon dioxide (PaCO(2)), arterial oxygen saturation (SaO(2)) and respiratory system compliance were measured before, three times during and two times after the patients were placed in the prone position. RESULTS: No significant changes were demonstrated in ICP, CPP or MABP. PaO(2) and SaO(2) were significantly increased in the prone position. HR was significantly increased in the prone position and after 10 min in the supine post-prone position and the respiratory system compliance was increased after 1 h in the supine post-prone position. CONCLUSION: Turning NICU patients from the supine to the prone position did not influence ICP, CPP or MABP, but significantly improved patient PaO(2), SaO(2) and respiratory system compliance.

CSF -neurofilament correlates with outcome after aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating event. Following the bleeding, a number of pathophysiological changes and clinical factors determine outcome. Not surprisingly, attempts to predict outcome based on a single factor have failed. The neurological status graded at admission to hospital and distributions of the blood on CT are the strongest predictors. There is evidence that cerebrospinal fluid (CSF) proteins may serve as markers of the extent of brain damage. The present study is focused on the light unit of neurofilament protein (NFL), previously not evaluated in aSAH. Lumbar puncture (LP), neurological grading according to World Federation of Neurological Surgeons (WFNS) and neurological examination according to the National Institute of Health Stroke Scale (NIHSS) were performed in 48 consecutive patients with aSAH 10-14 days after the hemorrhage. CSF-NFL concentrations were analyzed using an ELISA. Outcome was assessed after 1 year and categorised according to the extended Glasgow Outcome Scale (GOSE). A significant correlation between CSF-NFL and GOSE was detected at follow up after 1 year. CSF-NFL also correlated with WFNS and NIHSS on the day of the lumbar puncture. CSF-NFL is a biochemical marker of brain damage correlating to neurological status and long-term outcome after aneurysmal subarachnoid hemorrhage.

Increased serum-GFAP in patients with severe traumatic brain injury is related to outcome.

OBJECTIVES: Several studies have established the relevance of S-100 in blood as a marker of brain damage after traumatic brain injury. However, a more specific marker is required and glial fibrillary acidic protein (GFAP) is considered to be a good candidate. METHODS: In order to assess the increase of GFAP in serum (s-GFAP) after a severe traumatic brain injury (TBI) we collected daily serum samples from 59 patients with severe TBI starting on the day of the trauma. S-GFAP was measured using a sandwich ELISA. The Glasgow outcome scale (GOS) assessed outcome after 1 year. RESULTS: All but one patient had maximal s-GFAP values above the laboratory reference value (median increased 10-fold). The highest detected levels were seen during the first days after TBI and then decreased gradually. Patients with unfavourable outcome had significantly (p<0.001) higher maximal s-GFAP values in the acute phase compared with patients with favourable outcome. All patients (n=5) with s-GFAP>15.04 microg /L died (reference level<0.15 microg/L). We found no significant difference in the maximal s-GFAP levels of patients with isolated brain injury in comparison with patients with multiple traumas. CONCLUSION: Serum-GFAP is increased during the first days after a severe traumatic brain injury and related to clinical outcome.

Long-time outcome after transient transtentorial herniation in patients with traumatic brain injury.

BACKGROUND: This study investigates mortality and morbidity in patients with traumatic brain injury (TBI) who developed episode(s) of transtentorial herniation. The transtentorial herniation was defined as a deterioration of consciousness accompanied by uni- or bilateral pupil dilatation. METHODS: The medical records of all patients with traumatic brain injury admitted during 1999 to the Neuro- or General Intensive Care Units at Sahlgrenska University Hospital were analyzed, and patients with at least one episode of transtentoryal herniation were included. Information regarding patient age, gender, type of trauma, initial GCS, precipitating reason for herniation, uni-/bilateral pupil dilatation, treatment(s) and outcome after at least 6 months, assessed with the Glasgow Outcome Scale (GOS), was collected from medical records. RESULTS: The study included 27 patients, average age 44 years (range 6-81), with a male proportion of 81%. The majority of the patients were victims of traffic accidents and falls. The results demonstrated that 16/27(59%) of the patients had a favorable outcome (GOS 4/5), 4/27(15%) were severely disabled (GOS 3), none was vegetative (GOS 2) and 7/27(26%) died (GOS 1). When analyzing patient subgroups, best outcome was found in children where 3/4 (75%) had a GOS 4/5. CONCLUSION: Transtentorial herniation is a serious consequence of supratentorial edema/mass lesions in patients with TBI. However, with aggressive neurointensive care and neurosurgical treatments we found a 59% patient incidence of a favorable outcome.

Cardiopulmonary bypass induces neurologic and neurocognitive dysfunction in the rat.

BACKGROUND: Neurocognitive dysfunction is a common complication of cardiac surgery using cardiopulmonary bypass (CPB). Elucidating injury mechanisms and developing neuroprotective strategies have been hampered by the lack of a suitable long-term recovery model of CPB. The purpose of this study was to investigate neurologic and neurocognitive outcome after CPB in a recovery model of CPB in the rat. METHODS: Fasted rats (n = 10) were subjected to 60 min of normothermic (37.5 degrees C) nonpulsatile CPB using a roller pump and a membrane oxygenator. Sham-operated controls (n = 10) were not subjected to CPB. Neurologic outcome was assessed on days 1, 3, and 12 after CPB using standardized functional testing. Neurocognitive outcome, defined as the time (or latency) to finding a submerged platform in a Morris water maze (an indicator of visual-spatial learning and memory), was evaluated daily from post-CPB days 3-12. Histologic injury in the hippocampus was also evaluated. RESULTS: Neurologic outcome was worse in the CPB versus the sham-operated controls at all three measurement intervals (P < 0.001). The CPB group also had longer water maze latencies compared with the sham-operated controls (P = 0.004), indicating significant neurocognitive dysfunction after CPB. No difference in histologic injury between groups was observed. CONCLUSIONS: CPB caused both neurologic and neurocognitive impairment in a rodent recovery model. This model could potentially facilitate the investigation of CPB-related injury mechanisms and possible neuroprotective interventions.

Periischemic cerebral blood flow (CBF) does not explain beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats.

BACKGROUND: Isoflurane improves outcome from near-complete forebrain ischemia in rats compared with fentanyl-nitrous oxide (N2O). Sympathetic ganglionic blockade with trimethaphan abolishes this beneficial effect. To evaluate whether anesthesia-related differences in cerebral blood flow (CBF) may explain these findings, this study compared regional CBF before, during, and after near-complete forebrain ischemia in rats anesthetized with either isoflurane (with and without trimethaphan) or fentanyl-nitrous oxide. METHODS: Fasted, normothermic isoflurane anesthetized Sprague-Dawley rats were prepared for near-complete forebrain ischemia (10 min of bilateral carotid occlusion and mean arterial pressure = 30 mmHg). After surgery, rats were anesthetized with either 1.4% isoflurane (with or without 2.5 mg of trimethaphan intravenously at onset of ischemia) or fentanyl-nitrous oxide (25 microgram. kg-1. h-1. 70% N2O-1). Regional CBF was determined (14C-iodoantipyrine autoradiography) before ischemia, 8 min after onset of ischemia, and 30 min after onset of reperfusion. RESULTS: Regional CBF did not differ significantly among groups at any measurement interval. Ischemia caused a marked flow reduction to 5% or less of baseline (P < 0.001) in selectively vulnerable regions, such as the cortex, caudoputamen and hippocampus, whereas flow in the brain stem and cerebellum was preserved. Reperfusion at 30 min was associated with partial restoration of flow to 35-50% of baseline values in ischemic structures. CONCLUSIONS: The results indicate that improved histologic-behavioral outcome provided by isoflurane anesthesia cannot be explained by differential vasodilative effects of the anesthetic states before, during, or after severe forebrain ischemia. This study also shows severe postischemic delayed hypoperfusion that was not affected by choice of anesthetic or the presence of trimethaphan. Mechanisms other than effects on periischemic CBF must be responsible for beneficial effects of isoflurane in this model.

Anesthetic effects on cerebral metabolic rate predict histologic outcome from near-complete forebrain ischemia in the rat.

BACKGROUND: Although reduction of cerebral metabolic rate is thought to contribute to anesthetic neuroprotection, histologic evidence to support this concept has not been provided. In this study, histologic outcome was evaluated in rats subjected to different durations of severe forebrain ischemia while anesthetized with volatile anesthetics that have substantially different effects on cerebral metabolic rate. METHODS: Normothermic rats that underwent fasting were anesthetized with 0.75 minimum alveolar concentration (MAC) isoflurane-60% nitrous oxide (N2O) or 0.75 MAC halothane-60% N2O. Ischemia was induced with use of a combination of bilateral carotid occlusion and controlled hypotension. Rats in the isoflurane group were subjected to 6.5 min or 8.0 min ischemia, whereas the halothane group received 6.5 min ischemia. Histologic damage was assessed 4 days later. RESULTS: With 6.5 min ischemia, mean +/- SD, hippocampal CA1 percent of dead (% dead) neurons was reduced with isoflurane-N2O (45 +/- 18) versus halothane-N2O (60 +/- 23, P = 0. 023). Eight minutes of ischemia increased % dead neurons in the isoflurane-N2O group (60 +/- 17, P = 0.017). There was no difference between the isoflurane 8.0-min and halothane 6.5-min groups (P = 0. 935). A similar pattern was observed in hippocampal CA4 and the neocortex. Striatal damage was not affected by anesthetic or ischemic duration. CONCLUSIONS: At 6.5 min ischemia, isoflurane provided improved outcome versus halothane. Previous research has shown that 0.75 MAC isoflurane-N2O increases the time to onset of ischemic depolarization by 1.5 min and reduces cerebral metabolic rate by 42% versus 0.75 MAC halothane-N2O. In the current study, when the duration of ischemia was increased by 1.5 min in the isoflurane-N2O group, histologic outcome became similar to that in halothane-N2O-anesthetized rats. These results provide evidence that cerebral metabolic rate reduction has an advantageous effect on outcome from severe brain ischemia, but also suggest that such benefit is likely to be small.

The effects of anesthetics on stress responses to forebrain ischemia and reperfusion in the rat.

UNLABELLED: Rats exposed to forebrain ischemia have reduced injury when anesthetized with isoflurane versus fentanyl + N(2)O. The protection caused by isoflurane is reversed by trimethaphan. We hypothesized that these anesthetic-dependent effects on ischemic outcome can be associated with altered stress responses to ischemia. Rats were randomized to four treatments: isoflurane; fentanyl + N(2)O; isoflurane + trimethaphan; or isoflurane + metyrapone. Severe forebrain ischemia was then induced for 10 min. Plasma and brain corticosterone, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were assayed. Plasma corticosterone concentrations were similar in the isoflurane and isoflurane + trimethaphan groups, but greater than in the fentanyl + N(2)O and isoflurane + metyrapone groups. Brain corticosterone was similar among all groups except isoflurane + metyrapone, in which values were markedly reduced. The addition of metyrapone to isoflurane also reduced plasma TNF-alpha; however, values among other groups were similar. There were no differences among groups for brain TNF-alpha. Plasma IL-6 concentrations were below the limit of detection. Brain IL-6 concentrations were increased by ischemia; however, there was no difference among groups. In conclusion, there were no differences between the isoflurane and isoflurane + trimethaphan groups for any of the measured stress markers. Further, there was little difference between the isoflurane and fentanyl + N(2)O groups, except for plasma corticosterone concentration. Accordingly, isoflurane neuroprotection and its reversal by trimethaphan appear to be independent of effects on the stress responses measured in this study. IMPLICATIONS: Differential anesthetic effects on ischemic outcome are independent of effects on adrenergic/noradrenergic responses to ischemia. The absence of a consistent differential effect of anesthetics on either corticosterone or cytokine responses to ischemia serves to further refute the hypothesis that isoflurane neuroprotection can be attributed to dampening of adverse stress responses to ischemic insults.

Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat.

In a recent study of focal cerebral ischemia in rats, pre-ischemic administration of the synthetic allosteric hemoglobin modifier RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl] methyl] phenoxy]-2-methylproprionic acid) reduced cerebral infarct size when combined with the NMDA receptor antagonist dizocilpine (MK-801) but not when given alone. We hypothesized that post-ischemic RSR13 administration would enhance neuroprotection afforded by NMDA receptor antagonism in a rat model of transient middle cerebral artery occlusion (MCAO). Fasted normothermic Wistar rats underwent 75 min of temporary MCAO. At onset of reperfusion, rats randomly received: (1) 0.9% NaCl (vehicle) i.v. alone (n=16); (2) 0.9% NaCl+dizocilpine (0.25 mg/kg) i.v. (n=16); or (3) RSR13 (150 mg/kg)+dizocilpine (0.25 mg/kg) i.v. (n=17). Seven days later, neurologic deficit and cerebral infarct size were determined. Dizocilpine alone compared to vehicle reduced mean+/-S.D. subcortical (52+/-24 mm(3) vs. 122+/-64 mm(3), P=0.003) and cortical (35+/-35 mm(3) vs. 125+/-72 mm(3), P=0.00074) infarct volumes. When compared to dizocilpine alone, the combination of RSR13+dizocilpine further reduced subcortical (37+/-14 mm(3) vs. 52+/-24 mm(3), P=0. 034) and cortical (8+/-19 mm(3) vs. 35+/-35 mm(3), P=0.018) infarct size. RSR13+dizocilpine improved neurologic scores vs. either dizocilpine alone (P=0.0014) or vehicle (P=10(-7)). The combination of NMDA receptor antagonism and a RSR13 mediated rightward shift of the oxy-hemoglobin dissociation curve improved outcome from MCAO. Because this occurred after reperfusion, our results suggest that the post-ischemic brain continues to suffer from hypoperfusion defects, which are amenable to therapy by enhanced O(2) delivery. The results also support the concept that neuroprotective strategies, which combine drugs with different mechanisms of action, may yield cumulative benefits.

Pre-ischemic depletion of brain norepinephrine decreases infarct size in normothermic rats exposed to transient focal cerebral ischemia.

This study examined the importance of brain norepinephrine concentration on outcome from a focal ischemic insult. Fasted temperature-controlled male Wistar rats pretreated with DSP-4, (N-(chloroethyl)-N-ethyl-2-bromobenzylamine), to selectively deplete brain norepinephrine, were subjected to reversible filament occlusion of the middle cerebral artery for 75 min in the awake state. After 3 days recovery, total infarct volume in DSP-4 treated rats (185 +/- 107 mm3) was reduced vs. untreated control animals (242 +/- 71 mm3, P = 0.04). Subcortical infarct volume was also smaller in the DSP-4 group (93 +/- 44 vs. 121 +/- 28 mm3, P = 0.02). Cortical infarct volume was not statistically different between groups. Neurologic function correlated with infarct-size. These findings suggest that brain norepinephrine affects stroke development either by direct neuronal toxicity and/or through influences on the penumbral circulation. Dampening of the central stress response induced by the onset of stroke may thus be advantageous.

Effect of intracerebral norepinephrine depletion on outcome from severe forebrain ischemia in the rat.

Manipulations of plasma catecholamine concentrations influence outcome from ischemic brain insults. It has been suggested that these effects are mediated by influences on brain catecholamine concentrations. This study examined whether major changes in brain norepinephrine concentrations can alter outcome from severe forebrain ischemia. Sprague-Dawley rats were administered 50 mg/kg i. p. N-(chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) or were left untreated (control). One week later, these rats were subjected to either 7 or 8 min of normothermic forebrain ischemia (bilateral carotid occlusion and MABP=30 mmHg) and allowed to recover for 4 days. Histologic damage was then evaluated. In other control and DSP-4-treated animals, hippocampal microdialysate norepinephrine concentrations were measured before, during and after 8 min of forebrain ischemia. Norepinephrine concentrations were also determined in brain homogenates from non-ischemic DSP-treated and control rats. A 95% depletion of norepinephrine was observed in brain homogenates from non-ischemic DSP-4-treated rats compared with control. During ischemia, microdialysate norepinephrine concentrations increased in control but not in DSP-4-treated rats (P=0.002). For plasma, intra-ischemic epinephrine concentrations increased 8-10-fold and returned to baseline values post-ischemia with no differences between groups. Plasma norepinephrine values remained unchanged in both groups. Histologic damage resulting from either 7 or 8 min of ischemia in hippocampal structures, caudoputamen, and neocortex was similar between DSP-4-treated and control groups. This study could not identify any effect of major changes in brain norepinephrine concentrations on ischemic brain damage. These data indicate that peripheral catecholamine effects on near-complete forebrain ischemic outcome are unlikely to be mediated by effects on central catecholamine concentrations.

Effects of isoflurane, ketamine, and fentanyl/N2O on concentrations of brain and plasma catecholamines during near-complete cerebral ischemia in the rat.

UNLABELLED: We postulated that adrenergic responses to global cerebral ischemia are anesthetic-dependent and similar in both brain and arterial blood. Rats were anesthetized with isoflurane (1.4%), ketamine (1 mg x kg(-1) x min(-1)), or fentanyl (25 microg x kg(-1) x h(-1))/70% N2O. The carotid arteries were occluded for either 20 min with mean arterial pressure (MAP) 50 mm Hg (incomplete ischemia) or 10 min with MAP 30 mm Hg (near-complete ischemia). Norepinephrine was measured in hippocampal microdialysate. Norepinephrine and epinephrine were measured in arterial plasma. In both hippocampus and plasma, basal norepinephrine was similar among anesthetics. During incomplete ischemia, hippocampal norepinephrine was twofold greater with fentanyl/N2O than with isoflurane (P = 0.037), but plasma norepinephrine and epinephrine were similar and unchanged among all three anesthetics. During near-complete ischemia, hippocampal norepinephrine was threefold greater with ketamine than fentanyl/N2O (P = 0.005), whereas plasma norepinephrine and epinephrine were markedly greater with fentanyl/N2O than with ketamine (P < 0.0005) or isoflurane (P = 0.05). There was no correlation between norepinephrine concentrations in hippocampus and plasma for either incomplete or near-complete ischemia. This study demonstrates that adrenergic responses to global ischemia are anesthetic-dependent, particularly during more severe insults. The absence of a correlation between plasma and brain catecholamine concentrations indicates that adrenergic responses to ischemia are independent in brain and blood. IMPLICATIONS: It has been proposed that anesthetics modulate cerebral ischemic outcome by influencing peripheral adrenergic responses to ischemia. This experiment demonstrates that anesthetics differentially modulate adrenergic responses to ischemia but that effects in plasma and brain are independent. This suggests that events detected in the peripheral circulation do not implicate direct mechanisms of action of catecholamines at the neuronal/glial level.